Base by Base

Marchi F et al., Nature Communications - This study builds the Acute Leukemia Methylome Atlas (ALMA) from 3,314 patient methylomes and presents three models—ALMA Subtype, AML Epigenomic Risk, and a 38‑CpG signature—that classify WHO2022 subtypes and predict 5‑year survival. The authors also demonstrate a nanopore-based specimen‑to‑result workflow for combined genome and epigenome profiling. Key terms: acute myeloid leukemia, DNA methylation, epigenomics, nanopore sequencing, machine learning.

Study Highlights:
The authors harmonized DNA methylation from 3,314 leukemia patient samples (331,556 CpGs) to create ALMA and a PaCMAP‑based representation that supports supervised classifiers. ALMA Subtype accurately stratifies 27 WHO2022 diagnostic subtypes and the AML Epigenomic Risk model predicts 5‑year overall survival with validation across independent pediatric and adult cohorts. A 38‑CpG prognostic signature derived by EWAS and penalized Cox modeling predicts 5‑year OS and remains independently prognostic after multivariable adjustment. A rapid long‑read nanopore specimen‑to‑result protocol on 20 specimens showed high concordance between epigenomic signatures and genomic lesions, with limitations for rare subtypes and very low coverage.

Conclusion:
ALMA and its derived models demonstrate that DNA methylation profiling, combined with machine learning and a nanopore specimen‑to‑result workflow, can improve diagnostic subtyping and 5‑year prognostication in AML, though broader training data and prospective validation are needed for rare subtypes.

Music:
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Article title:
Epigenomic diagnosis and prognosis of Acute Myeloid Leukemia

First author:
Marchi F

Journal:
Nature Communications

DOI:
10.1038/s41467-025-62005-4

Reference:
Marchi F. et al., Epigenomic diagnosis and prognosis of Acute Myeloid Leukemia. Nature Communications (2025). doi:10.1038/s41467-025-62005-4

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/alma-epigenomic-aml-episode-100

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

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's presentation of ALMA atlas construction, subtype and risk modeling, 38-CpG signature, nanopore specimen-to-result workflow, and discussed limitations. Compared these to the canonical article text.
- transcript topics: ALMA atlas construction and data scale; PaCMAP dimensionality reduction; ALMA Subtype classification across WHO2022; AML Epigenomic Risk prognostic modeling; 38-CpG AML Signature prognostic capability; Nanopore specimen-to-result protocol and clinical validation

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:
- ALMA built from 3314 patient samples across 11 harmonized cohorts (331556 CpGs).
- ALMA Subtype classifies 27 WHO2022 subtypes plus otherwise-normal control with robust cross-cohort performance.
- AML Epigenomic Risk predicts 5-year overall survival; HR ~4.40 in discovery; independent predictor after adjusting for MRD.
- 38-CpG AML Signature predicts 5-year OS; significant HRs across discovery and validation cohorts; independent predictor.
- A 38-CpG panel provides prognostic capacity with simpler data requirements compared to 331K CpGs.
- Specimen-to-result protocol uses long-read nanopore sequencing on small volumes (≈200 µL) with ~48 h turnaround; 20 specimens from 17 patients; concordance with genomic calls obser

QC result: Pass.

Dicke A-K et al., Nature Communications - Proteomics, molecular and genetic analyses identify NXT2 as the predominant NXT protein in the human testis that binds NXF1, NXF2 and NXF3 and associates with nucleoporins. Loss-of-function variants in NXT2 are linked to azoospermia with Sertoli cell-only testes, while an NXF3 LoF causes severe sperm defects. Key terms: NXT2, NXF3, RNA export, azoospermia, spermatogenesis.

Study Highlights:
Proteomic pulldowns from adult human testis reveal NXT2 enrichment together with NXF1, testis-specific paralogs NXF2 and NXF3, and multiple nucleoporins, suggesting a testis-adapted mRNA export complex. Co-immunoprecipitation and deletion mapping show binding between NXT2 and NXF2/NXF3 is mediated by NTF2-like domains. Rare hemizygous loss-of-function variants or deletion of NXT2 were found in infertile men with non-obstructive azoospermia and predominant Sertoli cell-only histology, and an NXF3 stop-gain variant is associated with extreme oligoasthenoteratozoospermia. Functional assays in cells and tissue staining corroborate absent or truncated protein expression and link disrupted NXT2/NXF3 activity to impaired germ cell development and spermatogenesis.

