Base by Base

Malbranke C et al., Proceedings of the National Academy of Sciences (PNAS) - ProteomeLM is a transformer-based language model trained on complete proteomes that produces contextualized protein embeddings and attention signals which recover protein–protein interactions unsupervised and support supervised PPI and gene essentiality prediction across diverse taxa. Key terms: proteome language model, protein–protein interactions, gene essentiality, ProteomeLM, deep learning.

Study Highlights:
ProteomeLM was trained on ~32,000 proteomes using ESM‑C embeddings and a custom polar loss to reconstruct masked protein embeddings in proteome context. Its attention heads encode protein–protein interactions without supervision and distinguish direct physical binding, complex membership, and broader functional associations. As a fast first-pass filter it outperforms amino-acid coevolution (DCA) in recall while reducing compute by orders of magnitude. Downstream supervised models—ProteomeLM-PPI and ProteomeLM-Ess—achieve state-of-the-art cross-species PPI prediction and strong gene essentiality prediction that generalizes to held-out and synthetic minimal genomes.

Conclusion:
Representing proteins in whole-proteome context yields interpretable attention signals that capture functional and physical relationships, enabling rapid, accurate interactome screening and improved gene essentiality prediction across the tree of life.

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

Article title:
ProteomeLM: A proteome-scale language model enables accurate and rapid prediction of protein–protein interactions and gene essentiality across taxa

First author:
Malbranke C

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

DOI:
10.1073/pnas.2524201123

Reference:
Malbranke C, Zalaffi GP, Bitbol A-F. ProteomeLM: A proteome-scale language model enabling accurate and rapid prediction of protein–protein interactions and gene essentiality across taxa. Proc Natl Acad Sci U S A. 2026;123:e2524201123. doi:10.1073/pnas.2524201123

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/proteomelm-interactomes-essentiality

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in transcript: ProteomeLM architecture, functional encoding, polar loss, unsupervised PPI via attention, speed/screening benefits, supervised PPI (ProteomeLM-PPI), gene essentiality predictions (ProteomeLM-Ess), and cross-species/minimal cells.
- transcript topics: ProteomeLM architecture and training on whole proteomes; Functional encoding using orthology (OrthoDB); Polar loss and avoiding reliance on coarse functional encoding; Attention coefficients encoding protein-protein interactions (PPI) in unsupervised manner; Unsupervised PPI detection and protein complex membership; Speed and scalability of whole-interactome screening vs DCA

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ProteomeLM trained on ~32,000 annotated proteomes spanning the tree of life and uses a functional encoding via orthologous groups (OrthoDB).
- ProteomeLM’s attention coefficients encode PPI without supervision (no interaction labels during training).
- ProteomeLM enables fast whole-interactome screening and is substantially faster than DCA (up to six orders of magnitude); inference under 10 minutes per proteome on a single GPU.
- Unsupervised PPI performance in Escherichia coli: a single attention head (head7, layer3) achieves AUC = 0.92.
- ProteomeLM can distinguish direct interactions, same-complex interactions, and genetic associations; ribosome and TRiC/CCT complex analyses yield high AUC (>= 0.99 for some tests).
- ProteomeLM-PPI achieves state-of-the-art supervised PPI predictions across species; ProteomeLM-Ess predicts gene essentiality; best reported AUC = 0.93 with layer-8 embeddings from

QC result: Pass.

Ortiz-Rodríguez M et al., Proceedings of the National Academy of Sciences (PNAS) - Single-molecule optical tweezers and fluorescence reveal how the S. pombe Pif1-family helicase Pfh1 alternates ATP-dependent unwinding and ATP-modulated rewinding at replication-fork-like substrates, and how mitochondrial SSB spRim1 tunes those activities. Key terms: Pfh1 helicase, Pif1-family, DNA unwinding, spRim1, single-molecule.

Study Highlights:
Using single-molecule optical tweezers and fluorescence, the authors show Pfh1 performs ATP-dependent unwinding–rewinding cycles with an intrinsic ~20–22 bp processivity. Contacts with the translocating strand modulate apparent ATP affinity while engagement of the displaced strand limits maximum unwinding velocity. The mitochondrial SSB spRim1 binds the displaced strand, disrupts those contacts, and increases unwinding and rewinding velocities. Rewinding is ATP-dependent and proceeds via a sliding-back mechanism rather than strand switching.

