Pimplaskar A et al., The American Journal of Human Genetics - In UCLA ATLAS EHR-linked biobank analyses, random forest-derived enrollment probabilities and inverse-probability weighting increased replication of known GWAS variants and altered PGS associations. Key terms: inclusion bias, UCLA ATLAS, inverse-probability weighting, random forest, polygenic scores.

Study Highlights:
Using the UCLA ATLAS EHR-linked biobank, the authors trained random forest classifiers on demographics, healthcare utilization, and ICD-10 features to distinguish enrolled from background patients. They converted predicted enrollment probabilities into inverse-probability weights and applied these to GWAS replication tests and PGS-PheWAS scans. The classifier achieved AUROC≈0.85 and weighting increased replication of known GWAS variants by 54% while changing phenome-wide PGS association patterns. These results indicate that enrollment-driven inclusion bias can materially affect variant discovery and downstream PGS-based phenotypic associations in health-system biobanks.

Conclusion:
Inclusion bias in EHR-linked biobanks like UCLA ATLAS measurably affects common-variant discovery and PGS associations, and enrollment-aware inverse-probability weighting can improve replication while reducing effective sample size.

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

Article title:
Inclusion bias affects common variant discovery and replication in a health-system linked biobank

First author:
Pimplaskar A

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.02.011

Reference:
Pimplaskar A, Qiu J, Lapinska S, Tozzo V, Chiang JN, Pasaniuc B, Olde Loohuis LM. Inclusion bias affects common variant discovery and replication in a health-system linked biobank. The American Journal of Human Genetics. 2026;113:1–13. https://doi.org/10.1016/j.ajhg.2026.02.011

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/inclusion-bias-ucla-atlas

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing enrollment-bias methodology (random forest classifier, inverse-probability weighting), key numeric results (AUROC/AUPRC, enrollment counts, ORs), GWAS replication improvements, and PGS-PheWAS outcomes, plus implications and limitations.
- transcript topics: Enrollment bias in UCLA ATLAS biobank; Random forest classifier for enrollment prediction; Inverse-probability weighting and normalization; Effective sample size and trade-offs; GWAS variant replication under weighting; Variant-level associations and ancestry effects

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:
- Enrollment in ATLAS: background population ~1.57–1.57 million; enrolled ~104,516
- Primary care at UCLA strongly predicts enrollment: ~70.2% enrolled vs ~21.8% unenrolled; OR ≈ 8.44
- Enrolled individuals have higher healthcare utilization: ~12.8 visits/year vs ~6.7
- RF model discriminates enrollment with AUROC ≈ 0.85 and AUPRC ≈ 0.82
- Inverse-probability weighting reduces effective sample size to ≈11,319.9 (4.3× reduction; from ≈48k)
- Weighting increases replication of known GWAS variants by ≈54%

QC result: Pass.

Mathur Y et al., Nature - Clinical surveillance in Bangladesh shows Vibrio cholerae acquired PLE11 encoding Rta that restricts ICP1 tail assembly, driving a selective sweep of phage-resistant strains. Key terms: Vibrio cholerae, ICP1, PLE11, Rta, phage coevolution.

Study Highlights:
This study analysed clinical Vibrio cholerae and ICP1 isolates from stool in Bangladesh using genomic surveillance, plaque assays, qPCR, experimental phage evolution, TEM and mass spectrometry. The authors identify a newly acquired mobile element, PLE11, whose small protein Rta disrupts ICP1 tail assembly by targeting the phage tape measure protein (TMP), producing genome-filled tailless capsids. PLE11 also encodes a TMP and other tail factors enabling assembly of chimeric virions that incorporate PLE-encoded TMP and BhuB, preserving satellite transmission. Continued surveillance documented natural ICP1 counteradaptation via CRISPR–Cas acquisition and convergent TMP substitutions that restore infectivity.

Conclusion:
Acquisition of PLE11 encoding the tail-targeting protein Rta drove selection of phage-resistant Vibrio cholerae in Bangladesh and prompted convergent ICP1 counteradaptations that restore phage propagation.

