Base by Base

Gustavo Barra
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

  1. 1 DAY AGO

    262: Human Langerhans cells reprogrammed by tick saliva (CXCR4/CCR7 migration and IDO1/IRF4 tolerance)

    Strobl et al., & Stary, G. Human epidermal Langerhans cells induce tolerance and hamper T cell function upon tick-borne pathogen transmission. Nature Communications - Human epidermal Langerhans cells exposed to Ixodes ricinus tick saliva and Borrelia burgdorferi adopt a tolerogenic state with CXCR4/CCR7-driven emigration that impairs T cell priming. Study Highlights: The study uses clinical human tick bite biopsies, an ex vivo human skin tick bite model, in vitro monocyte- and CD34-derived Langerhans cells, immune spheroid cultures and single-cell RNA-sequencing of erythema migrans lesions, employing imaging, migration assays, co-cultures and scRNA-seq. Tick salivary gland extract (SGE) up-regulates CXCR4 and CCR7 on LCs, promotes emigration from the epidermis into dermis and lymphatic vessels, and reduces keratinocyte TGF-β consistent with migration. SGE and Borrelia burgdorferi drive up-regulation of tolerogenic transcription factors IDO1 and IRF4 while blunting immunogenic IRF1/NFκB programs, and SGE-primed LCs induce Treg and Th2 bias with reduced Tfh, Th17 and Th9 induction. Functionally, these changes dampen protective adaptive responses in lymphoid models and in patient lesions, which may reduce bacterial clearance and memory formation. Conclusion: Tick saliva reprograms human epidermal Langerhans cells to migrate to lymphatics and adopt a tolerogenic program that impairs protective T cell responses and may facilitate Borrelia transmission. Music: Enjoy the music based on this article at the end of the episode. Reference: Strobl, J., Kleissl, L., Eder, J., Conolly, S., Frey, T., Gail, L. M., Kopf, A., Weninger, S., Markowicz, M., Bartíková, P., Freystätter, C., Schmetterer, K., Strobl, H., Stockinger, H., Wijnveld, M. & Stary, G. Human epidermal Langerhans cells induce tolerance and hamper T cell function upon tick-borne pathogen transmission. Nature Communications. 2025. https://doi.org/10.1038/s41467-025-66821-6 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/langerhans-tick-saliva-tolerance

    22 min

  2. 2 DAYS AGO

    261: MHz-XPCS reveals anomalous ferritin diffusion and nanoscale cage trapping

    Girelli et al., Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions. Nat Commun ( - MHz-XPCS of ferritin solutions at EuXFEL shows anomalous, cage-trapped protein diffusion with reduced long-time transport and ~1.2 nm rattling at high concentration. Study Highlights: The study probes crowded ferritin solutions using megahertz X-ray Photon Correlation Spectroscopy (MHz-XPCS) at EuXFEL combined with SAXS and δγ-theory modeling. Intensity autocorrelation functions g2(q,t) become non-exponential at high concentrations, and double-exponential analysis yields short- and long-time diffusion components with Dlong/Dshort ≈ 0.12 ± 0.04 at 730 mg/ml and an interaction time estimated near 4.25 µs. δγ-theory of hydrodynamically interacting spheres reproduces the q-dependent hydrodynamic function only when a scaling factor tied to direct protein interactions is included, indicating hydrodynamics set the q-dependence while direct forces reduce overall self-diffusion. Cage analysis finds an average rattling displacement δ ≈ 1.0 ± 0.3 nm for ≈89% of proteins, implying cage-trapping substantially slows molecular transport with consequences for ferritin-based drug delivery. Conclusion: MHz-XPCS measurements and δγ-theory modeling demonstrate that crowded ferritin solutions exhibit anomalous, cage-trapped diffusion with separate short- and long-time components and markedly reduced self-diffusion, indicating slower molecular transport under crowding. Music: Enjoy the music based on this article at the end of the episode. Reference: Girelli, A., Bin, M., Filianina, M. et al. Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66972-6 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/ferritin-anomalous-diffusion-xpcs

    16 min

  3. 3 DAYS AGO

    260: TSS hypermutability in human germline linked to RNAP II stalling, R-loops and early embryonic mosaics