Conclusion:
NXT2 is a testis-enriched core component of a human testis-adapted RNA nuclear export factor complex and loss of NXT2 function is strongly associated with disrupted germ cell development and male infertility.

Music:
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Article title:
NXT2 is a key component of the RNA nuclear export factor complex in the human testis and essential for spermatogenesis

First author:
Dicke A-K

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61463-0

Reference:
Dicke A-K, Ahmedani A, Ma L, Herrmann L, van der Heijden GW, Koser SA, Krallmann C, Kalyon O, Xavier MJ, Veltman JA, Kliesch S, Neuhaus N, Kotaja N, Tüttelmann F & Stallmeyer B. NXT2 is a key component of the RNA nuclear export factor complex in the human testis and essential for spermatogenesis. Nature Communications. 2025;16:6254. doi:10.1038/s41467-025-61463-0

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.com/episodes/ep99-nxt2-testis-rna-export

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the portions of the transcript that describe (1) the baseline RNA export pathway, (2) the NXT2-centered testis-specific export complex with NXF2/NXF3 and nucleoporins, (3) the genetic evidence from MERGE/Nijmegen cohorts linking NXT2 LoF to azoospermia and SCO, (4) the NXF3 LoF case and its phenotype, (5) LOEUF
- transcript topics: NXT2 as a testis-specific RNA export component; NXT2 interaction with NXF2 and NXF3 via NTF2-like domains; NXT2 predominance in adult human testis vs NXT1; Genetic evidence: NXT2 loss-of-function variants associated with azoospermia and Sertoli cell-only histology; NXF3 loss-of-function and extreme oligoasthenoteratozoospermia; Temporal expression: NXT2 in fetal germ cells; NXF3 in post-meiotic germ cells

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:
- NXT2 is a key component of the RNA nuclear export factor complex in the human testis
- NXT2 binds NXF2 and NXF3 via the NTF2-like domains; this interaction is domain-dependent
- NXT2 is the predominant NXT protein in the adult human testis; NXT1 is not part of the NXT2–NXF interaction network
- Loss-of-function variants in NXT2 are associated with azoospermia and Sertoli cell-only histology
- NXF3 loss-of-function variant linked to extreme oligoasthenoteratozoospermia
- LOEUF score for NXT2 indicates strong intolerance to loss-of-function variants

QC result: Pass.

Busarello E et al., Nature Communications - This episode covers the Cell Marker Accordion, an integrated marker database plus R package and Shiny app that weights marker genes by specificity and evidence consistency to deliver faster, more accurate and interpretable cell-type annotations in single-cell and spatial datasets, including disease contexts. Key terms: single-cell, spatial-omics, cell-type annotation, marker-database, disease-biomarkers.

Study Highlights:
The authors built the Cell Marker Accordion by integrating 23 marker gene sources and standardizing nomenclature to the Cell Ontology and Uberon. Markers are weighted by specificity and an evidence consistency score to produce gene- and cell-type impact metrics used for annotation. Benchmarking across multiple human and murine single-cell and spatial datasets showed an average ~23% improvement in annotation accuracy versus other marker-based tools and much faster runtimes. The tool additionally identifies disease-critical cells, extracts altered marker signatures, and highlights pathway activation and cell-cycle changes.

Conclusion:
The Cell Marker Accordion is a fast, flexible, and interpretable platform that standardizes and improves annotation of single-cell and spatial omics in health and disease, enabling detection of disease-critical cells and candidate biomarkers.

