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Axakova A et al., The American Journal of Human Genetics - Axakova et al. produced comprehensive missense variant-effect maps for human SOD1 by assaying enzymatic activity in yeast and protein abundance in human HEK293T cells for ~86% of possible missense substitutions. The study links map patterns to sequence-structure-function features, uses kernel-density calibration to provide LLRp evidence for clinical interpretation, and shows the abundance map best discriminates pathogenic variants and supplies new evidence for many VUSs. Data and LLRp-calibrated scores are available on MaveDB and in supplemental DataS2. Key terms: SOD1, missense variants, VAMP-seq, variant-effect map, ALS.

Study Highlights:
The authors measured functional impacts for over 2,600 missense substitutions across SOD1 using multiplexed yeast complementation (total enzymatic activity) and VAMP-seq in HEK293T cells (protein abundance). Abundance and activity maps reveal complementary mechanisms: many deleterious variants reduce abundance (stability) while others impair activity through effects on metal binding, CCS interaction, or the electrostatic loop. The abundance map outperformed tested computational predictors, was calibrated to log-likelihood ratios (LLRp) for ACMG-style use, and provided new evidence for reclassifying 41% of ClinVar SOD1 VUSs. Map scores also correlated with ALS phenotypes such as age of onset and disease duration.

Conclusion:
Large-scale activity and abundance variant-effect maps for SOD1 provide mechanistic insights and calibrated functional evidence that can improve clinical interpretation of missense variants and prioritize individuals for SOD1-directed interventions.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Landscapes of missense variant impact for human superoxide dismutase 1

First author:
Axakova A

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.08.019

Reference:
Axakova A., Ding M., Cote A.G., et al. Landscapes of missense variant impact for human superoxide dismutase 1. The American Journal of Human Genetics. 2025;112:1–21. https://doi.org/10.1016/j.ajhg.2025.08.019

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/landscapes-of-missense-variant-impact-for-human-superoxide-dismutase-1

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing saturation mutagenesis of SOD1, yeast enzymatic activity assay, VAMP-seq abundance assay, the resulting variant-effect maps (activity and abundance), structural/MD insights (metal binding, Asn87, Gly128), genotype-phenotype associations, clinical implications, and limitations.
- transcript topics: SOD1 saturation mutagenesis and library generation; Yeast-based total enzymatic activity assay; VAMP-seq abundance assay in HEK293T cells; Variant-effect maps: activity versus abundance quadrants; Metal binding, CCS interactions, and electrostatic loop in SOD1; Second-shell residues (Asn87) and Gly128 dynamics via MD

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:
- 86% of all possible SOD1 missense variants were assayed in the variant-effect maps (activity and abundance).
- Over 2,000 SOD1 amino acid substitutions were generated via saturation mutagenesis.
- Variant-effect maps cover roughly 2,600 variants with substantial coverage (86% SNV-accessible substitutions detected).
- Two parallel assays were used: a yeast-based total enzymatic activity assay and a human-cell-based abundance assay (VAMP-seq).
- Abundance map outperforms activity map and several computational predictors in pathogenicity discrimination (e.g., AlphaMissense, CPT, ESM-1b, VARITY).
- Abundance scores show genotype–phenotype correlations with ALS features, including age of onset and disease duration; correlations with mouse protein half-life observed.

QC result: Pass.

Timonina V et al., The American Journal of Human Genetics - MosCoverY is a coverage-based method that estimates mosaic loss of the Y chromosome (mLOY) from exome or whole-genome sequencing by normalizing single-copy MSY exon coverage to matched autosomal exons. The method was validated in 212,062 UK Biobank men and applied to SHCS and TCGA datasets. Key terms: mosaic loss of Y, exome sequencing, whole-genome sequencing, coverage normalization, population genomics.

