Base by Base

Singh P et al., PNAS - This paper compares alternative splicing (AS) and gene expression (GE) across 200 transcriptomes from oral and pharyngeal jaws of 18 haplochromine cichlid species across Lakes Victoria, Malawi, and Tanganyika. The authors show that rapid changes in AS, often from low-frequency ancestral isoforms and some novel isoforms, contributed more to early trophic diversification than shifts in GE. Key terms: alternative splicing, adaptive radiation, cichlids, gene regulation, craniofacial development.

Study Highlights:
Using 200 jaw transcriptomes spanning three East African cichlid radiations, the authors found that alternative splicing (AS) diverged faster than gene expression (GE) and was enriched for craniofacial and jaw morphogenesis genes. Most adaptive isoforms were present at low levels in nonradiating ancestral lineages and increased in frequency in radiating lineages, consistent with standing splice variation fueling rapid adaptation. A subset of novel isoforms evolved rapidly, some within a few thousand years, and mapped to candidate craniofacial genes such as col21a1. Younger radiations (Victoria, Malawi) showed stronger AS divergence while the older Tanganyika radiation displayed more GE differences.

Conclusion:
Ancestral alternative splice variation, supplemented by rapidly evolved novel isoforms, provided a labile reservoir of protein-coding diversity that likely enabled the extremely rapid trophic diversification of African cichlid radiations; integrating splicing into regulatory perspectives is essential to understand rapid adaptive evolution.

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

Article title:
Ancestral splice variation is a key substrate for rapid diversification in African cichlids

First author:
Singh P

Journal:
PNAS

DOI:
10.1073/pnas.2516477123

Reference:
Singh P., Ahi E.P., Duenser A., Durdevic M., Gessl W., Schaeffer S., Gall J., Seehausen O., Sturmbauer C. Ancestral splice variation is a key substrate for rapid diversification in African cichlids. PNAS. 2026;123(20):e2516477123. doi:10.1073/pnas.2516477123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/ancestral-splice-variation-african-cichlids

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing AS vs GE dynamics, ancestral standing variation, novel isoforms (col21a1), lake-by-lake evolutionary patterns, and convergent/trophic evolution; cross-checked against the original article.
- transcript topics: Adaptive radiation and jaw anatomy in African cichlids; Gene expression vs alternative splicing (GE vs AS); Ancestral standing variation and novel isoforms; Temporal patterns: young vs old radiations (Victoria/Malawi vs Tanganyika); Key genes: col21a1 and craniofacial pathways; Convergent vs divergent regulation across radiations

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Transcript describes AS evolving faster than GE; AS divergence aligns with species/diet and not just tissue.
- Transcript cites ancestral standing variation: 86.0% of genes and 73.0% of isoforms present in riverine ancestors and radiations.
- Transcript notes novel isoforms (34 identified) with col21a1 isoforms linked to hypertrophied lips in Lake Victoria radiants.
- Transcript reports lake-by-lake patterns: Victoria/Malawi rely on AS for rapid jaw divergence; Tanganyika relies more on GE over time.
- Transcript mentions convergent differential expression in multiple lakes (e.g., odam) and convergent trophic evolution.
- Transcript emphasizes a two-phase view: AS provides rapid adaptive changes; GE provides longer-term tuning.

QC result: Pass.

Han YJ et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study showing that the BRCA1 pseudogene BRCA1P1 produces circular RNAs that suppress antiviral innate immunity in human cancers; depleting BRCA1P1 activates interferon-stimulated genes, increases apoptosis and chemosensitivity, and enhances immune clearance in preclinical models. Key terms: BRCA1P1, pseudogene, circular RNA, antiviral immunity, breast cancer.

Study Highlights:
BRCA1P1 is expressed broadly across human cancer cell lines and is elevated in breast tumors. The majority of BRCA1P1 transcripts are circular RNAs that bind the NF-κB subunit RelA to attenuate NF-κB–driven antiviral gene transcription. Loss of BRCA1P1 by ASO or CRISPR induces ISGs, IFNβ and TNF, increases apoptosis and sensitivity to chemotherapy, and enhances macrophage phagocytosis. In patient-derived organoids and humanized mouse xenografts BRCA1P1 depletion reduces tumor viability and increases T cell and M1 macrophage infiltration.