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

Article title:
Cell Marker Accordion: interpretable single-cell and spatial omics annotation in healthand disease

First author:
Busarello E

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60900-4

Reference:
Busarello E., Biancon G., Cimignolo I., et al. Cell Marker Accordion: interpretable single-cell and spatial omics annotation in healthand disease. Nature Communications (2025). DOI: 10.1038/s41467-025-60900-4

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/cell-marker-accordion

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments describing the Cell Marker Accordion platform, marker weighting (SPS/ECs), use of positive/negative markers, benchmarking results (accuracy and speed), and disease-related findings (AML LHSCs, glioblastoma, MDS, METTL3 innate immunity). Cross-checked with canonical article.
- transcript topics: Marker database inconsistencies across reference sources; Cell Marker Accordion platform: integration and ontology standardization; Marker weighting: specificity score (SPS) and evidence consistency score (ECs); Positive and negative markers and their impact on annotation; Benchmark results: accuracy improvement and speed; Disease-focused applications and interpretable outputs

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:
- Integrates 23 marker databases and standardizes to Cell Ontology and Uberon
- Uses specificity score (SPS) and evidence consistency score (ECs) to weight markers
- Considers both positive and negative markers in annotation
- Benchmark shows ~23% average improvement in annotation accuracy across multiple datasets and very fast runtimes (~2 minutes)
- Identifies disease-critical cell types and pathways (e.g., AML LHSCs, neoplastic monocytes, glioblastoma, lung adenocarcinoma, MDS, METTL3-related innate immunity)
- Provides interpretable outputs detailing genes/pathways driving annotations

QC result: Pass.

️ Episode 97: Pancreatic Cancer Genomics: Insights from the COMPASS Trial

In this episode of PaperCast Base by Base, we explore how integrated whole genome and transcriptome sequencing uncovers clinically relevant subtypes and molecular features in advanced pancreatic ductal adenocarcinoma (PDAC).

Study Highlights:

The COMPASS trial profiled 268 advanced PDAC patients, generating whole genome and RNA sequencing data before chemotherapy initiation. Distinct subgroups emerged, including KRAS wild-type cases with BRAF alterations and homologous recombination-deficient (HRD) tumors enriched for mutational signature SBS3 and high HRDetect scores. Patients with basal-like subtypes and elevated systemic inflammation (GRIm-S high) had significantly poorer outcomes, despite transcriptional signs of immune infiltration. KRAS allelic imbalance, especially major imbalances, associated with worse overall survival and higher prevalence of pre-existing diabetes.

Conclusion:

This large prospective genomic profiling effort reinforces the need for subtype-specific therapeutic strategies and shows how integrating molecular and clinical data can inform precision oncology in PDAC.

Reference:

Knox, J. J., Jang, G. H., Grant, R. C., Zhang, A., Ma, L., et al. (2025). Whole genome and transcriptome profiling in advanced pancreatic cancer patients on the COMPASS trial. Nature Communications, 16, 5919. https://doi.org/10.1038/s41467-025-60808-z

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/

️ Episode 96: Early Cerebrospinal Fluid Proteomic Changes in Down Syndrome and Alzheimer’s Disease

In this episode of PaperCast Base by Base, we explore a large-scale proteomic study comparing cerebrospinal fluid (CSF) profiles in individuals with Down Syndrome (DS), late-onset Alzheimer’s disease (LOAD), and autosomal dominant Alzheimer’s disease (ADAD). This study uncovers unique and shared molecular signatures across these conditions, with a particular focus on the early and progressive changes in DS-associated Alzheimer’s disease (DSAD).

Study Highlights:

Using tandem mass tag mass spectrometry, researchers profiled over 1000 proteins in CSF from 365 individuals, including 229 with DS across different stages of cognitive decline. They found that most proteomic alterations in DS occurred before the onset of Alzheimer’s symptoms and were linked to immune response, extracellular matrix remodeling, and plasma proteins, suggesting early disruption of the blood-brain barrier. Compared to LOAD and ADAD, DS showed earlier and more severe alterations in markers of white matter degeneration, synaptic dysfunction, and cerebral amyloid angiopathy. Protein co-expression network analysis identified modules correlated with disease progression and highlighted chromosome 21–encoded proteins and immune-related pathways as key features of DSAD. Notably, proteins like MFGE8 and NEFL changed earlier in DS than in ADAD, revealing a distinct temporal molecular trajectory.

Conclusion:

These findings demonstrate that Down Syndrome–associated Alzheimer’s disease has unique early molecular signatures that may inform tailored therapeutic approaches and improve clinical trial design.

