Base by Base

️ Episode 61: Monkeypox on the Frontline — Developing Brazil’s First qPCR Diagnostic Assay
In this episode of Base by Base, we trace the rapid development and rigorous validation of the first laboratory-developed qPCR test for monkeypox virus in Brazil’s Federal District. Back in July 2022, researchers at Sabin Diagnóstico e Saúde and the Catholic University of Brasília joined forces to design, optimize, and deploy a sensitive molecular assay that went from concept to clinical use in just 45 days. Along the way, they tackled challenges in sample collection, nucleic acid extraction, primer–probe design, and statistical modeling to ensure accurate, reliable detection of Mpox in patient specimens.
Key highlights: the assay demonstrated 100 % accuracy and a limit of detection as low as 21.25 copies per reaction, showcasing exceptional sensitivity; careful optimization of input and elution volumes on both QiaSymphony and Maxwell platforms maximized viral recovery from pustule swabs; Probit regression on over 100 replicates underpinned a robust LoD estimation; targeted Sanger sequencing of four genomic regions confirmed perfect specificity and identity to reference sequences; a head-to-head comparison with the Federal District’s reference lab (LACEN-DF) yielded full concordance, securing official recognition for national surveillance reporting; and a retrospective epidemiological analysis of 295 tests revealed a 30 % overall positivity rate, pronounced male predominance, and spatial–temporal trends that illuminate the dynamics of Mpox spread in central Brazil.
Conclusion: By integrating innovative extraction protocols, rigorous statistical validation, and collaborative cross-verification, this laboratory-developed test not only strengthened Brazil’s Mpox diagnostic capacity but also delivered crucial epidemiological insights, underscoring the power of agile molecular tools in outbreak response and public health preparedness.
Reference: Silva, L.P.d.; Hurtado, F.A.; Belmok, A.; Correa, R.; Sousa, C.F.; Gil, G.P.; Velasco, L.; Jácomo, R.H.; Nery, L.F.; Rodrigues, M.T.d.O.; Andrade, M.S.; de Andrade, R.V. Development and Evaluation of a Molecular Test for Monkeypox Virus in the Federal District, Brazil. Genes 2025, 16, 779, https://doi.org/10.3390/genes16070779.
License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

Zeng W et al., PNAS - This paper introduces Epi-PRS, a workflow that uses genomic large language models to impute cell-type-specific epigenomic features from diploid genotypes and trains nonlinear risk models to improve polygenic prediction from WGS. The method improves AUC for breast cancer and type 2 diabetes in UK Biobank and shows gains from modeling regulatory context and rare variants. Key terms: Epi-PRS, genomic LLM, polygenic risk score, epigenomics, whole-genome sequencing.

Study Highlights:
The authors developed Epi-PRS which uses a genomic LLM (Enformer) to predict epigenomic signals from phased maternal and paternal sequences and uses local PCA plus GBRT to predict disease risk. Simulation studies show nonlinear models and epigenomic intermediates recover signal missed by linear PRS methods, especially when epigenetic effects or rare variants contribute. In UK Biobank case-control tests for breast cancer and T2D, Epi-PRS outperformed LDpred2 and PRS-CS using selected LD blocks. Tissue-specific feature selection and bin-level importance analyses linked top features to relevant regulatory marks in pancreas, liver, and blood.

Conclusion:
Integrating LLM-imputed, cell-type-specific epigenomic features with nonlinear modeling improves polygenic risk prediction from WGS, particularly when regulatory effects and rare variants are important, and offers interpretable links to disease-relevant regulatory elements.

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

Article title:
Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features

First author:
Zeng W

Journal:
PNAS

DOI:
10.1073/pnas.2419202122

Reference:
Zeng W., Guo H., Liu Q., Wong W.H. Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features. PNAS. 2025;122(24):e2419202122. doi:10.1073/pnas.2419202122

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/epi-prs-llm-imputed-epigenomics

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments covering Epi-PRS concept, three-stage workflow, epigenomic feature inference via an LLM, dimension reduction, nonlinear modeling, simulation results, UKBB findings for breast cancer and T2D, tissue-enrichment interpretations, and discussion of limitations/future directions.
- transcript topics: Epi-PRS concept and goals; Personal genome construction (maternal/paternal genomes); Epigenomic feature extraction with Enformer; Local PCA dimension reduction; GBRT risk prediction; Nonlinear vs linear PRS in simulations