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

Article title:
Capturing dynamic phage–pathogen coevolution by clinical surveillance

First author:
Mathur Y

Journal:
Nature

DOI:
10.1038/s41586-026-10136-z

Reference:
Mathur Y., Boyd C. M., Farnham J. E., Monir M. M., Islam M. T., Sultana M., Ahmed T., Alam M. & Seed K. D. Capturing dynamic phage–pathogen coevolution by clinical surveillance. Nature (2026). https://doi.org/10.1038/s41586-026-10136-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/ple11-rta-icp1-tail-assembly

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections that discuss the phage–bacteria arms race, PLE11 and Rta, TMP/TAC/BhuB, chimeric tail assembly, phage counterdefenses (CRISPR–Cas, Odn, Adi), and clinical surveillance data from Bangladesh, including outbreak dynamics and convergent evolution.
- transcript topics: Phage–bacteria arms race overview; Phage satellites (PLEs) and anti-PLE strategies; Rta-mediated tail assembly restriction via TMP targeting; Chimeric tail assembly with PLE11-encoded components; ICP1 counterdefenses (CRISPR–Cas, Odn, Adi) and phage evolution; Clinical surveillance in Bangladesh (BD-1.2 sweep, 2022 outbreak)

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:
- Rta (PLE11-encoded) restricts ICP1 tail assembly by targeting TMP
- PLE11 encodes its own TMP and tail assembly factors (TAC) and BhuB to form chimeric tails enabling PLE transmission
- BD-1.2 Vibrio cholerae populations acquired PLE11 and reached ~91% prevalence within 9 months
- ICP1 populations shifted from Odn-mediated resistance to CRISPR–Cas–mediated resistance, with TMP substitutions (e.g., L362P, N355S) observed
- TEM and proteomics show PLE11 tails incorporate PLE11 TMP and BhuB and lack ICP1 TMP/BhuB, producing shorter tails (~10 nm)
- Outbreak in Dhaka, Bangladesh in early 2022 involved >42,000 cholera patients

QC result: Pass.

Rockowitz S et al., Human Genetics and Genomics Advances - Boston Children's Hospital used VS-NN, HPO NLP, and DRAGEN reprocessing in a proactive genomic reanalysis to identify candidate diagnoses in 2% of pediatric ES/GS cases. Key terms: genomic reanalysis, proactive reanalysis, VS-NN, HPO NLP, rare disease diagnostics.

Study Highlights:
The study deployed a centralized Proactive Genomic Reanalysis (PGR) workflow on a Boston Children’s Hospital pediatric ES/GS cohort integrated into the CRDC infrastructure. Key methods combined DRAGEN reprocessing, automated HPO extraction from EHR notes, CFA filtering on the GeneDx research platform and a VS-NN variant-scoring neural network followed by two-pass manual review. Applied to 2,144 previously unsolved cases, the pipeline flagged 310 variants, manual review prioritized 45 variants in 42 patients, and clinicians judged 33 variants to have high suspicion of disease causality, yielding ~2% candidate diagnostic rate. The work shows that institution-led, semi-automated reanalysis can produce clinically actionable findings while reducing reliance on clinician-initiated lab reanalysis, though it requires infrastructure for data transfer, confirmation and patient recontact.

Conclusion:
A centralized, semi-automated, clinically integrated Proactive Genomic Reanalysis workflow at Boston Children’s Hospital is feasible and identified candidate diagnostic variants in 2% of reviewed pediatric ES/GS cases, demonstrating a scalable model that can increase diagnoses while requiring institutional resources for confirmation and recontact.

Music:
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Article title:
Scaling genomic reanalysis to unlock diagnoses and transform rare disease care

First author:
Rockowitz S

Journal:
Human Genetics and Genomics Advances

DOI:
10.1016/j.xhgg.2026.100582

Reference:
Rockowitz S, Shao W, French C, Truong TK, Hagen J, McGonigle R, et al.; and Wendy K. Chung. Scaling genomic reanalysis to unlock diagnoses and transform rare disease care. Human Genetics and Genomics Advances. 2026;7:100582. https://doi.org/10.1016/j.xhgg.2026.100582.