Reference:

Johnson E.C.B., Fortea J., et al. Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer’s disease. Nature Communications. 2025;16:6003. https://doi.org/10.1038/s41467-025-61054-z

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/

Kubat GB et al., Nature Communications - This Perspective surveys recent biotechnological advances that enhance mitochondria transfer and transplantation (MTT) — including surface functionalization, extracellular and engineered vesicles, hydrogels and nanomotors — and evaluates their therapeutic promise and limitations across cardiac, neural and other models. Key terms: mitochondrial transplantation, nanotechnology, extracellular vesicles, delivery systems, therapeutic potential.

Study Highlights:
The article reviews delivery strategies (CPPs, TPP/dextran coatings, EVs, liposomes, hydrogels, nanomotors) that increase mitochondrial protection, cellular uptake and tissue targeting in preclinical models. Encapsulation in EVs or lipid bilayers preserves mitochondrial integrity under Ca2+ and oxidative stress and improves functional rescue compared with naked mitochondria. Key translational barriers include immune activation, short post-isolation mitochondrial lifespan, low targeting efficiency across barriers like the BBB, and scalability and regulatory challenges.

Conclusion:
Biotechnology-enabled delivery systems substantially improve MTT efficacy in preclinical settings, but immune, mechanistic, scalability and safety issues must be resolved before routine clinical use.

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

Article title:
Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation

First author:
Kubat GB

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61239-6

Reference:
Kubat GB, Picone P, Tuncay E, et al. Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation. Nature Communications. 2025;16:5709. doi:10.1038/s41467-025-61239-6

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

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/mitochondria-transfer-transplantation-biotech-potential

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s sections describing mitochondrial transfer strategies and barriers, including surface modification, extracellular and engineered vesicles, hydrogels, and oral nanomotorized mitochondria, plus BBB/clinical translation considerations.
- transcript topics: Barriers to mitochondrial transplantation (immune recognition, extracellular hostile environment, barriers like the BBB); Surface modification strategies (CPPs; Pep-1; TAT-dextran; Dex-TPP coatings); Natural and engineered extracellular vesicles as delivery vehicles (EVs, AM-Mito, liposomes, synaptosomes, FMCs); Hydrogels and other local delivery systems (PF127 hydrogel, xyloglucan, alginate-based hydrogels); Oral nanomotorized mitochondria (CM/NM/Mito@Cap) and targeted cardiac delivery; BBB crossing challenges and systemic delivery limitations

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:
- Delivery strategies summarized: surface modification, extracellular vesicles, engineered vesicles, hydrogels, and oral nanomotors
- Exogenous mitochondria can fuse with host mitochondrial networks or be degraded via lysosomal pathways
- Oral nanomotorized mitochondria achieved ~7.9% cardiac tissue delivery versus ~1.0% for non-motorized controls
- Pep-1 and TAT-based surface modifications increase uptake; Dex-TPP coating reduces negative surface charge and enhances internalization
- AM-Mito encapsulation efficiency reported as ~86% with higher neuronal uptake
- EV encapsulation preserves mitochondrial function under Ca2+ and ROS stress for up to ~24 hours

QC result: Pass.

Mizuno K et al., Nature Communications - Multi-omic profiling (DNA methylation, RNA-seq, H3K27ac and H3K27me3) of 98 metastatic CRPC samples from 35 patients reveals patient-specific epigenetic signatures and methylation-driven regulation of lineage genes and therapeutic targets. Integrative analyses identify >21,000 region–gene links and highlight intraindividual heterogeneity including double-negative tumors with BMP4 signaling or immune-high profiles. Key terms: DNA methylation, castration-resistant prostate cancer, neuroendocrine prostate cancer, H3K27ac/H3K27me3, epigenetic heterogeneity.