Study Highlights:
MosCoverY focuses on single-copy genes in the male-specific region of chrY and normalizes exon coverage to 100 autosomal exons matched by GC content and length, then rescales to the haploid expectation. Applied to 212,062 UK Biobank men, MosCoverY identified mLOY in 5.6% and produced cell-fraction estimates that strongly correlated with mLRRY, PAR-LOY, and WGS Control-FREEC. The method replicated known associations of mLOY with age, smoking, all-cause mortality, and germline loci, was robust to downsampling, and worked on tumor exomes from TCGA. MosCoverY can be used for single-sample analysis if the same capture kit is used, but capture-kit-specific recalibration is recommended.

Conclusion:
MosCoverY enables reliable detection and quantification of mLOY from exome and WGS coverage data at population scale, facilitating epidemiological, genetic, and tumor-based analyses.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
MosCoverY: A method to estimate mosaic loss of Y chromosome from sequencing coverage data

First author:
Timonina V

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.08.016

Reference:
Timonina V., Marchal A., Abel L., Cobat A., Fellay J. MosCoverY: A method to estimate mosaic loss of Y chromosome from sequencing coverage data. The American Journal of Human Genetics (2025) 112, 1–11. https://doi.org/10.1016/j.ajhg.2025.08.016

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/moscovery-a-new-method-to-estimate-mosaic-loss-of-y-chromosome-from-sequencing-coverage-data

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited sections describing MosCoverY methodology (13 Y-exons and 100 autosomal exons, normalization, thresholding, and conversion to cell fraction), UK Biobank validation results, cross-method comparisons (mLRRY, PAR-LOY, Control-FREEC), TCGA tumor data, and SHCS/single-sample applicability along with li
- transcript topics: MosCoverY method overview; Y chromosome sequencing challenges in exome data; 13 Y exons and 100 autosomal exons normalization; Normalization to autosomal exons and scaling to 0.5; Binary mLOY threshold via IQR rule; Conversion to fraction of cells with mLOY

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:
- MosCoverY focuses on 13 Y-chromosome single-copy genes in X-degenerate regions and uses 100 autosomal exons matched by GC content and length for normalization.
- Normalized chrY coverage is scaled so the population median equals 0.5 (haploid Y baseline).
- Binary mLOY calls are defined by thresholding the scaled chrY coverage at Q1 - 1.5 × IQR.
- UK Biobank exome data: 212,062 male participants; MosCoverY identifies 11,897 (5.6%) mLOY carriers; mean cell fraction ~2.8%.
- Compared methods show mLRRY identifying ~5.4% and PAR-LOY ~10.1% mLOY carriers; MosCoverY exhibits higher concordance with WGS-derived Control-FREEC.
- TCGA data show higher mLOY prevalence in tumors (38%), with extremely high prevalence in papillary kidney adenocarcinoma (around 89%).

QC result: Pass.

Migeot J et al., Nature Communications - Large multicenter study linking a multidimensional social exposome (education, food insecurity, finances, healthcare access, childhood experiences) to cognition, function, neuropsychiatric symptoms, brain atrophy and connectivity in AD, FTLD and healthy aging across six Latin American countries. Key terms: social exposome, dementia, Latin America, brain connectivity, food insecurity.

Study Highlights:
The study evaluated 2,211 participants across six Latin American countries using a validated multidimensional social exposome (MSE) score spanning education, food insecurity, financial status, assets, healthcare access, childhood labor and traumatic events. Greater adverse MSE correlated with poorer cognition in healthy aging and with lower cognitive and functional performance and increased neuropsychiatric symptoms in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Higher MSE adversity associated with reduced gray matter and altered resting-state functional connectivity in fronto-temporo-limbic and cerebellar regions. Food insecurity, financial resources, subjective socioeconomic status and access to healthcare emerged as key predictors and cumulative MSE outperformed individual factors.