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/proactive-genomic-reanalysis-bch

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the portion of the transcript describing the centralized Proactive Genomic Reanalysis (PGR) workflow, VS-NN AI scoring, NLP-based HPO extraction, CFA/DRAGEN pipelines, pilot results, and implementation challenges including data access and recontact.
- transcript topics: Centralized Proactive Genomic Reanalysis (PGR) workflow; VS-NN variant scoring neural network; HPO NLP and phenotype matching; DRAGEN read mapping and CFA filtering; Two-pass manual review process; Pilot results: dataset size, variant counts, and diagnostic yield

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:
- PGR pipeline yielded a 2% diagnostic rate in the initial pilot
- Pilot dataset: 2,144 patients; 62,637 variants; 310 flagged by VS-NN; 45 returnable in 42 patients; 33 high-suspicion variants
- VS-NN AUC: 0.99 for pathogenic/likely pathogenic (P/LP); 0.94 for variants of uncertain significance (VUS)
- NLP-extracted HPO terms enabled dynamic phenotyping; including NLP terms did not significantly change VS-NN scores

QC result: Pass.

Cromer SJ et al., The American Journal of Human Genetics - This paper reviews polygenic risk scores (PRS) and social determinants of health (SDoH) and outlines best practices for integrating PRS and SDoH across diverse populations to improve prediction and equity. Key terms: polygenic risk scores, social determinants of health, PRS transferability, data harmonization, type 2 diabetes.

Study Highlights:
This review focuses on human populations and uses conceptual frameworks, hypothetical population examples, and synthesis of methodological studies to evaluate PRS and SDoH integration. It summarizes methods for PRS construction and transferability, SDoH measurement at individual and area levels, and analytic approaches including interaction, mediation, and calibration. Quantitatively, the authors note substantial declines in PRS predictive accuracy when applied to genetically distinct populations (for example, African-ancestry performance often ~20–40% of European-derived PRS). The review highlights harmonization, population-specific calibration, and interdisciplinary teams as functional steps to improve predictive validity and reduce inequitable impacts.

Conclusion:
Integrating PRSs with carefully measured and harmonized SDoH across diverse populations requires population-aware conceptual frameworks, calibrated analytic methods, diverse datasets, and ethical safeguards to improve predictive validity and equity.

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

Article title:
Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research

First author:
Cromer SJ

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.02.007

Reference:
Cromer SJ, Cobran EK, Iyer HS, Hysong MR, Vargas LB, Smith JL, Konigsberg IR, Bogumil D, Glover L, King G, PRIMED Consortium SDoH Working Group, Lange LA, Patel A, Wojcik G, Raffield L, Conti DV, et al. Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research. The American Journal of Human Genetics. 2026;113:1–25. https://doi.org/10.1016/j.ajhg.2026.02.007

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/polygenic-risk-sdoh-harmonization

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive sections of the transcript covering PRS basics, PRS transferability across populations, SDoH domains and measurement, harmonization challenges, analytical frameworks (main effects, interactions, mediation), T2D as an illustrative case, and ethical considerations.
- transcript topics: PRS basics and transferability; SDoH four-domain framework (socioeconomic, sociocultural, physical environment, healthcare access); Individual vs area-level SDoH measures; SDoH harmonization across datasets; Analytical frameworks (main effects, interaction/effect modification, mediation); T2D as illustrative example

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:
- PRS predictive accuracy declines across populations; African-ancestry accuracy ~20–40% of European-derived PRS
- SDoH clustering, distribution, and effect sizes vary across populations and can modify PRS effects; harmonization improves transferability
- Ethical and representation issues are critical to study design and interpretation
- Race and ethnicity are socially constructed; genetic similarity is a continuous spectrum
- SDoH measured at individual and area levels across four domains
- Harmonization of SDoH measures is challenging; ecological fallacy cautions apply

QC result: Pass.