Conclusion:
BRCA1P1-derived circular RNAs act as immunosuppressive regulators of antiviral and antitumor immunity in human cancers, and targeting BRCA1P1 activates antiviral programs that reduce tumor growth and boost immune infiltration.

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

Article title:
Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers

First author:
Han YJ

Journal:
Proceedings of the National Academy of Sciences (PNAS)

DOI:
10.1073/pnas.2528911123

Reference:
Han YJ, Zhang J, Shariff M, Wu S, Khramtsova G, Nguyen LC, Peiffer DS, Li N, Lewicka A, Moore M, Piccirilli JA, Olopade OI. Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers. Proc Natl Acad Sci U S A. 2026;123(19):e2528911123. doi:10.1073/pnas.2528911123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/brca1p1-pseudogene-antiviral-immunity

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing BRCA1P1 background, circular RNA nature, RelA/NF-κB interaction, depletion experiments (ASO/CRISPR), pancancer expression, antiviral gene upregulation, apoptosis, chemotherapy sensitivity, immune infiltration, PDOs, and humanized mouse models, plus clinical implications and de
- transcript topics: BRCA1P1 background and primate-specificity; BRCA1P1 circular RNA and RelA/NF-κB interaction; BRCA1P1 depletion methods (ASO, CRISPR) and pancancer scope; Antiviral gene induction and cytokine responses; Apoptosis and chemotherapy sensitivity after BRCA1P1 loss; Macrophage phagocytosis and T cell infiltration

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- BRCA1P1 is a primate-specific, chimeric BRCA1/RPLP1 pseudogene; majority of BRCA1P1 transcripts are circular RNAs (~70-80%).
- BRCA1P1 circRNA binds RelA (NF-κB p65) and suppresses NF-κB–driven antiviral gene transcription.
- BRCA1P1 depletion (via ASO or CRISPR) increases antiviral ISGs (IFIH1, IFIT3, OAS2) and cytokines (IFNB1, IL1B, TNF) across multiple cancer cell types.
- BRCA1P1 depletion induces apoptosis in cancer cells and increases sensitivity to doxorubicin, with minimal toxicity to nonmalignant cells.
- BRCA1P1 loss enhances macrophage phagocytosis and elevates CD3/CD4/CD8 T cell and CD86+ macrophage infiltration into tumors.
- BRCA1P1 depletion reduces viability of patient-derived organoids and decreases tumor volume in humanized mouse models.

QC result: Pass.

Bourgeois et al., Nature Communications - This study used enhanced CRISPR base editor screens, structural biology, biochemical assays, and in vitro/in vivo selection to map MEN1 mutations that drive resistance to five clinical menin inhibitors and to explain their mechanisms. Key terms: MEN1, menin inhibitors, CRISPR base editing, drug resistance, KMT2A.

Study Highlights:
CRISPR base editor screens tiled MEN1 and profiled resistance to five clinical menin inhibitors, revealing shared (M327 I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) substitutions. Co-crystal structures of mutant menin bound to each inhibitor explain resistance via steric clashes or disrupted interactions and correlate with measured Ki and cellular IC50 shifts. Orthogonal in vitro selection and PDX experiments show many predicted mutations arise spontaneously under drug pressure and that higher inhibitor potency or dosing can suppress or overcome some resistant clones. The particular amino acid substitution at a residue critically determines the magnitude and breadth of resistance.

Conclusion:
Enhanced CRISPR base editing combined with structural and biological validation maps a mutational landscape in MEN1 that can produce pan-class or drug-specific resistance to menin inhibitors; these data can guide clinical monitoring, choices between inhibitors, dosing strategies, and next-generation inhibitor design.