Conclusion:
A cumulative, lifespan multidimensional social exposome strongly associates with worse clinical, cognitive and brain outcomes in aging and dementia across Latin America, highlighting the need for prevention and interventions that address social disparities.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Social exposome and brain health outcomes of dementia across Latin America

First author:
Migeot J

Journal:
Nature Communications

DOI:
10.1038/s41467-025-63277-6

Reference:
Migeot J, Pina-Escudero SD, Hernandez H, et al. Social exposome and brain health outcomes of dementia across Latin America. Nature Communications. 2025;16:8196. doi:10.1038/s41467-025-63277-6

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/social-exposome-and-brain-health-outcomes-of-dementia-across-latin-america

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the MSE concept, lifespan-domain assessment, reverse-causation controls, neuroimaging findings (GMV and rs-fMRI connectivity), cross-site harmonization, and broader implications for dementia risk and social disparities.
- transcript topics: Multidimensional social exposome (MSE) concept; Lifespan-domain scoring and 10 domains; Reverse causation controls and SEM; Brain structural correlates: gray matter volume reductions in AD/FTLD; Functional connectivity and compensatory hyperconnectivity; Scanner harmonization and sensitivity analyses

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:
- MSE is a lifespan, multi-domain construct spanning 10 domains (education, food insecurity, financial status, assets, healthcare access, childhood labor, subjective SES, childhood e
- MSE is associated with worse cognition, reduced functional ability, and more neuropsychiatric symptoms across the sample; the global MSE is a stronger predictor than single factors
- In healthy aging, top MSE indicators include assets, education, and financial status; in dementia (AD, FTLD), predictors spread across domains with food insecurity, financial statu
- Adverse MSE is linked to reduced gray matter volume in dementia, with AD showing involvement of frontal lobes, insula, and cerebellum; FTLD shows fronto-temporo-cerebellar patterns
- Resting-state connectivity shows compensatory hyperconnectivity in AD with higher MSE, and patterns differ for FTLD; cross-network changes accompany structural decline.
- Analyses account for scanner differences via harmonization and covariates; sensitivity analyses show robustness to SNR and motion across sites.

QC result: Pass.

Hentze MW et al., Cell - A review that examines the expansion of the RNA-binding proteome, evaluates evidence for many non-canonical RBPs, and highlights riboregulation as an emerging mechanism by which RNA controls protein function, complexes, and metabolism. Key terms: RNA-binding proteins, non-canonical RBPs, riboregulation, intrinsically disordered regions, RNA interactome.

Study Highlights:
Large-scale UV crosslinking and proteomic approaches have dramatically expanded the catalogue of RNA-binding proteins to include many non-canonical, well-studied proteins that lack classical RNA-binding domains. Mapping efforts show that IDRs and nucleotide cofactor-binding folds frequently mediate these interactions, and validated examples reveal RNA can regulate protein-protein interactions, enzymatic activity, complex assembly, and transmembrane import. Representative cases include IRP1, GAPDH, ENO1, SHMT1, p62/vtRNA1-1, and lncRNA/circRNA regulators of metabolic enzymes and signaling complexes. The authors emphasize the need for orthogonal validation, high-resolution structures, and in vivo functional studies to distinguish biologically relevant riboregulation from methodological artifacts.

Conclusion:
Riboregulation extends RNA function beyond classical targets: many non-canonical RBPs engage RNA via IDRs or metabolic folds and RNA can directly modulate protein activity, interactions, and assemblies; rigorous validation and structural work are essential to define mechanism and relevance for physiology and disease.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Rethinking RNA-binding proteins: Riboregulation challenges prevailing views

First author:
Hentze MW

Journal:
Cell

DOI:
10.1016/j.cell.2025.06.021

Reference:
Hentze MW, Sommerkamp P, Ravi V, Gebauer F. Rethinking RNA-binding proteins: Riboregulation challenges prevailing views. Cell. 2025;188:4811-4827. https://doi.org/10.1016/j.cell.2025.06.021

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base 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/rethinking-rna-binding-proteins-riboregulation-challenges-prevailing-views

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the narration's depiction of riboregulation concepts, non-canonical RBPs, validation methods (UV crosslinking, RIC/eRIC, OOPS/PTex, EU labeling, PLA, NMR), IDRs and Rossmann-fold binding surfaces, and functional examples (P62/vtRNA1-1, SHMT1, ENO1, metabolon formation with GlycoLINC, ATP5A1 import), plus virolo
- transcript topics: Riboregulation concept and paradigm shift; Non-canonical RNA-binding proteins (RBPs) and loss of classical RBDs; Validation technologies for RNA–protein interactions (UV crosslinking, RIC/eRIC, OOPS/PTex, EU labeling, PLA, NMR); IDRs as RNA-binding surfaces and Rossmann-fold cofactor pockets; Functional mechanisms: allostery, oligomerization, metabolon scaffolding; Specific riboregulation examples: P62/vtRNA1-1, SHMT1, ENO1, ATP5A1