Conclusion:
Pfh1 balances unwinding and rewinding through coordinated ATP-dependent interactions with both fork strands; binding of spRim1 to the displaced strand disrupts inhibitory helicase–strand contacts and accelerates fork dynamics, providing a mechanistic framework for how Pif1-family helicases promote replication fork progression without disrupting replisome organization.

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

Article title:
Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB

First author:
Ortiz-Rodríguez M

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

DOI:
10.1073/pnas.2602528123

Reference:
Ortiz-Rodríguez M, Singh SP, Cao-García FJ, Galletto R, Ibarra B. Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB. PNAS. 2026;123(21):e2602528123. doi:10.1073/pnas.2602528123

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/pfh1-helicase-unwinding-rewinding

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing Pfh1 unwinding/rewinding cycles, force and ATP dependencies, spRim1 modulation, DNA fork vs RNA–DNA fork experiments, and the proposed sliding-back mechanism and its biological relevance.
- transcript topics: Pfh1 helicase function and 5'-3' directionality; Unwinding–rewinding cycles and ~20 bp processivity; ATP concentration and force dependencies (Km(f), Vmax); Role of spRim1 in DNA fork unwinding/rewinding; RNA–DNA fork experiments and strand-switching debate; Rewinding mechanism and ATP hydrolysis effects

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- PfH1 operates via unwinding–rewinding cycles with coordination between fork strands
- Intrinsic unwinding processivity is ~20 bp (not extending beyond ~22 bp per burst)
- Unwinding velocity increases with ATP and is modulated by force via Km(f) and Vmax
- spRim1 binds displaced strand, increasing unwinding velocity on the DNA fork to ~115 bp/s and shortening inter-burst recovery
- spRim1 accelerates rewinding on the DNA fork; on RNA–DNA forks, spRim1 does not stimulate unwinding/rewinding
- RNA–DNA fork experiments support a sliding-back mechanism over strand-switching

QC result: Pass.

Douzgou Houge S et al., Human Genetics and Genomics Advances - This paper reports six individuals with biallelic loss-of-function DSCAM variants, delineating a recessive syndrome of moderate-to-severe neurodevelopmental delay with poor language, early focal seizures, hypotonia, short stature, and characteristic rotatory/vertical nystagmus with cone-pathway retinal dysfunction. Key terms: DSCAM, neurodevelopmental delay, nystagmus, retinal dysfunction, electroretinography.

Study Highlights:
The authors describe six patients (including four newly reported) with homozygous or compound heterozygous predicted loss-of-function variants in DSCAM. All individuals share moderate-to-severe neurodevelopmental delay, impaired language, frequent hypotonia, and short stature, with focal seizures in some. A consistent ophthalmic phenotype of rotatory/vertical nystagmus and poor vision was observed, and ERG in two patients showed relative rod preservation but marked cone-pathway dysfunction, implicating cone-associated bipolar cells. The clinical and electrophysiological findings align with animal models showing disrupted retinal lamination and mosaic spacing caused by loss of DSCAM.

Conclusion:
Biallelic DSCAM loss-of-function defines a rare recessive neurodevelopmental syndrome characterized by motor and cognitive impairment and a distinctive, developmentally origin retinal dysfunction primarily affecting the cone pathway detectable by ERG.

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

Article title:
Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction

First author:
Douzgou Houge S

Journal:
Human Genetics and Genomics Advances

DOI:
10.1016/j.xhgg.2026.100622

Reference:
Douzgou Houge S., Bredrup C., Wivestad Jansson R., Bojovic O., Aljamal B.M., Al-Otaibi M., Plomp A.S., Motazacker M.M., van Genderen M.M., Mellgren A., Alkuraya H., Hikmat O., Haukanes B.I., Alkuraya F.S., Douzgos Houge G. Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction. Human Genetics and Genomics Advances 7, 100622 (July 9, 2026). https://doi.org/10.1016/j.xhgg.2026.100622.