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

Article title:
CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials

First author:
Bourgeois

Journal:
Nature Communications

DOI:
10.1038/s41467-026-72685-1

Reference:
Bourgeois, W., Rice, H.E., Wenge, D.V. et al. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72685-1

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/papercast-base-by-base-menin-mutations-365

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the CRISPR base editor screen identifying MEN1 mutations that affect five clinical menin inhibitors, including shared vs inhibitor-specific mutations, biochemical and structural validation, and in vivo PDX confirmation, as well as dose-related resistance dynamics and limitatio
- transcript topics: Menin-KMT2A interaction and menin inhibitors in leukemia; CRISPR base editor screen design and MV4;11 cells; Shared and inhibitor-specific MEN1 mutations (M327, G331, T349, C334R, E368K/V, V372A); Biochemical binding: TR-FRET and Ki shifts; Structural insights: co-crystal structures; In vivo validation: PDX models

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Five inhibitors tested: DS-1594, JNJ-6617, KO-539, SNDX-5613, DSP-5336
- Base editing screen in MV4;11 A>G and C>T lines mutates MEN1 across residues; screen yields enriched residues near the KMT2A binding pocket
- Mutations show shared (pan-class) resistance, notably M327I and G331D, and inhibitor-specific resistance (C334R for DS-1594; E368K/V for DSP-5336; V372A for KO-539)
- Ki shifts measured by TR-FRET correlate with cellular IC50 shifts
- Co-crystal structures explain resistance via steric clashes or disrupted interactions
- In vivo PDX validation shows mutations arise under therapeutic pressure; higher potency can suppress or overcome resistance

QC result: Pass.

Kalinowski A et al., PNAS - This study reports that C4 protein is enriched in human neutrophils and monocytes and that neutrophil C4 protein levels correlate with C4A gene copy number specifically in people with schizophrenia, linking peripheral innate immunity to disease-related biology. Key terms: schizophrenia, complement C4, neutrophils, monocytes, innate immunity.

Study Highlights:
Using public gene-expression data and fresh whole blood, the authors show C4 protein is primarily localized to neutrophils and monocytes. In a clinical cohort, neutrophil C4 protein positively correlated with C4A gene copy number in schizophrenia (Spearman rho = 0.63). Neutrophil and classical monocyte C4 protein were reduced in schizophrenia versus controls, and neutrophil C4 associated with perceived stress and symptom measures. Findings support a peripheral, cell-associated source of complement activation in schizophrenia.

Conclusion:
Neutrophils are a peripheral cellular reservoir of C4 that links C4A gene copy number to complement protein levels in schizophrenia, implicating innate immune cell mechanisms as potential contributors and targets for disease modification.

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

Article title:
Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes

First author:
Kalinowski A

Journal:
PNAS

DOI:
10.1073/pnas.2536376123

Reference:
Kalinowski A., Macaubas C., Guo H., et al. Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes. PNAS. 2026;123(20):e2536376123. doi:10.1073/pnas.2536376123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/peripheral-c4-schizophrenia-neutrophil-link

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript’s core scientific narrative: peripheral C4 biology in SZ (cellular localization, genetic associations, plasma vs cellular activation), links to symptoms/stress, and translational implications, with attention to study limitations.
- transcript topics: Innate immunity and C4 in schizophrenia; C4 protein expression in neutrophils and monocytes; C4A gene copy number correlates with neutrophil C4 protein in SZ; Plasma C4 vs cell-associated C4 activation; Clinical associations: perceived stress and PANSS; Limitations and confounds (medication, BMI, sample size)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- C4 protein is expressed and localized in neutrophils and monocytes (cellular localization, not plasma only)
- C4A gene copy number correlates with neutrophil C4 protein in schizophrenia (Spearman rho ≈ 0.63; P ≈ 0.012)
- In schizophrenia, neutrophil C4 protein is lower than controls after adjustment (BMI or related covariates; notable P-values in exploratory analyses)
- Plasma C4 did not show the same correlations with C4A gene copies, suggesting a non-plasma cellular source
- Neutrophil C4 protein depletion correlates with higher perceived stress (PSS) and PANSS general psychopathology in SZ
- Study limitations include all SZ participants being medicated; replication in medication-naive/first-episode samples is needed

QC result: Pass.