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- DOI alignment between episode metadata and canonical article record
- Article title alignment between episode metadata and canonical article record
- Journal alignment between episode metadata and canonical article record
- License alignment between episode metadata and canonical article record
- Transcript claims about riboregulation concepts and specific mechanistic examples grounded in the article description

QC result: Pass.

Jassim A et al., Cancer Cell - This episode summarizes Jassim et al.'s introduction of RECODR, a graph-embedding pipeline that measures gene co-expression context drift from sc/snRNA-seq to reveal drivers of tumorigenesis and treatment resistance and to nominate combination therapies validated in mouse models and predicted for human tumors. Key terms: RECODR, gene context drift, single-cell RNA-seq, treatment resistance, combination therapy.

Study Highlights:
The authors developed RECODR, which combines co-expression graph networks with Node2Vec/Word2Vec embeddings and alignment to quantify gene context drift between treatment states. In a mouse choroid plexus carcinoma (CPC) model RECODR prioritized ATM as a vulnerability and guided use of an ATM inhibitor; it also identified PARP1 as a target to mitigate monotherapy resistance. For combination AZD1390 and radiation resistance RECODR revealed an expanded immune-like program and nominated dasatinib, which in specific combination schedules produced marked survival benefit in mice. Applied to paired human medulloblastoma and TNBC samples, RECODR detected context-drift signatures and proposed subtype-specific therapies for testing.

Conclusion:
Measuring changes in gene co-expression context (gene context drift) with RECODR reveals resistance mechanisms invisible to expression-level analyses and can nominate context-specific targets and combination regimens for preclinical and clinical testing.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Gene context drift identifies drug targets to mitigate cancer treatment resistance

First author:
Jassim A

Journal:
Cancer Cell

DOI:
10.1016/j.ccell.2025.06.005

Reference:
Jassim A, Nimmervoll BV, Terranova S, et al. Gene context drift identifies drug targets to mitigate cancer treatment resistance. Cancer Cell. 2025;43:1608–1621. doi:10.1016/j.ccell.2025.06.005

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base 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/gene-context-drift-identifies-drug-targets-to-mitigate-cancer-treatment-resistance

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-13.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections include: gene context drift concept; RECODR pipeline and four context-drift metrics; single-cell RNA-seq co-expression graphs; Node2Vec/Word2Vec embedding and Procrustes alignment; CPC mouse model with AZD1390 and radiation; PARP1 inhibitor AZD9574; dasatinib targeting of an immune-like network; transl
- transcript topics: Gene context drift concept; RECODR pipeline and context drift metrics; Single-cell RNA-seq and co-expression graphs; Node2Vec and Word2Vec embedding; Four context-drift metrics: neighbor number, graph reach, neighbor cosine, index gene cosine; CPC mouse model and DNA repair remodeling

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 alignment between metadata and canonical article
- Article title alignment with canonical form
- Journal alignment with provided journal label
- License variant CC BY 4.0 alignment
- RECODR concept: context drift as resistance mechanism
- Single-cell RNA-seq data used to build co-expression graphs

QC result: Pass.

Rees J et al., The American Journal of Human Genetics - Rees et al. analyze signatures of positive selection in 276 genes linked to 13 dietary micronutrients across 40 global populations (HGDP). Using simulations and complementary selection scans, they report widespread local and oligogenic adaptation, with notable signals for zinc, iodine, and selenium. Key terms: micronutrients, positive selection, human evolution, local adaptation, zinc.