Wong BHH et al., Proc. Natl. Acad. Sci. U.S.A - Mouse and human studies show the LPC transporter Mfsd2a enables plasma-derived LPC uptake into keratinocytes, preserving linoleate-rich phosphatidylcholine pools and promoting epidermal differentiation. Key terms: Mfsd2a, lysophosphatidylcholine, keratinocyte differentiation, linoleic acid, lipidomics.

Study Highlights:
Using epidermis-specific (2aEpKO) and conventional (2aKO) Mfsd2a-deficient mice, lineage tracing, untargeted shotgun lipidomics, LightOx-LPC uptake assays, and primary human keratinocyte cultures, the authors mapped Mfsd2a expression to suprabasal/granular keratinocytes and demonstrated Mfsd2a-dependent uptake of plasma-derived LPC in vivo. Lipidomic quantification showed reductions in linoleate-containing phospholipids (PL-18:2 decreased ~15% in 2aEpKO and ~13% in 2aKO) and a marked loss of TAG-18:2 (−79% in 2aEpKO). Inducible epidermal Mfsd2a loss produced transient dermatitis, defective desquamation, retained lamellar bodies, and keratinocyte activation, while MFSD2A knockdown in human keratinocytes reduced LPC-driven differentiation. Functional rescue experiments in vitro revealed that LPC-18:1 and LPC-18:2 promote keratinocyte differentiation in an MFSD2A-dependent manner, linking plasma LPC uptake to epidermal lipid homeostasis and differentiation.

Conclusion:
Mfsd2a mediates uptake of plasma-derived LPC (notably LPC-18:2) into suprabasal keratinocytes to maintain linoleate-containing phospholipid pools and support keratinocyte differentiation and normal desquamation.

Music:
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Article title:
Mfsd2a is important for maintaining epidermal homeostasis

First author:
Wong BHH

Journal:
Proc. Natl. Acad. Sci. U.S.A

DOI:
10.1073/pnas.2531159123

Reference:
Wong BHH, Behmoaras J, Chua AWC, Galam DLA, Tan BC, Torta F, Chin CF, Mishra K, Ding M, Silver DL. Mfsd2a is important for maintaining epidermal homeostasis. Proc. Natl. Acad. Sci. U.S.A. 2026 Feb 19;123(8):e2531159123. https://doi.org/10.1073/pnas.2531159123

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/mfsd2a-lpc-epidermal-homeostasis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-09.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing MFSD2A expression in epidermal keratinocytes, inducible epidermis-specific and conventional Mfsd2a knockout phenotypes, epidermal lipidomics (18:2 species and DAG shifts), LightOx-LPC uptake demonstrating MFSD2A dependence, and MFSD2A-dependent differentiation of human keratin
- transcript topics: MFSD2A expression in differentiated epidermal keratinocytes; Inducible postnatal Mfsd2a deficiency and dermatitis; Conventional Mfsd2a knockout and desquamation defects; Epidermal lipidomics: PL-18:2 and TAG-18:2 reductions; DAG shifts; LPC uptake into epidermis using LightOx-LPC and MFSD2A dependence; MFSD2A-dependent differentiation of human keratinocytes with LPCs

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:
- MFSD2A is predominantly expressed in differentiated epidermal keratinocytes, enriched in the granular layer
- Inducible epidermis-specific Mfsd2a deficiency (2aEpKO) causes dermatitis, defective desquamation, hyperkeratosis, and keratinocyte activation
- Conventional Mfsd2a knockout (2aKO) shows desquamation defects with hyperkeratosis and parakeratosis
- Epidermal lipidome is altered by Mfsd2a deficiency, with reduced PL-18:2 and TAG-18:2 and reciprocal DAG changes
- Plasma-derived LPC uptake into epidermis is MFSD2A-dependent, demonstrated by LightOx-LPC uptake being absent in 2aEpKO/2aKO but present in controls
- LPC18:1 and LPC18:2 promote human primary keratinocyte differentiation in an MFSD2A-dependent manner

QC result: Pass.