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:
- Epi-PRS uses a genomic large language model to impute cell-type-specific epigenomic signals from personal diploid genomes as intermediaries between genotype and phenotype.
- Epi-PRS workflow comprises three steps: personal genome construction, epigenomic feature extraction, and disease risk prediction.
- Nonlinear models outperform linear models when training data exceed about 2,000 individuals; performance improves further with higher epigenetic/rare variant burden.
- In UK Biobank, Epi-PRS outperforms LDpred2 and PRS-CS for breast cancer and type 2 diabetes; reported lambda values: breast cancer around 0.40; T2D around 0.515.
- Top predictive epigenomic features for T2D are enriched in pancreas and liver tissues (e.g., 44% of top features; ~88% top 1% bins overlap DNase signals in liver/pancreas; ~81% ove
- Limitations include reliance on informer annotations and potential missing of protein-coding variant effects; future directions include hybrid models and improved scalability/high-

QC result: Pass.

Crossnohere NL et al., Genetics in Medicine - Overview of how the PE-CGS Network defined, implemented, and evaluated strategies to engage participants and communities in cancer genomic sequencing research, and how engagement optimization using scientific methods informed study practices. Key terms: participant engagement, community engagement, engagement optimization, cancer genomics, return of results.

Study Highlights:
The PE-CGS Network conducted a document review and key informant interviews across five research centers to characterize engagement and optimization strategies during the first three years. Centers implemented tailored participant- and community-focused approaches spanning outreach, consent, data collection, return of results, and retention. Engagement optimization applied methods from behavioral science, implementation science, randomized experiments, surveys, and rapid-cycle research to iteratively refine practices. Harmonized definitions of engagement and optimization were developed to support evidence-based approaches across the network.

Conclusion:
PE-CGS established shared definitions and a range of participant and community engagement strategies and applied scientific methods to optimize them; these efforts informed changes to consent, return-of-results, recruitment, and retention and provide a foundation for developing evidence-based engagement practices in cancer genomics research.

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

Article title:
Optimizing participant and community engagement in cancer genomic sequencing research

First author:
Crossnohere NL

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101483

Reference:
Crossnohere NL, Schuster ALR, Blair CK, Bland H, Carpten JD, Claus EB, Colditz GA, Diehl D, Ding L, Drake BF, Fields RC, George S, Janeway K, Kim H, Lenz HJ, Mack JW, Ricker C, Stern MC, Sussman A, Trent J, Van Allen E, Verhaak R, Willman C, Bridges JFP, Mishra SI, Kwan BM, For PE-CGS Network, Optimizing participant and community engagement in cancer genomic sequencing research, Genetics in Medicine (2025), doi: https://doi.org/10.1016/j.gim.2025.101483

License:
© 2025 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

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/optimizing-engagement-cancer-genomics-59

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-29.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited definitions of engagement and optimization, center-focused strategies, methods, and key tactical examples (consent visuals, language changes, bilingual webinars, educator training, decision support tools), plus discussion on outcomes and recommendations.
- transcript topics: Definitions of engagement and engagement optimization; Center populations and focus (JUNIPER, Count Me In, OPTIMUM, KOPEC, WU-PE-CGS); Indigenous consent materials and tribal advisory oversight; Language changes in return of results (shared learnings about your tumor); Multilingual outreach and community education (bilingual webinars); Community health educator training and evaluation

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:
- Engagement is defined as sustained, beneficial interaction between researchers and diverse individuals to inform research processes and improve outcomes
- Engagement optimization uses scientific methods (e.g., randomized trials, surveys, rapid-cycle research) to refine engagement and research processes
- PE-CGS comprises five centers focusing on distinct cancers/populations with engagement spanning outreach, consent, data collection, return of results, and retention
- Indigenous consent materials were enhanced with visual Indigenous artwork and reviewed by a Tribal Advisory Committee
- Return of results language was updated (e.g., 'return of somatic results' to 'shared learnings about your tumor') to improve the participant experience
- OPTIMUM conducted bilingual (English/Spanish) webinars addressing immediate community needs and posted recordings publicly

QC result: Pass.

Fusari E et al., Cell Genomics - Fusari et al. use FLP/FRT–based mosaic methods in Drosophila imaginal epithelia to generate defined segmental monosomies and trisomies and quantify their immediate effects on clonal growth, survival, and interclonal interactions. Key terms: aneuploidy, cell competition, Drosophila, segmental monosomy, trisomy.