Zhou Z et al., Nature Communications - This study develops a Lorentzian deconvolution model of cfDNA fragment length distributions across bodily fluids, identifies a ~159 bp component that demarcates intra- vs inter-nucleosomal fragments, and shows that intra-nucleosomal fragmentation entropy distinguishes tumor-derived ctDNA from non-tumor shortening. Key terms: cell-free DNA, fragmentomics, nucleosome, ctDNA, size deconvolution.

Study Highlights:
The authors modeled cfDNA size profiles as sums of Cauchy–Lorentz distributions with ~10 bp periodicity and applied deconvolution across plasma, saliva, urine, CSF and lymphatic fluid. A distinct ~159 bp component emerged as a pivot between intra- and inter-nucleosomal fragments. Tumor-derived ctDNA shows increased intra-nucleosomal fragmentation entropy and inverse amplitude changes across the 159 bp boundary, whereas phagocytosis-associated shortening increases intra-nucleosomal amplitude without raising entropy. The intra/inter-nucleosomal entropy ratio improved cancer detection performance relative to standard size-ratio metrics across multiple cohorts.

Conclusion:
Size deconvolution using Lorentzian components reveals nucleosomal structure in cfDNA, identifies a 159 bp demarcation between fragmentation regimes, and provides an entropy-based metric that enhances ctDNA detection while separating tumor-associated fragmentation from phagocyte-related signals.

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

Article title:
Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations

First author:
Zhou Z

Journal:
Nature Communications

DOI:
10.1038/s41467-026-72925-4

Reference:
Zhou Z, Cooper WN, Cheng Z, et al. Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72925-4

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/cfdna-size-deconvolution-nucleosomal-origins

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-09.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of the transcript's discussion of cfDNA fragmentology, Lorentzian deconvolution, the 159 bp pivot, entropy vs amplitude distinctions, Li-Fraumeni context, phagocytosis vs tumor fragmentation, and diagnostic performance metrics.
- transcript topics: cfDNA fragmentomics basics; Lorentzian size deconvolution and nucleosome structure; 159 bp boundary between intra- and inter-nucleosomal cfDNA; intra-/inter-nucleosomal amplitude and entropy ratios; ctDNA fragmentation entropy as cancer signature; phagocytosis vs tumor-derived fragmentation

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- cfDNA size profiles deconvoluted into Lorentzian components across multiple fluids with ~10 bp periodicity
- a ~159 bp component demarcates intra- vs inter-nucleosomal cfDNA
- intra-nucleosomal fragmentation entropy is elevated in ctDNA; phagocytosis-associated shortening increases amplitude but not entropy
- intra-/inter-nucleosomal entropy ratio improves cancer detection performance (gastric cancer AUC ~0.87; multi-cancer AUC ~0.81–0.85; stage-specific AUCs up to ~0.91)
- radiotherapy and organ transplantation contexts show short-fragment enrichment with amplitude changes but entropy changes are not increased in non-tumor scenarios
- dd-cfDNA analyses show differences in amplitude but not entropy between high vs low donor-derived DNA groups

QC result: Pass.

Kearns FL et al., PNAS - Simulations and HDXMS reveal how the D614G substitution alters internal communication in SARS-CoV-2 spike, enabling faster receptor-binding-domain opening through newly engaged allosteric pathways. Key terms: D614G, SARS-CoV-2 spike, RBD opening, allostery, weighted ensemble simulations.

Study Highlights:
Weighted ensemble simulations of Ancestral, Delta, and Omicron BA.1 spikes show distinct RBD opening landscapes and identify two S1 linkers (N2R and a previously underappreciated antiparallel R2N) that connect the NTD to the RBD. In the Ancestral spike a D614–K854 salt bridge constrains the R2N and must break before RBD opening; D614G abolishes that constraint, increasing local flexibility and enabling communication through both linkers. Delta and Omicron BA.1, both carrying D614G, open faster and use balanced N2R/R2N signaling; Omicron also forms a K856–D568 salt bridge and can adopt a unique “peel” conformation. Hydrogen–deuterium exchange mass spectrometry on VLPs confirms altered dynamics around the 614-proximal region consistent with the simulations.