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/biallelic-dscam-neurodevelopmental-nystagmus

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: The transcript covers the study’s core claims: DSCAM function and retinal organization, genetic evidence for biallelic LoF variants, the neurodevelopmental phenotype, ERG findings showing cone pathway impairment with rod preservation, animal-model context, consanguinity patterns, and ASD-related discussions.
- transcript topics: DSCAM role in retinal self-avoidance and patterning; Genetic identification of DSCAM LoF variants via trio exome sequencing; Clinical phenotype: neurodevelopmental delay, language impairment, seizures, hypotonia, short stature; Ophthalmic phenotype and ERG-based retinal function (cone vs rod); Cone-associated bipolar cells in the retina as the site of dysfunction; Animal-model evidence (chicken retina and DSCAM KO mice) for retinal organization

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 individuals with biallelic DSCAM loss-of-function variants described in the study
- Cone-pathway dysfunction with preserved rod-pathway function demonstrated by ERG in some individuals
- Cone-associated bipolar cells implicated as the site of dysfunction in the retina
- DSCAM is required for self-neuronal avoidance; animal models show retinal disorganization when DSCAM is disrupted
- Consanguineous parental relationships and twin pairs observed in the cohort
- Monoallelic DSCAM variants have been associated with autism in separate studies

QC result: Pass.

Wu X et al., Nature Biotechnology - The authors engineer synthetic PAM-containing DNA guides (crDNA) that bind Cas12a to form a deoxyribonucleoprotein (DNP) complex that recognizes and cleaves complementary RNA. Structural, biochemical and cellular data define a PAM-dependent activation route distinct from canonical RNA-guided systems and demonstrate applications in sensitive diagnostics and intracellular RNA knockdown. Key terms: DNA-guided Cas12a, crDNA, RNA targeting, SLEUTH diagnostic, RNA knockdown.

Study Highlights:
The team designed single-stranded PAM-bearing crDNA that assembles with Cas12a to form a stable DNP complex and recruit complementary RNA substrates. Cryo-EM and modeling show crDNA occupies the PI/WED/REC groove, preserves PAM engagement and positions an RNA–DNA heteroduplex for RuvC-mediated cleavage. DNA-guided Cas12a selectively binds and cleaves ssRNA, enables robust trans-cleavage across targets and orthologs, and supports an amplification-coupled SLEUTH diagnostic with attomolar sensitivity. In cells, phosphorothioate-stabilized crDNA with Cas12a produced sequence-specific knockdown of reporter and endogenous transcripts with minimal off-target signal.

Conclusion:
Cas12a can be reprogrammed into a DNA-guided, RNA-targeting effector: PAM-mediated crDNA engagement forms a catalytically competent complex that achieves sequence-specific RNA cleavage, enabling a new architecture for diagnostics and a proof-of-concept for intracellular RNA knockdown while highlighting stability and optimization challenges.

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

Article title:
DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage

First author:
Wu X

Journal:
Nature Biotechnology

DOI:
10.1038/s41587-026-03120-5

Reference:
Wu X., Lam W.H., Zhao Z., Feng X., Zhai Y., Hsing I.-M. DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage. Nature Biotechnology (2026). doi:10.1038/s41587-026-03120-5

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/dna-guided-cas12a-reprogrammed-to-target-rna

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing crDNA design and PAM activation, structural data from cryo-EM, RNA targeting and cleavage mechanics, SLEUTH diagnostic workflow and performance, and intracellular RNA knockdown in cells.
- transcript topics: DNA-guided Cas12a concept and crDNA design; PAM-dependent activation and DNP formation; Cryo-EM structure and DNA–RNA duplex within Cas12a; Two-step binding kinetics (Kd1 and Kd2); Trans-cleavage activity and RNA targeting kinetics; SLEUTH diagnostic workflow and performance

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- DNA-guided Cas12a can target RNA using crDNA with PAM-dependent activation
- crDNA occupies PAM-interacting site to form a DNP complex and enables RNA targeting
- Cryo-EM shows a 20-bp DNA–RNA heteroduplex in the Cas12a binding channel with PAM engaging the PI domain
- RNA cleavage is Mg2+-dependent via the RuvC active site and exhibits trans-cleavage
- SLEUTH achieves attomolar sensitivity and 100% concordance with RT–qPCR on a limited SARS-CoV-2 set
- PS-modified crDNA enables intracellular RNA knockdown in HEK293T cells with 56% reduction in EGFP fluorescence and 76% reduction in EGFP mRNA, with minimal off-target effects

QC result: Pass.

McGowan J et al., PLOS Genetics - Genome and transcriptome sequencing of an uncultured Oligohymenophorea ciliate (PL0344) reveals a novel nuclear genetic code in which UAA translates as lysine and UAG as glutamic acid, supported by suppressor tRNAs and phylogenomic context. Key terms: genetic code, ciliate, UAA, UAG, suppressor tRNA.