Study Highlights:
Using curated micronutrient-associated gene sets and whole-genome data from 913 individuals, the authors detect enriched signatures of positive selection across many populations. Power analyses with SLiM guided use of L_ST and Relate to identify both individual gene sweeps and oligogenic signals. SUMSTAT and CLUES2 timing analyses indicate some adaptations predate the Neolithic and align with migrations into novel soil environments. The results implicate micronutrient availability, driven by local geology and later cultural change, as a recurrent selective force in recent human evolution.

Conclusion:
Micronutrient-driven selection has likely shaped modern human genetic diversity more broadly than previously recognized; ongoing soil depletion and environmental change may increase risk of micronutrient-related disorders in populations lacking matching adaptations.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Global impact of micronutrients in modern human evolution

First author:
Rees J

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.08.005

Reference:
Rees J., Castellano S., Andrés A.M. Global impact of micronutrients in modern human evolution. The American Journal of Human Genetics. 2025;112:1–24. doi:10.1016/j.ajhg.2025.08.005

License:
© 2025 Published by Elsevier Inc. on behalf of American Society of Human Genetics.

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/global-impact-of-micronutrients-in-modern-human-evolution

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing the study's design, methods (FST, Relate, CLUES2, SUMSTAT), core findings across iodine, zinc, selenium, and magnesium, timing analyses, and implications for precision nutrition and evolutionary health.
- transcript topics: Soil geology as driver of micronutrient variation; Zinc transporter adaptations and out-of-Africa migrations; Iodine deficiency and thyroid gene adaptations (THRA, THRB, TRIP4, IYD); Selenium-related oligogenic adaptation (SGCD, AKAP6, PRKG1, KCNMA1); Magnesium toxicity adaptation and Neanderthal introgression (MECOM, FXYD2); Timing of selection with CLUES2 (iron/calcium pre-Neolithic, 28–42 ka)

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:
- 276 genes associated with 13 micronutrients analyzed; 269 MA genes after accessibility masking
- 40 populations; 913 HGDP individuals used in the analysis
- Methods included FST, Relate, CLUES2, SUMSTAT; haplotype networks (POPART) used for selected regions
- Key findings include iodine-associated adaptations in THRA/THRB/TRIP4/IYD and zinc transporter adaptations (SLC30A9, SLC39A11, SLC39A4) across non-African populations; selenium oli
- Transcript describes Neanderthal introgression contributing to magnesium-uptake adaptations via MECOM region
- Evolutionary timeline indicates adaptations long predate Neolithic farming for several nutrients

QC result: Pass.

Wenzel M et al., Cell Genomics - This episode reviews a single-cell transcriptional atlas comparing Barrett's esophagus, intestinal metaplasia, normal esophagus/gastric samples and esophageal adenocarcinoma. The study uses single-cell RNA profiling and UMAP clustering to resolve epithelial, stromal and immune cell populations, identify gastric-like and intestinal metaplasia cell states, and characterize tumor-associated CNV and transcriptional programs. We unpack the cell-type maps, marker gene patterns and implications for understanding progression from Barrett's lesions to EAC. Key terms: Barrett's esophagus, esophageal adenocarcinoma, intestinal metaplasia, single-cell RNA-seq, cell atlas.

Study Highlights:
The authors performed single-cell RNA‑seq with UMAP clustering across samples from Barrett's esophagus, intestinal metaplasia, gastric and esophageal adenocarcinoma specimens to define cell states. They identified discrete epithelial clusters (foveolar cells, chief cells, parietal cells, intestinal metaplasia cells, enteroendocrine cells) and multiple EAC tumor clusters, and reported CNV-level differences and transcriptional signatures distinguishing EAC from non-malignant tissues. The atlas documents gastric-like cell states within Barrett's lesions and changes in stromal and immune compartments associated with progression.