Conclusion:
Ablation of the D614–K854 salt bridge by D614G relieves local frustration, opens an additional allosteric lane via the R2N linker alongside N2R, and accelerates RBD opening—providing a mechanistic link between the D614G substitution and increased infectivity; Omicron BA.1 further tunes this network with compensatory interactions.

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

Article title:
D614G reshapes allosteric networks and opening mechanisms of SARS - CoV - 2 spikes

First author:
Kearns FL

Journal:
PNAS

DOI:
10.1073/pnas.2504793123

Reference:
Kearns FL, Bogetti AT, Calvó-Tusell C, et al. D614G reshapes allosteric networks and opening mechanisms of SARS-CoV-2 spikes. PNAS. 2026;123(19):e2504793123. doi:10.1073/pnas.2504793123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/d614g-reshapes-allosteric-networks

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-09.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for alignment with the PNAS article's core findings: D614G reshapes spike allostery, dual N2R/R2N pathways, D614-K854 salt-bridge dynamics, Delta/Omicron opening differences, Omicron peel state, and HDXMS corroboration; plus methodological details (WE/MA binning, glycans, and limitations).
- transcript topics: D614G impact on RBD opening dynamics; Weighted Ensemble simulations (WE) and minimal adaptive binning (MAB); N2R and R2N flexible linkers as allosteric pathways; D614-K854 salt bridge role and congestion; Variant-specific opening pathways: Delta and Omicron; Omicron BA.1 peel state and K856-D568 salt bridge

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- D614G abolishes the D614-K854 salt bridge, increasing local flexibility and accelerating RBD opening via dual N2R and R2N linkers
- Delta and Omicron spikes open faster than ancestral and utilize both N2R and R2N pathways
- Ancestral spike relies mainly on the N2R linker; Delta and Omicron use both linkers for RBD opening
- Omicron BA.1 adopts a peel state with a new K856-D568 salt bridge to restabilize FPPR and enable broader opening
- HDXMS on VLPs shows altered dynamics near the 614 region consistent with simulation predictions; peptides near D614G region demonstrate altered deuterium uptake
- WE simulations with minimal adaptive binning mapped RBD opening across variants; hundreds of microseconds of aggregated time over ~2 months on GPUs

QC result: Pass.

Beckner RL et al., PNAS - This episode examines a PNAS study using Chiral Inversion Mutagenesis (ChIM) to scan low-complexity domains (LCDs) of Emerin and neurofilament light chain (NEFL). Targeted L-to-D amino acid inversions reveal position-dependent, chirality-sensitive hotspots that control LCD self-association. Key terms: chiral inversion, low-complexity domains, Emerin, neurofilament light chain, synthetic protein chemistry.

Study Highlights:
The authors applied synthetic protein chemistry to introduce site-specific L-to-D Cα inversions (ChIM) in LCDs of Emerin (EMD) and NEFL. ChIM scans identified discrete enantioselective hotspots—EMD residues ~191–203 and NEFL residues ~22–41—where D substitutions strongly reduce self-association measured by GST pulldown and turbidity assays. Minimal inversions, including single D substitutions, can abrogate EMD self-association, while an all-D mirror-image C-terminal fragment restored activity, implicating backbone geometry and secondary-structure involvement. These results show that polypeptide homochirality and transient structure underpin certain LCD–LCD interactions.

Conclusion:
Cα stereochemistry is a determinant of LCD self-association at specific sequence hotspots, and ChIM provides a positional-resolution chemical approach to identify backbone-constrained elements that mediate oligomerization of disordered domains.