Herpe L et al., Proc. Natl. Acad. Sci. U.S.A - CRISPR knockout of Drosophila mtG3PDH (GPO1) reduces ATP production by ~60% and O2 consumption by ~33%, lowering mitochondrial efficiency and ROS emission. Key terms: mtG3PDH, GPO1, Drosophila melanogaster, mitochondrial efficiency, reactive oxygen species.

Study Highlights:
Using CRISPR/Cas9-generated GPO1 mutant Drosophila and isolated thoracic mitochondria, the authors combined enzymatic assays, ATP production and oxygen consumption measurements, and H2O2 emission assays to probe mtG3PDH function. Loss of mtG3PDH markedly reduced mtG3PDH enzymatic activity and drove a ~60% decrease in ATP production and ~33% decrease in O2 consumption, producing a pronounced drop in mitochondrial efficiency (ATP/O). mtG3PDH-linked ROS emission was also strongly reduced (~70%), reflecting diminished direct and reverse electron-transfer ROS generation. Functionally, GPO1 flies showed sharply reduced survival and severe climbing impairment, linking the bioenergetic defects to organismal outcomes.

Conclusion:
mtG3PDH is essential for mitochondrial bioenergetics and redox homeostasis in Drosophila, with GPO1 loss causing major decreases in ATP production, O2 consumption, mitochondrial efficiency, and mtG3PDH-linked ROS that correlate with reduced survival and locomotion.

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

Article title:
When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase

First author:
Herpe L

Journal:
Proc. Natl. Acad. Sci. U.S.A

DOI:
10.1073/pnas.2535701123

Reference:
Herpe L, Aminot M, Pichaud N. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 2026;123(9):e2535701123. https://doi.org/10.1073/pnas.2535701123

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/drosophila-mtg3pdh-gpo1

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-08.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections cover mtG3PDH function, CRISPR/Cas9 GPO1 knockout in Drosophila, thoracic mitochondria bioenergetics (ATP production, oxygen consumption, ATP/O), ROS production and RET, organismal outcomes (lifespan, climbing), and translational implications.
- transcript topics: mtG3PDH shuttle function and GPO1; CRISPR/Cas9 GPO1 knockout in Drosophila; thoracic mitochondria bioenergetics: ATP production; oxygen consumption and coupling efficiency (ATP/O); ROS production and reverse electron transfer; complex I independence and grid collapse

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:
- mtG3PDH knockout reduces ATP production by ~60%
- O2 consumption decreases by ~33%
- mitochondrial efficiency (ATP/O) is markedly reduced (uncoupling observed)
- mtG3PDH-linked ROS emission decreases by ~70%
- survival (median lifespan) drops from ~33 days to ~12 days in GPO1 mutants
- climbing performance declines to ~1% in mutants (vs ~68.5% in controls)

QC result: Pass.

Korpela K et al., Gut Microbes - Review finds maternal fecal microbiota transplantation and targeted probiotics can restore Bifidobacterium and Bacteroides after C‑section or intrapartum antibiotics, with breastfeeding aiding recovery. Key terms: maternal fecal microbiota transplantation, C-section, Bifidobacterium, vaginal seeding, probiotics.

Study Highlights:
This review focuses on term infants, particularly C‑section and intrapartum antibiotic–exposed neonates, synthesizing cohort and intervention data using 16S rRNA gene amplicon sequencing and metagenomic approaches. Maternal fecal microbiota transplantation (maternal FMT) shifted C‑section infants’ gut communities to resemble vaginally born infants and uniquely restored Bacteroidaceae, while a Bifidobacterium–Lactobacillus–FOS supplement increased bifidobacteria; vaginal seeding did not normalize overall gut composition. The authors link restoration of key taxa to potential reductions in risks such as allergy and overweight and emphasize breastfeeding as an essential adjunct to restoration strategies.