Study Highlights:
The authors assembled a macronuclear genome from low-input G&T-Seq data for Oligohymenophorea sp. PL0344 and found widespread in-frame UAA and UAG codons. Codetta and PhyloFisher analyses predict UAA→lysine and UAG→glutamic acid, and multiple corresponding suppressor tRNA genes were identified. UGA remains as a stop and is enriched as tandem stops in the 3' UTR, suggesting selection to limit readthrough. Phylogenomic mapping shows numerous independent genetic code changes across ciliates, making this the first reported case where UAA and UAG specify different amino acids.

Conclusion:
This study documents a previously unknown nuclear genetic code variant in a ciliate where UAA and UAG have distinct sense meanings, expanding known genetic code diversity and highlighting the need to consider noncanonical codes in genome annotation and evolutionary analyses.

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

Article title:
Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids

First author:
McGowan J

Journal:
PLOS Genetics

DOI:
10.1371/journal.pgen.1010913

Reference:
McGowan J, Kilias ES, Alacid E, Lipscombe J, Jenkins BH, Gharbi K, et al. (2023) Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids. PLoS Genet 19(10): e1010913. https://doi.org/10.1371/journal.pgen.1010913

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/non-canonical-ciliate-code-373

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the transcript sections that discuss genetic code reassignments (UAA/UAG), suppressor tRNAs, UGA handling (stop/Sec), tandem stop codons, sequencing approach (G&T-Seq), and phylogenetic context.
- transcript topics: Canonical vs noncanonical genetic code in ciliates; UAA and UAG reassignment to Lys and Glu; Suppressor tRNA genes and wobble binding; G&T-Seq single-cell genome/transcriptome methodology; UGA stop codon usage and tandem stop codons; Phylogenomics and independent genetic code changes in ciliates

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- UAA codon reassigned to lysine and UAG codon reassigned to glutamic acid in PL0344
- Presence of multiple suppressor tRNA genes corresponding to UAA (Lys) and UAG (Glu)
- tRNA-SeC(UCA) identified, suggesting UGA can encode selenocysteine in addition to stop
- UGA codons enriched in the 3'-UTR downstream of genes as tandem stops to mitigate readthrough
- Genome assembly size around 69.7 Mb with thousands of transcripts and tRNA genes
- Wobble-coupling constraint circumvented; UAA and UAG have different meanings in this organism

QC result: Pass.

Kajonius PJ et al., Scientific Reports - This episode examines a twin-study analysis from the German TwinLife panel showing that cognitive ability at age 23 predicts socioeconomic status at age 27, and that much of this longitudinal association is explained by genetic factors rather than shared or unique environments. Key terms: cognitive ability, IQ, socioeconomic status, genetics, twin study.

Study Highlights:
Using TwinLife panel data, IQ measured at 23 predicted educational and occupational outcomes at 27 with phenotypic correlations typically above .30. Univariate twin models estimated IQ heritability at about 75% and substantial heritability for SES measures. Bivariate Cholesky decompositions found that genetics accounted for 69–98% of the IQ–SES association and that genetic correlations exceeded environmental correlations. These results held across two education and two occupation measures.

Conclusion:
In this emerging-adult sample, both IQ and SES showed sizable heritability and the longitudinal link from IQ to future SES was largely attributable to shared genetic influences, suggesting that research and policy should account for genetic contributions when interpreting individual socioeconomic trajectories.

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

Article title:
Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature

First author:
Kajonius PJ

Journal:
Scientific Reports

DOI:
10.1038/s41598-026-37786-3

Reference:
Kajonius PJ. Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature. Scientific Reports. 2026;16:4315. doi:10.1038/s41598-026-37786-3

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/genes-iq-ses-twinlife

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-20.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited sections covering: study design (TwinLife, MZ/DZ twins), measurement (CFT-20-R IQ at 23; education and occupation SES at 27), main results (heritability estimates; 69–98% genetic explanation of IQ–SES link; C factor minimal), pleiotropy pathways (direct and mediated), and discussion of limitations
- transcript topics: TwinLife study and sample characteristics; Measurement of IQ and SES; Univariate and bivariate twin-model analyses (ACE/AE; Cholesky/related description); Genetic and environmental contributions to IQ and SES; Genetic overlap and pleiotropy pathways; Limitations and policy implications

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- IQ23 heritability around 75%
- SES27 heritability for education around 49% (AE) and 66% (Casmin); occupation around 32% (ACE) and 71% (AE)
- Genetic factors explained 69–98% of the IQ–SES longitudinal association
- Occupational SES shows up to 98% genetic overlap with IQ
- Common environment (C) often minimal or dropped in best-fitting models
- Two pleiotropy pathways: direct (biological) pleiotropy and mediated pleiotropy

QC result: Pass.