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

Article title:
Chiral inversion mutagenesis identifies geometrically constrained residues within self - associating low - complexity domains

First author:
Beckner RL

Journal:
PNAS

DOI:
10.1073/pnas.2535888123

Reference:
Beckner RL, Kim L, Carter C, Walterscheid A, Liszczak G. Chiral inversion mutagenesis identifies geometrically constrained residues within self-associating low-complexity domains. Proc Natl Acad Sci U S A. 2026;123(19):e2535888123. doi:10.1073/pnas.2535888123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/chiral-inversion-lcd-hotspots-361

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-08.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken sections describing: ChIM methodology; Emerin LCD hotspot mapping (188–201) with 3×Pro and 3×D scans; single-residue effects (1×D) and all-D mirror-image rescue; NEFL head domain hotspot (22–41) with 5×D scans; assay descriptions (GST pulldown, turbidity); cross-β/anti-selective interactions; drug-de
- transcript topics: Chiral inversion mutagenesis (ChIM) methodology; Emerin (EMD) LCD self-association hotspot mapping (188–201) with Pro/ D-inversions; NEFL head domain hotspot mapping (22–41) with 5×D inversions; Mutational scan results: 3×D, 1×D, 5×D variants and effects on pulldown/turbidity; Mirror-image (all-D) fragment rescue for Emerin; Assays: GST pulldown and turbidity measurements

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ChIM identifies enantioselective interaction hotspots in LCD self-association
- Emerin hotspot localized to residues 188–201; 3×Pro insertions disrupt, 3×D inversions within hotspot abrogate pulldown
- Single 1×D inversion reduces turbidity by ~6.4-fold in Emerin
- All-D mirror-image C-terminal fragment restores Emerin LCD self-association
- NEFL head domain hotspot localized to residues 22–41; 5×D inversions yield ~9.1-fold and ~20-fold turbidity reductions (22–30 and 33–41 respectively)
- Outside NEFL hotspot, inversions do not disrupt self-association to the same extent

QC result: Pass.

Graff A et al., PNAS - A PNAS study linking global population-genetic data and structural linguistic features finds an inverse correlation: regions with lower genetic diversity show higher structural linguistic diversity, after controlling for geography, phylogeny, and environment. Key terms: linguistic diversity, population genetics, Wright's F, language contact, structural typology.

Study Highlights:
The authors merged global genomic samples (Wright’s F / homozygosity) with curated structural linguistic datasets and estimated local structural entropy per grid cell. Using Bayesian GAMMs that adjust for spatial, phylogenetic, environmental, and sampling confounds, they find that higher excess homozygosity (lower genetic diversity) predicts higher structural linguistic entropy. The genetic predictor outperforms other covariates and the effect is robust across grid resolutions and sensitivity checks, though it varies by region and by specific linguistic features. The pattern supports a model where isolation promotes linguistic diversification while contact and admixture promote homogenization.

Conclusion:
An inverse, regionally variable correlation between local human genetic diversity and structural linguistic diversity suggests isolation-driven hotspots are key windows into the flexibility and evolution of language structure.

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

Article title:
An inverse correlation between structural linguistic and human genetic diversity

First author:
Graff A

Journal:
PNAS

DOI:
10.1073/pnas.2526762123

Reference:
Graff A., Ringen E.J., Zakharko T., Stoneking M., Shimizu K.K., Bickel B., Barbieri C. An inverse correlation between structural linguistic and human genetic diversity. Proc. Natl. Acad. Sci. U.S.A. 2026;123(18):e2526762123. doi:10.1073/pnas.2526762123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/inverse-correlation-linguistic-genetic-diversity

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing inverse relationship between local genetic diversity and structural linguistic diversity, methods (F coefficient, entropy, geodesic hex grids), magnitude of effects, regional patterns, and study limitations; cross-checks with article content performed.
- transcript topics: Inverse relationship between genetic diversity and linguistic structural diversity; Genetic metric Wright's F and linguistic entropy (normalized Shannon entropy); Geodesic hex grid methodology and grid resolutions (500 km and 300 km); Regional variation and strongest signals (North-Central Asia, Southeast Asia); Feature-level impact and percent of features affected by genetic diversity; Limitations: correlation vs causation and blind spots of genetic data