Conclusion:
Single-cell profiling maps cellular diversity across Barrett's esophagus, intestinal metaplasia and esophageal adenocarcinoma, producing an atlas to dissect tissue-specific and tumor-associated transcriptional programs.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Single-cell analysis of Barrett’s esophagus and carcinoma reveals cell types conferring risk via genetic predisposition

First author:
Wenzel M

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100980

Reference:
Wenzel M.C., Dasmeh P., Plum P.S., Giel A., Hoppe S., Franitza M., et al.. Single-cell analysis of Barrett’s esophagus and carcinoma reveals cell types conferring risk via genetic predisposition. Cell Genomics, 5, 100980. (2025). https://doi.org/10.1016/j.xgen.2025.100980

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/single-cell-maps-link-intestinal-metaplasia-to-esophageal-adenocarcinoma-risk

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific themes: Barrett's esophagus and cancer risk, single-cell RNA sequencing atlas, LDSR integration with GWAS, intestinal metaplasia as a risk-rich cell type, distinct EAC tumor clusters, microenvironment contributions, and translational/clinical implications.
- transcript topics: Barrett's esophagus and esophageal adenocarcinoma risk; Single-cell RNA sequencing atlas across BE, intestinal metaplasia, normal esophagus, gastric tissue, and EAC; LDSR integration of GWAS risk variants with cell-type expression; Intestinal metaplasia cells as key risk-enriched population; Esophageal cancer tumor clusters (EAC-01 to EAC-04) with distinct programs; Tumor microenvironment and stromal/immune enrichment of risk

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:
- Single-cell atlas generated across Barrett's esophagus, intestinal metaplasia, normal esophagus, and gastric tissues with esophageal adenocarcinoma (EAC) samples using single-cell
- GWAS-derived cancer risk variants overlaid with single-cell map via linkage disequilibrium score regression (LDSR) to identify cell-type enrichment
- Intestinal metaplasia cells show the strongest enrichment for esophageal cancer risk variants, despite relative genomic stability
- EAC contains multiple tumor clusters with divergent transcriptional programs (e.g., EAC-02 proliferative via WNT11 and CNV patterns; EAC-01 invasive via MMP/MMP7-related activity)
- Microenvironmental cell types (fibroblasts, memory CD4+ T cells, plasmacytoid dendritic cells) also show risk variant enrichment
- Barrett's esophagus risk is described as more systemic/mechanical (reflux mechanics, LES integrity) whereas cancer risk is driven by local cellular processes

QC result: Pass.

Minich JJ et al., Cell - Minich et al. apply PacBio and Oxford Nanopore long‑read metagenomics to generate 986 complete metagenome‑assembled genomes from Malawian toddler fecal samples, then use pangenome analyses, mGWAS and machine learning to link microbial genes, strains and genome stability to child linear growth and breastfeeding. Key terms: long-read metagenomics, cMAGs, pangenome, pediatric undernutrition, microbial GWAS.

Study Highlights:
Long‑read sequencing (PacBio, ONT) recovered far more complete genomes per Gbp than short reads, yielding 986 cMAGs (839 circular) across 47 samples and an expanded 210-sample set. Pangenome and microbial GWAS analyses identified gene-level associations with linear growth and breastfeeding, including annotated hits such as arnC in multiple clades. Machine learning found microbial species predictive of linear growth, while longitudinal genome comparisons showed greater within-strain genomic instability and prophage dynamics in children with declining length‑for‑age Z scores. PacBio with metaMDBG produced the highest-quality and most cost‑effective cMAGs in this study.

Conclusion:
High-throughput long‑read metagenomics enables recovery of near-complete gut genomes at scale, allowing species‑constrained pangenome and mGWAS analyses that reveal gene- and genome-level microbial associations with pediatric linear growth and breastfeeding status.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition

First author:
Minich JJ

Journal:
Cell

DOI:
10.1016/j.cell.2025.08.020

Reference:
Minich JJ, Allsing N, Din MO, et al. Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition. Cell. 2025;188:1–21. https://doi.org/10.1016/j.cell.2025.08.020

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:
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On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/culture-independent-metapangenomics-reveals-gut-genome-links-to-child-growth

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections cover long-read versus short-read performance, generation of complete MAGs (cMAGs) and circular genomes, longitudinal associations between genome dynamics and LAZ, pangenome and gene-level associations with growth and breastfeeding, prophage integration findings, environmental/geographic influences on
- transcript topics: Global malnutrition and LAZ definitions; Limitations of short-read sequencing for MAG recovery; Long-read metagenomics in Malawi cohort (PacBio and ONT); Generation of complete MAGs (cMAGs) and circular genomes; Longitudinal genome instability and LAZ decline; Pangenome analyses and gene-level associations with linear growth and breastfeeding (arnC, Prevotella, Megasphaera, Faecalibacterium, etc.)