Han et al., Nature Communications - This study uses paired single-nucleus chromatin accessibility and gene expression profiling across Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy to map disease-dynamic cis-regulatory elements (CREs). Dynamic chromatin changes concentrate genetic risk in glial cell states and co-regulated regulatory modules. Integrating GWAS, sn-eQTLs and MPRA validates functional noncoding variants that tune lysosomal, lipid and vesicular pathways. Experimental CRISPRa and histology support a stress-inducible SOX10-driven glial program linked to resilience. Key terms: snATAC-seq, tauopathies, microglia, chromatin accessibility, SOX10.

Study Highlights:
The authors profiled matched snATAC-seq and snRNA-seq from three brain regions across AD, PiD and PSP and defined cell-type-specific CREs and 50 subclusters. Disease-dynamic peaks concentrated in glia and disproportionately capture GWAS heritability, with PiD-linked mg.C4 microglia and PSP-linked ast.C1 astrocytes identified as risk-associated states. MPRA in microglial models and sn-eQTL integration validated functional regulatory variants that converge on MEF2C/SOX10 and SNARE-centered modules affecting lysosomal, sphingolipid and trafficking pathways. CRISPRa induction of SOX10 in iPSC-derived microglia under synaptosome stress recapitulated mg.C4 programs, and RNAscope/IHC confirmed SOX10+/PLP1+ glial states in human tissue.

Conclusion:
Dynamic, disease-context-specific chromatin remodeling in glia concentrates genetic risk into co-regulated regulatory modules that modulate lysosomal, lipid and vesicular pathways; these modules nominate SOX10-, MEF2- and SNARE-centered circuits as candidate modulators of glial resilience across tauopathies.

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

Article title:
Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states

First author:
Han

Journal:
Nature Communications

DOI:
10.1038/s41467-026-73007-1

Reference:
Han, X., Rosenberg, G.M., Kisling, V.M. et al. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73007-1

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/epigenomic-glial-genetic-risk-tauopathies

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing glial states mg.C4 microglia and ast.C1 astrocytes, regulatory networks (MEF2C/MEF2D), SOX10's role and ectopic expression, MPRA validation, CRISPRaSOX10 experiments, dynamic CREs and heritability findings, and study limitations.
- transcript topics: Glial states mg.C4 microglia and ast.C1 astrocytes across tauopathies; MEF2C/MEF2D regulatory modules linking to lysosomal and phagocytic pathways; SOX10 as a stress-responsive regulator and ectopic expression in glia; MPRA validation of regulatory variants in microglia (frVars); CRISPRa SOX10 activation in hiPSC-derived microglia and recapitulation of mg.C4 programs; Dynamic CREs and GWAS heritability enrichment across disorders

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:
- Number of nuclei and samples studied: 682,667 high-quality nuclei from 41 brains
- Regions analyzed in main comparisons: Precentral Gyrus (PreCG) and insula; calcarine cortex excluded due to variability
- Identification of disease-associated glial states mg.C4 microglia and ast.C1 astrocytes
- Dynamic CREs enrich disease heritability, with PiD mg.C4 driving FTD heritability and PSP ast.C1 contributing PSP heritability
- MEF2C/MEF2D regulatory modules link to lysosomal and phagocytic pathways in mg.C4 microglia
- SOX10 is enriched/activated in mg.C4 and ast.C1 and acts as a stress-responsive regulator

QC result: Pass.

Yang X et al., Proceedings of the National Academy of Sciences - Genetic and pharmacologic inhibition of ICMT suppresses proliferation, invasion, and tumor growth in BRAFV600E-driven models and identifies INPP5E as an ICMT-dependent CAAX substrate whose membrane targeting supports melanoma growth. Key terms: ICMT, INPP5E, BRAFV600E, melanoma, UCM-1336.