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Inverse correlation between local genetic diversity (F) and local structural linguistic diversity (entropy) after adjusting for geography, phylogeny, environment
- F coefficient reflects excess homozygosity, proxy for historical isolation; high F indicates low genetic diversity
- Structural linguistic diversity quantified via normalized Shannon entropy across 333 features in 4,257 languages (TLI dataset) with cross-check in GBI (196 features, 2,467 language
- Two grid resolutions used: 500 km and 300 km; analyses include jittered coordinates as sensitivity checks
- Genetic predictor emerges as strongest correlates of linguistic diversity, outperforming environment and population density in main models
- Magnitude: approximately 2.3% increase in entropy per SD increase in F (500 km grid); about 2.1% in the finer grid (300 km)

QC result: Pass.

Avery NG et al., PNAS - This episode covers a PNAS study reporting the de novo design of miniprotein inhibitors targeting porcine deltacoronavirus (PDCoV). The lead minibinder, MB11, binds the PDCoV RBD with picomolar affinity, broadly neutralizes diverse deltacoronaviruses, and resists multiple biochemical stresses. Key terms: Porcine deltacoronavirus, miniprotein inhibitor, MB11, protein design, neutralization.

Study Highlights:
Researchers used computational design (BindCraft and AlphaFold3) to generate miniprotein inhibitors targeting the PDCoV receptor-binding domain and screened candidates by BLI and pseudovirus neutralization. MB11 binds the PDCoV RBD with KD ~155 pM and neutralizes PDCoV and several distantly related DCoVs with superior potency to known antibodies. Cryo-EM shows MB11 occludes receptor-binding loops and sterically blocks APN engagement, explaining broad neutralization. Deep mutational scanning indicates a high barrier to escape and biochemical tests show MB11 retains function after high temperature and low pH exposure but is susceptible to pepsin.

Conclusion:
MB11 is a promising preclinical PDCoV inhibitor combining ultrapotent, broad neutralization, mechanistic receptor blockade, and favorable stability, supporting further development for pandemic preparedness.

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

Article title:
Computational design of an ultrapotent deltacoronavirus miniprotein inhibitor

First author:
Avery NG

Journal:
PNAS

DOI:
10.1073/pnas.2533456123

Reference:
Avery NG, Yoshiyama CN, Taylor AL, Park Y-J, Asarnow D, Perruzza L, Brown JT, Corti D, Benigni F, Starr TN, Veesler D. Computational design of an ultrapotent deltacoronavirus miniprotein inhibitor. PNAS. 2026;123:e2533456123. doi:10.1073/pnas.2533456123

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/mb11-pdcoronavirus-minibinder

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the sections covering MB11 design (BindCraft/AF3), binding measurements (BLI), neutralization assays (PDCoV and related DCoVs), cryo-EM structural validation, deep mutational scanning escape analysis, biophysical stability tests (heat/acid/enzymes), and delivery/manufacturing implications discussed.
- transcript topics: Computational minibinder design (BindCraft and AlphaFold3); Biolayer interferometry binding screening; Pseudovirus neutralization assays and breadth across DCoVs; Cryo-EM structure and mechanism of entry inhibition; Deep mutational scanning and viral escape barriers; Biophysical stability under heat, low pH, and proteases

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- MB11 has KD ≈ 155 pM to PDCoV RBD (binds with high affinity).
- MB11 neutralizes PDCoV pseudovirus with IC50 ≈ 216 pM.
- MB11 shows broad neutralization across DCoVs, including SparrowCoVISU42824 (IC50 ≈ 14 pM) and MuniaCoVHKU13 (IC50 ≈ 152 nM).
- Cryo-EM reveals MB11 wedges into PDCoV RBD receptor-binding loops, blocking APN engagement; structure at 2.8 Å resolution with AF3 predicted model within ~0.6 Å RMSD.
- Deep mutational scanning shows a high barrier to escape; only a few mutations (at residues such as Y394 and V395) can modestly affect binding without severely compromising APN affi
- MB11 remains functional after heating to 70 °C for 1 h and after exposure to pH 2.2; largely resistant to proteases (except pepsin) and not aggregated after stress.