Study Highlights:
The study profiled 98 metastatic tumor samples from 35 patients using RRBS/ERRBS, RNA-seq and H3K27ac/H3K27me3 ChIP-seq or CUT&Tag and found DNA methylation patterns were generally conserved within patients across metastases. Integrative analyses produced 21,721 significant methylation region–gene links implicating epigenetic regulation of lineage genes (e.g., ASCL1, AR) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Five patients showed intraindividual molecular subtype heterogeneity, and double-negative CRPC samples segregated into BMP4-activated or immune-enriched subsets. Functional inhibition of BMP4 signaling reduced viability in a DN model cell line (DU145), supporting pathway relevance.

Conclusion:
Integration of DNA methylation with transcriptomic and histone mark data reveals patient-specific epigenetic landscapes that drive phenotypic diversity in advanced prostate cancer and identify methylation-linked mechanisms regulating lineage programs and therapeutic target expression, with potential implications for biomarker development and targeted therapy selection.

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

Article title:
Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer

First author:
Mizuno K

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60654-z

Reference:
Mizuno K., Ku S-Y., Venkadakrishnan VB., et al. Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer. Nature Communications (2025). DOI: https://doi.org/10.1038/s41467-025-60654-z

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/ep94-intraindividual-epigenetic-heterogeneity-advanced-prostate-cancer

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-02.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited portions describing study design and cohorts, multi-omics methods, DNA methylation–gene expression links, intraindividual heterogeneity and subtypes, BMP4/immune pathways, and BMP4 inhibition functional data.
- transcript topics: Study cohort and rapid autopsy samples; Multi-omics profiling (RRBS/ERRBS, RNA-seq, H3K27ac, H3K27me3, CUT&Tag/ChIP-seq); DNA methylation–gene expression links and epigenetic regulation; Intraindividual heterogeneity and molecular subtypes (AR+/NE-, AR-/NE-, double-negative); BMP4 signaling and immune-high double-negative CRPC; Functional validation of BMP4 pathway inhibition in DU145 (LDN-193189)

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:
- 98 tumor samples from 35 patients were analyzed (including 21 rapid autopsies).
- Multi-omic profiling was performed using RRBS/ERRBS, RNA-seq, and histone marks H3K27ac/H3K27me3 (ChIP-seq/CUT&Tag).
- 21,721 significant region–gene links connecting DNA methylation to gene expression were identified.
- Global DNA methylation patterns were generally conserved across metastases within the same patient; intraindividual heterogeneity observed in five patients with different subtypes
- Double-negative CRPC (AR−/NE−) tumors exhibited two distinct pathways: BMP4 signaling activation and immune-high signatures.
- LDN-193189 (BMP4 receptor inhibitor) reduced DU145 cell viability by 68% and decreased phospho-SMAD1/5 levels.

QC result: Pass.

Tipih T et al., Nature Communications - Comparative mouse study finds a dairy-cow-derived H5N1 clade 2.3.4.4b (genotype B3.13) isolate is highly virulent, producing rapid respiratory failure, systemic spread, and neurologic disease with high lung and brain viral loads and inflammatory responses. Key terms: H5N1, clade 2.3.4.4b, bovine isolate, neuroinvasion, mouse model.

Study Highlights:
Researchers compared bovine, mountain lion, mink and reference VN1203 H5N1 isolates in C57BL/6J and BALB/c mice using intranasal and orogastric inoculation. The bovine isolate caused uniformly lethal, rapid disease and clear neurologic signs in C57BL/6J mice with high lung and brain titers. Brain tissue from bovine-isolate infected mice showed elevated pro-inflammatory cytokines despite limited histologic lesions. BALB/c mice were more susceptible to respiratory disease but showed less neurologic manifestation, indicating strain-dependent outcomes.

Conclusion:
A bovine clade 2.3.4.4b H5N1 isolate (genotype B3.13) demonstrates enhanced neuroinvasion and virulence in mice, supporting the use of C57BL/6J and BALB/c models for countermeasure testing and highlighting the need to monitor mammalian-adapted phenotypes.