Conclusion:
Evidence supports action to address early-life gut microbiota disruption: probiotics and maternal FMT show promising restorative effects, but optimal, scalable solutions and long-term immune outcomes remain to be established.

Music:
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Article title:
Infant gut microbiota restoration: state of the art

First author:
Korpela K

Journal:
Gut Microbes

DOI:
10.1080/19490976.2022.2118811

Reference:
Korpela K, de Vos WM. Infant gut microbiota restoration: state of the art. Gut Microbes. 2022;14(1):e2118811. https://doi.org/10.1080/19490976.2022.2118811

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/maternal-fmt-bifidobacterium-restoration

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing vertical transmission, HMOs and breast milk, birth-mode and antibiotic effects, restoration interventions (vaginal seeding, Lactobacillus probiotics, Bifidobacterium-Lactobacillus-FOS multispecies, maternal FMT), PCA-based analysis, preterm considerations, and long-term health
- transcript topics: Vertical transmission and HMOs feeding infant gut microbes; Birth mode and intrapartum antibiotic effects on microbiota; Microbiota restoration interventions: vaginal seeding, probiotics, multispecies probiotics, maternal FMT; PCA analysis as a measure of restoration efficacy; Bifidobacteriaceae and Bacteroidaceae dynamics across interventions; Preterm infant microbiota and NICU interventions

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:
- Maternal FMT can restore CS-born infant gut microbiota toward vaginal births, with persistence at 1 and 3 months
- Bacteroidaceae restoration is achieved by maternal FMT; other interventions fail to restore this family
- Vaginal seeding does not restore gut microbiota composition (fails to move CS-born infants toward vaginal baseline)
- Lactobacillus-only probiotic shows minimal to no restoration of the gut microbiota in CS-born infants
- Multispecies Lactobacillus–Bifidobacterium–FOS probiotic partially restores gut microbiota toward vaginal composition; benefits observed in larger RCT with reduced IgE-allergy risk
- Breastfeeding enhances probiotic/restoration effects; HMOs fuel infant-adapted microbes and are essential for full restoration

QC result: Pass.

Li Z et al., Human Genetics and Genomics Advances - LASI-DAD 30× whole-genome sequencing of 2,680 Indian participants produced a 69.5M-variant LD panel that improves genotype imputation accuracy and PRS performance for Indian populations. Key terms: LASI-DAD, linkage disequilibrium, genotype imputation, whole-genome sequencing, polygenic risk scores.

Study Highlights:
Using 30× WGS of 2,680 LASI-DAD participants, the authors constructed an LD lookup panel (69.5 million variants), phased with Eagle2.4, and identified LD structure with LDetect and Big-LD. They compared regional varLD to 1000G super-populations and evaluated imputation with Minimac4 and meta-imputation against TOPMed and GAsP. LASI-DAD increased imputation accuracy (aggregated r2) by a mean 38% versus TOPMed and 27% versus GAsP across allele frequencies and improved PRS predictive performance by 2.1%–35.1% across traits and studies. Finer-scale stronger LD and regional LD differences in LASI-DAD translate into more accurate LD estimates and better imputation and PRS transferability for Indian sub-populations.

Conclusion:
LASI-DAD is the largest nationally representative Indian WGS reference panel to date and it improves LD estimation, genotype imputation accuracy, and PRS construction for Indian and South Asian populations.

Music:
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Article title:
A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India

First author:
Li Z

Journal:
Human Genetics and Genomics Advances

DOI:
10.1016/j.xhgg.2026.100579

Reference:
Li Z, Zhao W, Zhou X, Leung YY, Schellenberg GD, Wang L-S, Schönherr S, Forer L, Fuchsberger C, Dey S, Lee J, Smith JA, Dey AB, Kardia SLR. A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India. Human Genetics and Genomics Advances. 7 (2026) 100579. https://doi.org/10.1016/j.xhgg.2026.100579.