    Cortés Guzmán M et al., Nat Commun - Human germline transcription start sites show a hotspot of non-CpG variants driven by the early embryonic mosaicism, RNAP II stalling, R-loops and mitotic DSBs. Study Highlights: The authors analysed extremely rare variants from gnomAD and UK Biobank, de novo mutations from family sequencing, mosaic variant catalogs, and pan-cancer somatic data to map mutation density around transcription start sites in humans. They used 5-mer sequence-context normalization, negative binomial regression with 38 genomic and epigenetic covariates, PRO-seq and somatic DSB maps, and mutational-signature decomposition to identify drivers. They report a pronounced TSS hotspot of non(CpG>TpG) ERVs reaching ~14% excess at 1 kb and up to ~35% in the first 100 bp, and a 52% enrichment of early embryonic mosaic variants immediately downstream of the TSS. Mechanistic associations implicate divergent transcription, RNAP II stalling, R-loops and mitotic double-strand breaks, and the hotspot disproportionately affects genes linked to cancer and developmental phenotypes. Conclusion: Transcription start sites are a distinct germline mutational hotspot enriched for early embryonic mosaic variants and transcription- and mitosis-associated DNA damage and repair processes. Music: Enjoy the music based on this article at the end of the episode. Reference: Cortés Guzmán M, Castellano D, Serrano Colomé C, Seplyarskiy V & Weghorn D (2025) Transcription start sites experience a high influx of heritable variants fueled by early development. Nature Communications 16:10120. https://doi.org/10.1038/s41467-025-66201-0 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.castos.com/episodes/tss-germline-hotspot-rnapii

    16 min

  4. 4 DAYS AGO

    259: Ku filaments that hold DNA together

    Zahid S et al., Nat Commun - Cryo-EM and biophysical analyses show Mycobacterium tuberculosis Ku assembles into DNA-bound oligomeric filaments that synapse DNA ends and are required for survival under DNA-damaging conditions. Study Highlights: Deletion of ku in M. smegmatis causes marked survival defects after methyl methanesulfonate exposure and desiccation that are rescued by complementation. Cryo-EM structures of apo-Ku-Mtb (4.04 Å) and DNA-bound Ku-Mtb (2.96 Å) reveal a homodimer that assembles into extended filaments with a minimal repeating unit of two homodimers per DNA duplex. Biophysical assays (mass photometry, FIDA, AFM) and positive-stain EM confirm DNA-induced oligomerisation and show Ku can circularize DNA ends, holding them ~40 Å apart. Mutation of hydrophobic loop residues L13/V14 abolishes filament formation while preserving DNA binding and reduces bacterial survival, and the C-terminal α-helix blocks the filament interface in the apo state and is displaced on DNA binding to enable LigD recruitment. Conclusion: Ku oligomerisation mediates DNA end synapsis during bacterial NHEJ and is critical for mycobacterial survival under DNA-damaging stresses Music: Enjoy the music based on this article at the end of the episode. Reference: Zahid S, Baconnais S, Smith H, Atwal S, Bates L, Read H, Chadda A, Morati F, Stender EGP, Westerlund F, Galburt E, Mukamolova GV, Chaplin AK, et al. Oligomerisation of Ku from Mycobacterium tuberculosis promotes DNA synapsis. Nature Communications. 2025;16:10568. https://doi.org/10.1038/s41467-025-65609-y 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.castos.com/episodes/ku-mtb-dna-synapsis

    18 min

  5. 4 DAYS AGO

    258: Correcting GC bias in metagenomes

    Holcik L et al., Genomic GC bias correction improves species abundance estimation from metagenomic data. Nature Communications - GuaCAMOLE is an alignment-free algorithm that estimates and removes genomic GC-content-dependent sequencing bias to produce more accurate species abundance estimates from single metagenomic samples. Key terms: GC bias, metagenomics, species abundance, GuaCAMOLE, colorectal cancer. Study Highlights: GuaCAMOLE combines Kraken2/Bracken read assignment with per-taxon GC binning and a regularized least-squares estimator to infer GC-dependent sequencing efficiencies and bias-corrected abundances from a single sample. On simulations and mock communities across 28 library protocols it produced near-unbiased estimates and outperformed Bracken and MetaPhlAn4 when GC bias was present. Application to 3,435 gut microbiomes from 33 colorectal cancer studies revealed four distinct protocol-specific GC-bias shapes and systematic underestimation of GC-poor taxa. The tool also filters false-positive taxa by comparing observed and expected GC distributions and can apply inferred efficiencies to correct other tools' outputs. Conclusion: Per-sample GC-bias correction with GuaCAMOLE improves accuracy and comparability of metagenomic species abundance estimates across diverse protocols Music: Enjoy the music based on this article at the end of the episode. Reference: Holcik L., von Haeseler A., Pflug F. G. Genomic GC bias correction improves species abundance estimation from metagenomic data. Nature Communications. 2025;16:10523. https://doi.org/10.1038/s41467-025-65530-4 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.castos.com/episodes/gc-bias-correction-metagenomics Episode Slug: gc-bias-correction-metagenomics