QC result: Pass.

Mantecon M et al., Human Genetics and Genomics Advances - This episode reviews a brief communication reporting a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Functional studies in patient fibroblasts show decreased CHCHD4 protein, marked assembly defects of mitochondrial complexes I and IV, and broad downregulation of electron transport and complex I biogenesis. Lentiviral expression of wild-type CHCHD4 restored OXPHOS proteins and assembly, linking CHCHD4 deficiency to human mitochondrial disease. Key terms: CHCHD4, mitochondrial disease, OXPHOS, complex I, protein import.

Study Highlights:
A single infant carried a paternal c.5C>T (p.Ser2Phe) CHCHD4 variant and a maternal deletion encompassing CHCHD4, resulting in markedly reduced CHCHD4 protein and severe lactic acidosis with neurological regression. Fibroblast analyses revealed decreased complex I and IV subunits, assembly defects on BN-PAGE, and widespread downregulation of mitochondrial proteins by proteomics, with respiratory electron transport and complex I biogenesis identified as the main dysregulated pathways. Lentiviral overexpression of wild-type CHCHD4 in patient cells restored CHCHD4 levels, rescued complex I and IV protein abundance and assembly, and reversed many proteomic changes, supporting causality.

Conclusion:
Biallelic CHCHD4 deficiency causes a severe early-onset mitochondrial disease by impairing mitochondrial protein import and assembly of complexes I and IV; restoration of CHCHD4 rescues the molecular defects. Additional cases are needed to define the clinical spectrum and the functional impact of specific variants.

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

Article title:
Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease

First author:
Mantecon M

Journal:
Human Genetics and Genomics Advances

DOI:
10.1016/j.xhgg.2026.100615

Reference:
Mantecon M, Chhuon C, Roger K, et al. Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease. Human Genetics and Genomics Advances. 2026;7:100615. doi:10.1016/j.xhgg.2026.100615

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

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/biallelic-chchd4-oxphos-defect

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the sections describing CHCHD4 function in the MIA pathway, the pediatric case with biallelic CHCHD4 variants, AlphaFold structural predictions for Ser2Phe, lentiviral complementation rescuing OXPHOS defects, and the proteomics results including selective vulnerability and clinical implications.
- transcript topics: MIA pathway and CHCHD4 function in mitochondrial protein import; Genetic case and inheritance pattern (p.Ser2Phe with maternal CHCHD4 deletion); AlphaFold structural prediction of Ser2Phe destabilizing CHCHD4; Functional complementation rescue with WT CHCHD4 in patient fibroblasts; Proteomics results showing OXPHOS defects and selective vulnerability; Clinical implications: CHCHD4 deficiency as a novel cause of mitochondrial disease

QC 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:
- CHCHD4 is a component of the mitochondrial import and assembly (MIA) pathway that imports small cysteine-containing substrates and its deficiency impairs import and assembly of oxi
- Subject carried biallelic CHCHD4 variants: paternal Ser2Phe and a maternal CHCHD4 deletion; subject fibroblasts show reduced CHCHD4 and defects in OXPHOS protein levels and assembl
- AlphaFold predicted that Ser2Phe destabilizes CHCHD4 by disrupting a hydrogen-bond zipper near a beta-hairpin, explaining loss of function.
- Functional complementation with wild-type CHCHD4 via lentiviral expression rescues CHCHD4 levels and restores complex I and IV protein abundance and assembly in subject-derived cel
- Proteomics shows broad downregulation of mitochondrial proteins with CHCHD4 deficiency; rescue of CHCHD4 restores many affected proteins; iron-sulfur cluster export pathways largel
- CHCHD4 deficiency is identified as a novel cause of severe mitochondrial disease in humans; the study is limited by a single-case design and calls for additional cases to define na

QC result: Pass.