Study Highlights:
ICMT genetic knockdown or pharmacologic inhibition (UCM-1336) reduced proliferation and invasion of BRAFV600E-mutant melanoma cells, decreased tumor growth in xenografts and mouse models, and retained activity in BRAF-inhibitor-resistant cells. ICMT inhibition reduced INPP5E carboxyl methylation, displaced INPP5E from membranes to the cytosol, and increased cellular PI(4,5)P2. Forced membrane targeting of INPP5E (Lyn-INPP5E) partially rescued proliferation and tumor growth during ICMT suppression. These results implicate an ICMT–INPP5E axis that supports BRAFV600E-driven tumor growth without measurable suppression of MAPK signaling.

Conclusion:
ICMT-dependent methylation and membrane targeting of INPP5E contribute to BRAFV600E-driven tumor growth, and ICMT inhibition (genetic or with UCM-1336) impairs melanoma growth including in BRAF-inhibitor-resistant models, highlighting ICMT as a context-dependent therapeutic vulnerability.

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

Article title:
ICMT supports BRAF
V600E
-driven tumor growth by membrane targeting of the CAAX protein INPP5E

First author:
Yang X

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2601795123

Reference:
Yang X, Qiao X, Schmidt S, et al. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. PNAS. 2026;123(20):e2601795123. doi:10.1073/pnas.2601795123

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/icmt-inpp5e-brafv600e-membrane-targeting

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing ICMT/CAAX processing, INPP5E as an ICMT substrate, membrane targeting and PI(4,5)P2 effects, rescue experiments, in vitro/in vivo models, and therapeutic implications.
- transcript topics: ICMT and CAAX protein processing; INPP5E as an ICMT substrate and its membrane localization; Impact of ICMT inhibition on BRAFV600E melanoma cell proliferation and invasion; MAPK signaling independence from ICMT inhibition; In vivo models and genetic/pharmacologic ICMT suppression; Rescue experiments with Lyn-INPP5E and rescue implications

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ICMT inhibition reduces BRAFV600E-driven melanoma cell proliferation and invasion in vitro and tumor growth in vivo.
- INPP5E is an ICMT-dependent CAAX substrate; ICMT inhibition reduces INPP5E methylation and displaces it from membranes.
- Displacement of INPP5E increases plasma membrane PI(4,5)P2, disrupting signaling and contributing to tumor cell death.
- Forced membrane targeting of INPP5E (LYN-INPP5E) partially rescues proliferation and tumor growth during ICMT suppression.
- Nontransformed fibroblasts show less sensitivity to ICMT inhibition, indicating a therapeutic window.
- MEK/ERK phosphorylation is not reduced by ICMT inhibition, indicating a MAPK-independent mechanism.

QC result: Pass.

White MC et al., PNAS - This episode reviews a PNAS study showing that the kinase NEK2 is upregulated by EBV and its latency proteins and that NEK2 inhibition with the irreversible inhibitor JH295 selectively kills EBV-positive non-Hodgkin lymphoma cells, lowers drug resistance, and reduces tumor burden in mouse models. Key terms: NEK2, EBV, non-Hodgkin lymphoma, LMP1, drug resistance.

Study Highlights:
EBV infection and the latency proteins EBNA1, LMP1, and EBNA2 increase NEK2 expression in human B cells and patient tumors. Genetic depletion or pharmacologic inhibition of NEK2 with JH295 selectively kills EBV-positive NHL cells and induces inflammatory, ROS-associated cell death with gasdermin D cleavage. NEK2 inhibition reduces LMP1 and c-myc expression, decreases ABC transporter expression and MRP1-mediated drug efflux, and sensitizes cells to doxorubicin. In xenograft and cord blood-humanized mouse models JH295 lowered tumor burden, reduced tumor incidence, and prolonged survival without observable toxicity.

Conclusion:
NEK2 is a promising therapeutic target in EBV-positive non-Hodgkin lymphoma; NEK2 inhibition by JH295 both kills malignant cells and reduces drug resistance and viral oncoprotein expression in preclinical models.

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

Article title:
NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma

First author:
White MC

Journal:
PNAS

DOI:
10.1073/pnas.2535550123

Reference:
White MC, Lange PT, Stewart J, Damania B. NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2026;123:e2535550123. doi:10.1073/pnas.2535550123

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/nek2-drives-ebv-positive-nhl

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript passages on EBV-induced NEK2 upregulation, NEK2 inhibition mechanisms (ROS, gasdermin D), downstream effects (LMP1, c-Myc, beta-catenin, Bcl-2 family), MRP1/ABC transporters and drug resistance, and in vivo xenograft and cord blood–humanized mouse results.
- transcript topics: EBV-induced NEK2 upregulation in primary B cells; EBV latency proteins EBNA1, LMP1, EBNA2 drive NEK2 expression; JH295 NEK2 inhibitor and EBV+ NHL selectivity; Inflammatory cell death: ROS accumulation and gasdermin D cleavage; Downregulation of LMP1, c-Myc, beta-catenin; Bcl-2 family modulation; MRP1/MDR transporters and drug resistance reversal