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

Article title:
Highly pathogenic avian influenza H5N1 clade 2.3.4.4b genotype B3.13 is highly virulent for mice, rapidly causing acute pulmonary and neurologic disease

First author:
Tipih T

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60407-y

Reference:
Tipih T., Mariaappan V., Yinda K.C., Meade-White K., Lewis M., Okumura A., McCarthy N., Altynova E., Leventhal S.S., Bushmaker T., Clancy C.S., de Wit E., Munster V.J., Feldmann H. & Rosenke K. Highly pathogenic avian influenza H5N1 clade 2.3.4.4b genotype B3.13 is highly virulent for mice, rapidly causing acute pulmonary and neurologic disease. Nature Communications (2025) 16:5738. DOI: 10.1038/s41467-025-60407-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.com/episodes/base-by-base-ep93-h5n1-bovine-neurovirulence

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-01.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of the article's key experimental design (two mouse strains, two infection routes), main results (bovine isolate virulence, neuroinvasion, brain viral loads, cytokine response, tissue tropism, LD50), genetic determinants (M1/NS1 mutations; absence of PB2 E627K; NA stalk status), and pu
- transcript topics: Background and public health context of H5N1 clade 2.3.4.4b; Experimental design: mouse strains, infection routes, and isolates; Bovine isolate virulence and neuropathogenesis in mice; Brain infection without histological brain lesions and cytokine responses; Tissue tropism and systemic infection (lung, brain, blood); Genetic determinants of virulence (M1/NS1 mutations; PB2 E627K absence; NA stalk; NS1 deletion absence)

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:
- Bovine OH/2024 isolate caused rapid, uniform lethality in mice via intranasal and orogastric routes
- Neuroinvasion occurred in C57BL/6J mice with high brain viral loads and pro-inflammatory cytokine responses, and neurologic signs
- BALB/c mice showed faster fatal respiratory disease but fewer neurologic signs than C57BL/6J mice
- LD50 for bovine isolate: 1.8 TCID50 in BALB/c; 3.2 TCID50 in C57BL/6J
- Orogastric exposure resulted in systemic infection and was lethal for the bovine isolate
- Bovine isolate harbors mutations in M1 (e.g., 30D, 43M, 215A) and NS1 (e.g., 42S, 103F, 106M); lacks PB2 E627K mutation and NS1 linker deletion; NA stalk region is full-length

QC result: Pass.

Nature Communications - A FinnGen-based genetic and functional study identifies CFHR5 loss-of-function variants as independently protective against age-related macular degeneration and links reduced FHR-5 to altered complement activity and preserved photoreceptor structure. Key terms: CFHR5, age-related macular degeneration, FinnGen, complement system, FHR-5.

Study Highlights:
A GWAS and fine-mapping in 12,495 AMD cases and 461,686 controls deconvoluted four protective CFH-region haplotypes, two of which are driven by CFHR5 coding variants enriched in Finns. Carriers of a CFHR5 frameshift show dose-dependent loss of circulating FHR-5 and reduced FHR-2 and FHR-4 levels confirmed by SomaScan and Western blot. Functional assays indicate increased classical and alternative complement pathway activation capacity in CFHR5 frameshift homozygotes. UK Biobank retinal OCT analyses show CFHR5 loss-of-function carriers have photoreceptor layer changes consistent with protection from AMD.

Conclusion:
Genetic loss of CFHR5 function reduces FHR-5 levels, modulates complement activation, associates with protective retinal morphology, and identifies FHR-5 downregulation as a promising therapeutic target for AMD.

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

Article title:
Loss of CFHR5 function reduces the risk for age-related macular degeneration

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61193-3

Reference:
https://doi.org/10.1038/s41467-025-61193-3

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/cfhr5-loss-reduces-amd-risk

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-31.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the sections describing CFHR5 loss-of-function (fs), dose-dependent FHR-5 reduction and FHR-2/FHR-4 reductions, increased CP/AP complement activation, thicker photoreceptor layers on OCT, recall-by-genotype proteomics, and therapeutic implications; excluded non-scientific intro/outro and unrelated material.
- transcript topics: Overview of age-related macular degeneration (AMD) and forms; CFH/CFHR gene locus and CFHR5 focus; FinnGen cohort, population bottlenecks, and fine-mapping; CFHR5 frameshift variant and dose-dependent protein reductions; Proteomics: SomaScan measurements of FHR proteins; Complement pathways activation (classical, alternative, LP)

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:
- CFHR5 frameshift (fs) variant carriers show dose-dependent reductions in FHR-5 serum levels
- CFHR5 fs carriers also exhibit reduced levels of FHR-2 and FHR-4
- CFHR5 fs carriers have higher capacity to activate classical and alternative complement pathways
- CFHR5 fs carriers show thicker/healthier photoreceptor layers on OCT imaging
- Recall-by-genotype study in FinnGen with ~399 participants; AMD protection linked to CFHR5 fs
- CFH haplotypes contribute major AMD risk signals; CFHR5 signals show independent, additive protection

QC result: Pass.