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/lasi-dad-india-reference-panel

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of the transcript’s scientific content covered the LASI-DAD cohort design and sequencing depth; LD/imputation methodology (LD blocks, LDetect/Big-LD, varLD); LD panel variant counts; subpopulation structure (ANI/ASI) and PRS transferability; imputation performance and meta-imputation; and data avai
- transcript topics: LASI-DAD cohort design and 30× whole-genome sequencing; LD reference panel construction and variant counts (69.5 million) and comparisons; LD blocks and varLD analyses across populations; LASI-DAD sub-populations by ANI percentage and geographic cline; PRS transferability and cross-population performance; Imputation performance and meta-imputation across reference panels

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:
- LASI-DAD WGS sample size = 2,680 individuals
- Sequencing depth = 30×
- LD reference panel variant count = 69.5 million
- Imputation gains: mean aggregated r2 improvements = 38% versus TOPMed and 27% versus Genome Asia Pilot (GAsP)
- PRS predictive performance improvement = 2.1%–35.1% across traits and studies
- Rare variant imputation: 61,843,011 variants imputed

QC result: Pass.

Shi J et al., The EMBO Journal, doi:10.1038/s44318-025-00687-8 - PANDORA-seq profiling of mouse and human sperm heads identifies a conserved rsRNA length shift with age and a tsRNA/rsRNA 'aging cliff' that reprograms embryonic transcripts. Key terms: sperm sncRNA, rsRNA length shift, PANDORA-seq, aging cliff, tRNA-derived small RNA.

Study Highlights:
Using PANDORA-seq on C57BL/6J mouse sperm (intact and de-membranated heads) across five age groups and two independent human sperm cohorts, the authors identify a sharp tsRNA/rsRNA "aging cliff" in mice between 50–70 weeks and a head-specific rsRNA length shift. PANDORA-seq overcomes modification-induced detection bias to reveal increases in longer rsRNAs and decreases in shorter rsRNAs, particularly from 28S- and 18S-rRNAs, with parallel trends in human cohorts. Mitochondrial tsRNAs/rsRNAs in sperm heads, although low abundance, covary with genomic sncRNAs and help distinguish age groups. Transfection of age-mimicking tsRNA/rsRNA cocktails into mouse embryonic stem cells reprograms gene expression, upregulating metabolic and neurodegeneration-related pathways, providing a functional link to offspring phenotypes.

Conclusion:
PANDORA-seq uncovers a conserved, sperm head–specific rsRNA length shift and a tsRNA/rsRNA aging cliff in mice and humans, and age-mimicking sncRNA combinations can alter embryonic transcriptomes linked to metabolic and neurodegenerative pathways.

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

Article title:
Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging

First author:
Shi J

Journal:
The EMBO Journal, doi:10.1038/s44318-025-00687-8

DOI:
10.1038/s44318-025-00687-8

Reference:
Shi J, Zhang X, Cai C, Liu S, Yu J, James ER, et al. Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging. The EMBO Journal. 2026;45(4):1362–1380. https://doi.org/10.1038/s44318-025-00687-8

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.com/episodes/sperm-rsrna-length-shift

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the transcript segments describing (1) the aging cliff in mouse sperm tsRNA/rsRNA profiles, (2) rsRNA length shifts in sperm heads, (3) cross-species conservation in humans, (4) mitochondrial sncRNA patterns, (5) functional RNA transfection experiments in mouse embryonic stem cells, (6) the PANDOR
- transcript topics: PANDORA-seq methodology; mouse sperm aging cliff at 50-70 weeks; rsRNA length shift in mouse sperm heads (28S/18S origin); mitochondrial tsRNA/rsRNA patterns in sperm heads; conservation of rsRNA length shift in human sperm cohorts; functional reprogramming of mESC transcriptomes by age-mimicking sncRNA cocktails