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- EBV latency proteins EBNA1, LMP1, EBNA2 independently drive NEK2 upregulation
- Primary EBV infection increases NEK2 expression in human B cells
- NEK2 inhibition with JH295 induces inflammatory, ROS-associated cell death with gasdermin D cleavage in EBV-positive NHL
- EBV-positive NHL shows decreased LMP1 and c-myc expression following NEK2 inhibition
- NEK2 inhibition reduces MRP1/MDR transporter expression and activity, decreasing drug efflux and increasing chemosensitivity to doxorubicin
- JH295 reduces tumor burden and increases survival in NKTL xenograft and cord blood–humanized mouse models, with no observable systemic toxicity

QC result: Pass.

Jhaldiyal A et al., PNAS - This episode summarizes a PNAS study showing that PARP1 activation links Aβ1-42 toxicity to DNA damage, amyloid accumulation, neuroinflammation, and cognitive deficits, and that genetic or pharmacologic PARP1 suppression reduces pathology in cells and 5XFAD mice. Key terms: PARP1, poly(ADP-ribose), Alzheimer's disease, amyloid beta, neurodegeneration.

Study Highlights:
CSF poly(ADP-ribose) (PAR) is elevated in patients with MCI and AD and negatively correlates with the Aβ42/40 ratio. Oligomeric Aβ1-42 activates PARP1 in primary cortical neurons, causing DNA damage and cell death that are prevented by PARP1 inhibitors or PARP1 genetic deletion. In 5XFAD mice, PARP1 knockout halves plaque burden, preserves synapses and neurons, reduces glial activation and inflammatory gene expression, and rescues spatial learning and memory. Mechanistically, PARP1 deficiency lowers BACE1, alters γ-secretase subunits (PSEN1 up, nicastrin down), and increases the Aβ-degrading enzyme NEP2.

Conclusion:
PARP1 is a critical mediator of Aβ-driven toxicity, amyloid accumulation, neuroinflammation, and cognitive decline in a familial AD model, and its inhibition may be a promising disease-modifying strategy.

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

Article title:
PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model

First author:
Jhaldiyal A

Journal:
PNAS

DOI:
10.1073/pnas.2525028123

Reference:
Jhaldiyal A., Kumari M., Guttman L. C., et al. PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model. PNAS (2026). DOI: 10.1073/pnas.2525028123

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/parp1-amyloid-neurodegeneration-5xfad

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing CSF PAR elevation, Aβ42-induced PARP1 activation in neurons, in vitro neuroprotection by PARP inhibitors, in vivo 5XFAD/PARP1−/− outcomes (plaque burden, neuronal survival, gliosis, cognitive tests), APP metabolism changes, NEP2 involvement, inflammation, and translational cav
- transcript topics: CSF PAR elevation in MCI and AD and relation to Aβ42/40; Oligomeric Aβ42 activates PARP1 and induces DNA damage; Pharmacologic/genetic PARP1 inhibition confers neuroprotection in vitro; 5XFAD/PARP1−/− mice: reduced amyloid plaque burden and neuronal loss; APP processing changes: BACE1 reduction, PSEN1/nicastrin alterations, NEP2 up; Neuroinflammation and gliosis attenuation with PARP1 loss

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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CSF PAR levels are elevated in MCI and AD and inversely correlate with the Aβ42/40 ratio
- Oligomeric Aβ1-42 activates PARP1 and induces DNA damage; PARP1 inhibition or deletion confers neuroprotection in vitro
- PARP1 deficiency in 5XFAD mice reduces plaque burden (~50%) and preserves neurons and synapses while reducing gliosis and neuroinflammation
- PARP1 deficiency lowers APP processing toward reduced Aβ production (BACE1 decreased; PSEN1 up; nicastrin down) and increases NEP2-mediated Aβ degradation
- PARP inhibitors (e.g., veliparib, rucaparib, talazoparib) block Aβ-induced PAR accumulation and protect neurons in culture
- Translational considerations include blood-brain barrier crossing and long-term safety concerns for chronic PARP inhibition

QC result: Pass.