371: Glial epigenomic dysregulation and genetic risk in tauopathies

378: Dominant-negative PSMB8 variants stall immunoproteasome assembly

Wijngaard R et al., The American Journal of Human Genetics - Researchers describe seven individuals with monoallelic PSMB8 missense variants that impair immunoproteasome assembly, causing early-onset immunodeficiency and variable systemic inflammation via a dominant-negative mechanism. Key terms: PSMB8, immunoproteasome, PRAAS-ID, immunodeficiency, proteasome assembly. Study Highlights: Seven individuals from five families carrying distinct monoallelic PSMB8 variants presented with neonatal-onset immunodeficiency, B cell lymphopenia, hypogammaglobulinemia, and variable inflammatory disease. Structural modeling predicted destabilization of proteasome interfaces, and complexome profiling plus native assays showed reduced fully assembled immunoproteasomes with accumulation of a ∼440-kDa assembly intermediate. Mutant PSMB8 precursors accumulated, incorporation into 20S/26S complexes was reduced, immunoproteasome-specific activity decreased, and integrated stress response genes were induced. These data support a shared dominant-negative mechanism disrupting immunoproteasome biogenesis and immune signaling. Conclusion: Monoallelic PSMB8 missense variants impair incorporation of β5i into assembling immunoproteasomes, stalling biogenesis, reducing immunoproteasome abundance and activity, and producing clinically variable immunodeficiency with systemic inflammation consistent with PRAAS-ID. Music: Enjoy the music based on this article at the end of the episode. Article title: Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly First author: Wijngaard R Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.04.015 Reference: Wijngaard R., van der Made C.I., Kalkan Uçar S., et al. Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly. Am J Hum Genet. 2026;113:1–19. doi:10.1016/j.ajhg.2026.04.015 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/monoallelic-psmb8-praas-id-immunoproteasome-assembly 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: Substantive audit of immunoproteasome biology, dominant-negative mechanism of monoallelic PSMB8 variants, complexome profiling findings (440-kDa assembly intermediate, reduced IP abundance), functional consequences (IP activity reduction, ISR activation), and clinical implications described in the transcript. - transcript topics: Immunoproteasome structure and SP/IP distinction; Dominant-negative PSMB8 variants and mechanism; Complexome profiling methodology and IP assembly intermediates; Impaired IP biogenesis and 440-kDa intermediate; ISR activation and immune signaling effects; Clinical features: B cell lymphopenia, hypogammaglobulinemia, leukocyte inclusions 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: - Monoallelic PSMB8 variants cause PRAAS-ID via dominant-negative impairment of immunoproteasome assembly - Mutant PSMB8 subunits are inefficiently incorporated into immunoproteasomes, leading to defective IP biogenesis and reduced IP activity - Complexome profiling reveals accumulation of a ~440-kDa IP assembly intermediate with assembly factors - The 440-kDa intermediate is catalytically inactive despite partial assembly - Leukocyte vacuolization and inclusions observed in blood/bone marrow - B cell lymphopenia and hypogammaglobulinemia, frequently requiring IVIG QC result: Pass.

377: ProteomeLM — proteome-scale language modeling for interactomes and essential genes

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.

376: Pfh1's Balancing Act: Unwinding, Rewinding, and the Role of Mitochondrial SSB

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.

375: Biallelic DSCAM LoF: a syndromic NDD with nystagmus and cone-pathway retinal dysfunction

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.

374: DNA-guided Cas12a reprogrammed to target RNA

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.