    17 min

  6. 6 DAYS AGO

    257: PSMC5: proteasomes, immunity and neurodevelopment

    Küry S et al., Nat Commun - This study describes 26 distinct PSMC5 variants in 44 individuals and demonstrates that PSMC5 loss impairs proteasome function, driving proteotoxic stress, mitochondrial and lipid dysregulation, sterile type I interferon activation, and neurodevelopmental deficits. Key terms: PSMC5, proteasome, neurodevelopment, interferon, mitophagy. Study Highlights: Twenty-six distinct PSMC5 variants were identified in 44 affected individuals, mostly heterozygous and de novo, clustering in the AAA+ ATPase domain and predicted to be pathogenic. Functional assays and patient T cells show that many variants perturb PSMC5 incorporation into 26S proteasomes, reduce proteasome activity, and increase ubiquitin-positive aggregates and aggresomes. Multi-omics of patient T cells revealed disrupted mitochondrial proteostasis with increased mitophagy, altered glycerophospholipid profiles and impaired ribosome biogenesis. Neuronal models and Drosophila demonstrate reduced excitatory synapses, E/I imbalance, impaired neuritogenesis, deficits in reversal learning and compromised NPC differentiation, while ISR kinases PKR and GCN2 plus cGAS-STING and JAK pathways mediate a spontaneous type I IFN response that can be pharmacologically reduced. Conclusion: PSMC5 variants cause proteasome loss-of-function that links proteotoxic stress to innate immune activation and impaired neurogenesis, identifying ISR and JAK pathway components as potential therapeutic targets. Music: Enjoy the music based on this article at the end of the episode. Reference: Küry S, Bézieau S, Ebstein F, et al. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nature Communications. 2025;16:10545. https://doi.org/10.1038/s41467-025-65556-8 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.castos.com/episodes/psmc5-proteasome-neurodevelopment Episode Slug: psmc5-proteasome-neurodevelopment

    18 min

  7. 6 DAYS AGO

    256: Compartmental control of VSG silencing

    Antunes et al., Chromosome compartment assembly is essential for subtelomeric gene silencing in trypanosomes. Nat Commun ( - The study shows that spatial segregation of core and subtelomeric chromosome compartments, demarcated by protein-rich boundaries and controlled by a phosphoinositide regulator, is required to silence subtelomeric VSG genes. Key terms: RAP1, PIP5Pase, VSG, Hi-C, chromatin. Study Highlights: Hi-C and Pore-C reveal that T. brucei chromosomes are organized into transcribed core (A) and repressed subtelomeric (B) compartments that contain TADs and loops. XLMS and ChIP-seq identify compartment-boundary proteins including RAP1, HDAC1, HAT1 and BDF2, with RAP1 spreading across silent subtelomeric regions. Boundaries from multiple chromosomes co-interact and are enriched for repeat motifs resembling telomeric and centromeric sequences. Inactivation or knockdown of the PIP5Pase regulator disrupts intra-compartment contacts, displaces RAP1 from boundaries and subtelomeres, and activates hundreds of silent VSG genes. Conclusion: Assembly of chromosome compartments and PIP5Pase-regulated RAP1 binding are essential for subtelomeric VSG gene silencing in T. brucei. Music: Enjoy the music based on this article at the end of the episode. Reference: Antunes, L.B., Isebe, T., Kutova, O. et al. Chromosome compartment assembly is essential for subtelomeric gene silencing in trypanosomes. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66824-3 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.castos.com/episodes/compartment-vsg-silencing Episode Slug: compartment-vsg-silencing

    19 min

  8. 10 JAN

    255: Lipids, Ions and the AE1 Elevator

    Chen T et al., Nat Commun - Cryo-EM structures, uptake assays, and molecular dynamics show that PIP2 lipids bind at the AE1 dimer interface and inhibit the OF⇌IF conformational transition while substrate binding lowers the transition barrier. Key terms: AE1, PIP2, bicarbonate transport, cryo-EM, molecular dynamics. Study Highlights: Three high-resolution cryo-EM states were solved: two inward-facing (IF1, IF2) and one outward-facing (OF). Proteoliposome uptake assays show that depleting or masking PIP2 increases HCO3– and I– transport. MD simulations identify recurring anion binding in the lumen with R730 as a key coordinating residue and estimate tighter HCO3– binding than Cl–. Enhanced-sampling free energy profiles reveal that HCO3– binding lowers the OF⇌IF barrier by ~3 kcal/mol while removing PIP2 lowers it by ~2 kcal/mol. Mechanistically, HCO3– stabilizes a transition-state conformation by promoting R730 contact with the scaffold domain. Conclusion: PIP2 stabilizes AE1 in a conformation that raises the transport transition barrier and inhibits activity, whereas substrate binding promotes the transition and facilitates transport. Music: Enjoy the music based on this article at the end of the episode. Reference: Chen T, Vallese F, Gil-Iturbe E, Kim K, Calì T, Quick M, Clarke OB, Tajkhorshid E. Impact of anionic lipids on the energy landscape of conformational transition in anion exchanger 1 (AE1). Nature Communications. 2025. https://doi.org/10.1038/s41467-025-66786-6 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/pipt2-inhibits-ae1 Episode Slug: pipt2-inhibits-ae1

    19 min
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About

Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

Information

  • Creator
    Gustavo Barra
  • Years Active
    2025 - 2026
  • Episodes
    262
  • Rating
    Clean
  • Copyright
    © Gustavo Barra
  • Show Website
    Base by Base