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:
- Long-read sequencing (PacBio/ONT) yields 44–64× more complete MAGs per Gbp than short-read Illumina; SR yielded 0 complete genomes in this dataset.
- Recovered 986 complete cMAGs (839 circular), representing 363 species and 74 putative novel species (ANI < 95%).
- Genome instability (within-strain ANI divergence) is associated with declining LAZ, with detectable changes around ~5.5 months.
- Pangenome analyses and microbial GWAS reveal gene-level associations with linear growth and breastfeeding; arnC and related genes show predictive associations across several genera
- Breastfeeding status linked to higher prophage integrations in gut bacteria; temperate phages can carry metabolic genes and influence bacterial traits relevant to gut health.
- Environmental context (village) shapes strain-level gene content; Megasphaera clusters and gene-content variation show geographic association; integrated view via PanKmer and funct

QC result: Pass.

Grist E et al., Cell - Large-scale transcriptome profiling of 1,523 diagnostic prostate tumors from randomized STAMPEDE phase 3 trials linked expression signatures and immunohistochemistry to 14-year survival. The Decipher RNA classifier was both prognostic and predicted survival benefit from docetaxel in metastatic disease, and a transcriptome-based PTEN inactivity classifier identified docetaxel-sensitive, metabolically perturbed tumors. High tumor androgen receptor signaling associated with longer survival while increased proliferation predicted shorter survival. These results support clinical implementation of transcriptome classifiers to guide treatment selection in advanced prostate cancer. Key terms: prostate cancer, transcriptome, Decipher, docetaxel, PTEN.

Study Highlights:
The study generated transcriptome-wide expression profiles and Ki-67/PTEN immunohistochemistry for 1,523 patients (832 metastatic) from STAMPEDE phase 3 trials with 14-year follow-up. High Decipher scores were prognostic and pre-specified predictive for docetaxel benefit in metastatic disease (interaction p = 0.039). A PTEN_loss_Liu transcriptome classifier identified PTEN-inactive tumors that had shorter survival on hormone therapies but significant survival benefit from docetaxel (interaction p = 0.002). Tumor AR signaling associated with longer survival and proliferation signatures (and Ki-67) with shorter survival.

Conclusion:
Clinical-grade transcriptome classifiers (notably Decipher and a PTEN inactivity signature) predict which metastatic prostate cancers derive survival benefit from docetaxel and could be implemented to improve treatment selection.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers

First author:
Grist E

Journal:
Cell

DOI:
10.1016/j.cell.2025.07.042

Reference:
Grist E., Dutey-Magni P., Parry M.A., et al. Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers. Cell. 2025;188:1–18. https://doi.org/10.1016/j.cell.2025.07.042

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/tumor-transcriptome-classifiers-predict-treatment-sensitivity-in-advanced-prostate-cancer

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-09.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments describing the STAMPEDE biomarker cohort, transcriptome-wide profiling methods, prognostic vs predictive biomarkers, Decipher predicting docetaxel benefit, PTEN inactivity predicting docetaxel sensitivity, statistical design and level of evidence, and study limitations.
- transcript topics: Clinical treatment landscape for metastatic prostate cancer (ADT, docetaxel, abiraterone); Formalin-fixed, paraffin-embedded tissue transcriptome profiling and 59 signatures; Prognostic vs predictive biomarkers in STAMPEDE trials; Decipher classifier as predictor of docetaxel benefit (interaction with survival, p = 0.039); PTEN inactivity (PTEN_loss_Liu) as predictor of docetaxel sensitivity (interaction p = 0.002); Overlap of Decipher and PTEN inactivity and implications for treatment