Sharapov S et al., Nature Communications - This episode examines a large multi-cohort GWAS of the human plasma N-glycome (N≈10,764) that maps genetic regulation of protein N‑glycosylation. The study doubles known glyQTLs, prioritizes candidate genes expressed in liver and lymphoid tissue, integrates glycomics, proteomics and transcriptomics, and explores links to metabolic, liver and inflammatory diseases. Listeners will hear how tissue-specific regulatory networks and Mendelian randomization analyses nominate glycan biomarkers and mechanistic leads. Key terms: N-glycosylation, GWAS, liver disease, glycoproteins, glycomics.

Study Highlights:
Researchers performed the largest GWAS/meta-analysis of total plasma N-glycome in ~10,000 people and identified 40 replicated glyQTLs, including 25 loci newly associated with total plasma N-glycosylation. Using eight prioritization criteria they nominated 31 candidate genes and highlighted 13 novel genes—such as GCKR, TRIB1, HP, SERPINA1 and CFH—predominantly expressed in liver and linked to lipid metabolism and anti-inflammatory proteins. Network and colocalization analyses revealed strong tissue-specific regulation separating liver-secreted and immunoglobulin-linked glycans, and polygenic-score and Mendelian-randomization analyses connected high‑mannose glycans to lipid disorders and M6 glycans to asthma. The integrated resource supports discovery of glycan-based biomarkers and provides mechanistic hypotheses connecting glycosylation, liver disease, and inflammation.

Conclusion:
A comprehensive GWAS and multi-omics integration reveal extensive, tissue-specific genetic regulation of plasma N-glycosylation, nominate novel liver- and inflammation-related genes, and provide candidate glycan biomarkers and causal links to metabolic, liver and immune-related diseases.

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

Article title:
A genome-wide association study in 10,000 individuals links plasma N-glycome to liver disease and anti-inflammatory proteins

First author:
Sharapov S

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60431-y

Reference:
Sharapov S, Timoshchuk A, Zaytseva O, et al. A genome-wide association study in 10,000 individuals links plasma N-glycome to liver disease and anti-inflammatory proteins. Nature Communications. 2025;16:5525. doi:10.1038/s41467-025-60431-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.com/episodes/ep91-plasma-n-glycome-liver-links

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s coverage of glycosylation biology, study design and scale, glyQTL discovery and gene prioritization, tissue-specific regulation, Mendelian randomization and causal links to disease, biomarkers (A3G3S3/AST), and study limitations.
- transcript topics: Basics of protein N-glycosylation and glycans; Study design: GWAS meta-analysis of total plasma N-glycome; GlyQTL discovery and candidate gene prioritization; Tissue-specific regulation in liver vs immunoglobulins (lymphoid tissue); Mendelian randomization and causal links to liver, cardiovascular, and respiratory diseases; Biomarkers: A3G3S3 and AST

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:
- Total participants ~10,764 across seven studies; predominantly European ancestry
- 117 N-glycome traits analyzed (36 measured, 81 derived)
- 40 glyQTLs identified; 25 novel loci; 16 novel loci discovered; 13 prioritized genes (e.g., GCKR, TRIB1, HP, SERPINA1, CFH)
- Two tissue-specific regulatory subnetworks: liver-produced glycans vs immunoglobulin glycans; FUT8 shows tissue-specific regulation with distinct mechanisms
- Mendelian randomization indicates causal links: lipoprotein metabolism disorders affect M9/Mtotal; M6 glycan associated with asthma; bidirectional analyses
- A3G3S3 glycan associated with AST as a potential biomarker for liver pathogenesis

QC result: Pass.