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:
- Aging cliff between 50 and 70 weeks in mouse sperm sncRNA profiles detected by PANDORA-seq.
- Sperm-head rsRNAs show an age-related length shift: longer rsRNAs increase and shorter rsRNAs decrease, especially from 28S- and 18S-derived rsRNAs.
- Conserved rsRNA length shift observed in humans across two independent cohorts (longitudinal and cross-sectional).
- Mitochondrial rsRNAs/tsRNAs detected in de-membranated sperm heads co-vary with genomic sncRNA aging patterns.
- Age-mimicking tsRNA/rsRNA cocktails transfected into mouse embryonic stem cells reprogram transcriptomes toward metabolic and neurodegeneration pathways.
- Pandora-seq overcomes RNA modification-induced detection bias to reveal previously undetectable sncRNA species.

QC result: Pass.

Saxton DS et al., Nature, doi:10.1038/s41586-026-10207-1 - In E. coli, the membrane-bound nuclease SNIPE directly cleaves incoming phage λ DNA during genome injection, blocking infection via ManYZ and tape-measure protein interactions. Key terms: SNIPE, GIY-YIG nuclease, lambda phage, ManYZ, tape measure protein.

Study Highlights:
In Escherichia coli, the membrane-anchored protein SNIPE was shown to block phage λ by directly cleaving DNA during genome injection. The authors combined radiolabelled 32P phage DNA assays, time-lapse CFP-ParB/ParS microscopy, TurboID proximity labelling and pBPA crosslinking to map SNIPE localization and interactions. They report that membrane-localized SNIPE requires a DUF4041 domain and a GIY-YIG nuclease domain to generate DNA fragments during injection, reducing CFP-ParB puncta ~30-fold and producing a smear of 32P-labelled fragments; an E414A nuclease mutant abolished activity. Functionally, SNIPE prevents λ replication and cell lysis and provides broad defence against many siphoviruses via interactions with ManYZ and phage tape-measure proteins.

Conclusion:
SNIPE is a membrane-localized bacterial defence protein that associates with ManYZ and phage tape-measure proteins to directly cleave incoming phage DNA during genome injection, thereby blocking infection.

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

Article title:
A membrane-bound nuclease directly cleaves phage DNA during genome injection

First author:
Saxton DS

Journal:
Nature, doi:10.1038/s41586-026-10207-1

DOI:
10.1038/s41586-026-10207-1

Reference:
Saxton DS, DeWeirdt PC, Doering CR, Roney IJ & Laub MT. A membrane-bound nuclease directly cleaves phage DNA during genome injection. Nature. 2026. https://doi.org/10.1038/s41586-026-10207-1

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/snipe-membrane-nuclease-phage-injection

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-04.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering SNIPE architecture and membrane localization, autoinhibition, phage DNA cleavage during genome injection (Hershey–Chase style), interactions with ManYZ andTape-measure proteins (TMP), proximity labelling, Bas14 mutation experiments, and SNIPE homologues/evolution.
- transcript topics: SNIPE membrane localization and domain architecture; Autoinhibition and self-DNA protection at the membrane; Cleavage of phage DNA during genome injection and Hershey–Chase-like evidence; Interaction with ManYZ and phage tape-measure protein during infection; TurboID proximity labelling findings for ManYZ and TMP interactions; Broad siphovirus defense and Bas14 mutation findings

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:
- SNIPE is a membrane-anchored protein with an N-terminal transmembrane domain, a DUF4041 domain in the middle, and a GIY-YIG nuclease domain at the C-terminus.
- SNIPE autoinhibits its nuclease activity when anchored to the inner membrane to avoid autoimmune DNA cleavage.
- SNIPE cleaves phage DNA during genome injection, producing fragmented 32P DNA signals and reducing infection.
- CFP-ParB foci (parS-labelled phage DNA) are reduced by ~30-fold in SNIPE-expressing cells during λparS infection.
- A Hershey–Chase–style assay shows a smear of 32P-labelled DNA fragments in SNIPE-expressing cells, reversed by nuclease-inactive mutants (E414A).
- SNIPE associates with ManYZ before infection and with phage tape-measure proteins during genome injection.

QC result: Pass.