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:
- STAMPEDE biomarker cohort included 1,523 patients with metastatic (832) or non-metastatic (691) disease and up to 14 years of survival follow-up
- Molecular data were generated from FFPE diagnostic tissue using clinical-grade pan-transcriptome microarrays testing 59 expression signatures
- Decipher score was prognostic and predicted survival benefit from docetaxel in metastatic disease (biomarker–docetaxel interaction p = 0.039)
- PTEN_loss_Liu/PTEN-inactivation signature predicted docetaxel sensitivity in metastatic disease (biomarker–docetaxel interaction p = 0.002; RMST and HR improvements described)
- Combined high Decipher and PTEN inactivity identified tumors with the greatest docetaxel sensitivity (metastatic disease: HR 0.55, 99% CI 0.34–0.89)
- The study adhered to level 1B evidence guidelines for prospective-retrospective biomarker discovery/evaluation

QC result: Pass.

Fogarty EC et al., Cell (187:1206–1222, February 29, 2024) - This episode summarizes Fogarty et al. 2024, which characterizes pBI143, a 2.7 kb cryptic plasmid that is highly prevalent and abundant across industrialized human gut metagenomes. The team combines large-scale metagenomics, isolate experiments, structural analyses, qPCR assays, and gnotobiotic mouse work to map pBI143’s distribution, transmission, host range, evolutionary constraints, and responses to stress. Key terms: pBI143, cryptic plasmid, human gut microbiome, plasmid prevalence, IBD.

Study Highlights:
pBI143 is a ubiquitous, highly abundant 2.7 kb cryptic plasmid detected in the majority of gut metagenomes from industrialized populations and is estimated to be ~14 times more numerous than crAssphage by copy number. It is typically monoclonal within individuals, often vertically transmitted from mother to infant, and can transfer among Bacteroidales species. Population variation is concentrated at specific sites under strong purifying selection and localized amino-acid changes cluster near MobA DNA-binding regions. pBI143 copy number increases during oxidative stress in culture and is higher in metagenomes from individuals with IBD, and it can occasionally acquire additional cargo genes.

Conclusion:
pBI143 is a highly successful human-gut-restricted cryptic plasmid that behaves largely as a monoclonal, transmissible genetic element under purifying selection, with potential uses as a sensitive human fecal marker and as an indicator of microbial stress in the gut.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
A cryptic plasmid is among the most numerous genetic elements in the human gut

First author:
Fogarty EC

Journal:
Cell (187:1206–1222, February 29, 2024)

DOI:
10.1016/j.cell.2024.01.039

Reference:
Fogarty EC, Schechter MS, Lolans K, Sheahan ML, Veseli I, Moore RM, et al. A cryptic plasmid is among the most numerous genetic elements in the human gut. Cell. 2024;187:1206–1222. https://doi.org/10.1016/j.cell.2024.01.039

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/pbi143-the-human-guts-hidden-heavyweight

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-08.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing pBI143 biology (size, mobA/repA), global prevalence and host range, monoclonality and maternal transmission, horizontal transfer experiments, structural/variational analyses, oxidative stress response, cargo acquisition, and clinical/environmental implications.
- transcript topics: pBI143 basic features (size, mobA and repA); global prevalence and host range in Bacteroidales; monoclonality, priority effects, and maternal transmission; horizontal transfer between Bacteroidales species (transfer assays); mutational landscape and AlphaFold-based structure mapping; oxidative stress response and copy-number dynamics

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:
- pBI143 is ~2,747 bp with two annotated genes, mobA and repA
- Three versions of pBI143 exist with high overall identity; repA varies among versions
- pBI143 is highly prevalent in industrialized populations (roughly 73% across 4,516 gut metagenomes; up to 92% in Japan and 86% in the USA)
- pBI143 makes up approximately 0.1%–3.5% of metagenomic reads in carriers (with high coverage in carriers)
- pBI143 is largely monoclonal within individuals and is vertically transmitted from mother to infant via priority effects
- pBI143 can transfer between Bacteroidales species (demonstrated via conjugation experiments)

QC result: Pass.