Study Highlights:
Using RS- and TSG-FRT tools, the authors show that segmental monosomies of a few hundred genes commonly compromise clonal growth and present signs of outcompetition, whereas trisomies spanning up to ~1,500 genes often lack major autonomous growth defects. Haploinsufficiency of single loci (e.g., RpL26) or cumulative haploinsufficiency of discrete gene sets underlies many monosomy phenotypes. Complementary trisomic clones can exacerbate or rescue monosomy-driven loss, revealing distinct interaction modes including super-competition and lethal competition. The Xrp1–TOR–apoptosis axis and proteotoxic stress partially explain elimination of Rp-containing monosomies.

Conclusion:
Cell-to-cell interactions between complementary aneuploid clones, together with single-gene and cumulative haploinsufficiency, determine the in vivo depletion of aneuploid cells, highlighting cell competition as a key mechanism shaping aneuploid cell fate.

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

Article title:
Depletion of aneuploid cells is shaped by cell-to-cell interactions

First author:
Fusari E

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100894

Reference:
Fusari E, Muzzopappa M, Gracia J, Milán M. Depletion of aneuploid cells is shaped by cell-to-cell interactions. Cell Genomics. 2025;5:100894. https://doi.org/10.1016/j.xgen.2025.100894

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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/papercast-base-by-base-58

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the in vivo mosaic aneuploidy model in Drosophila imaginal discs, the Twin Spot Generator (TSG) and RS-FRT approaches, cell competition modalities (lethal, super-competition, compensatory proliferation), region-specific monosomy/trisomy findings (regions 1 and 2), and implicat
- transcript topics: In vivo mosaic aneuploidy in Drosophila imaginal discs; Twin Spot Generator (TSG) and RS-FRT recombination; Segmental monosomies and trisomies effects on growth; Cell competition: lethal competition, super-competition, compensatory proliferation; Region 1 (72A1–73A5) and flower gene–mediated competition; Region 2: compensatory proliferation and martyr signaling

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:
- Monosomies are outcompeted by neighboring euploid cells, leading to their elimination via cell competition.
- Trisomies up to around 1,500 genes generally do not show major autonomous growth defects in vivo.
- Complementary monosomies and trisomies can exacerbate or rescue monosomy-driven loss, showing region-specific interactions (e.g., region 1 super-competition; region 2 compensatory
- Region 1 contains a ~179-gene interval (72A1–73A5) with the flower gene implicated in competition, contributing to super-competition in trisomies.
- Region 2 exhibits compensatory proliferation where trisomic cells die and secrete signals that rescue monosomic neighbors.
- The XRP1–TOR–apoptosis axis and proteotoxic stress contribute to monosomy elimination; Xrp1 and mTor manipulations can modulate outcomes.

QC result: Pass.

Brown TR et al., Genetics in Medicine - This episode reviews a claims-based study of 241,060 Medicaid-enrolled children (ages 7–17) from 2008–2016 that measured use of genetic testing among those with ASD-only, ID-only, and ASD+ID. The authors report low overall testing rates, temporal shifts in test modalities from cytogenetics/Fragile X toward chromosomal microarray and gene panels, and disparities by race and urbanicity. We outline the methods, key findings, and clinical implications for guideline implementation and access to genetic services. Key terms: autism spectrum disorder, intellectual disability, genetic testing, Medicaid, chromosomal microarray.

Study Highlights:
Using T-MSIS Medicaid claims data from 2008–2016, the authors identified 241,060 children with ASD-only, ID-only, or ASD+ID and measured cumulative genetic testing via CPT codes. Genetic testing frequencies were low: ASD+ID 25.94%, ASD-only 16.86%, ID-only 13.09%, versus 1.23% in a random sample without these diagnoses. Testing modalities were dominated by cytogenetics and Fragile X through 2013, with increasing use of chromosomal microarray and gene panels in 2014–2016. The study also found lower adjusted odds of testing for Black children and for those in suburban or rural areas.

Conclusion:
Clinical implementation of guideline-recommended genetic testing among Medicaid-enrolled children with neurodevelopmental disorders was low from 2008–2016, indicating missed opportunities and the need to identify barriers to testing.

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

Article title:
Medicaid claims from 2008 to 2016 indicate low rates of genetic testing among children with intellectualdisability and autism spectrum disorder

First author:
Brown TR

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101451

Reference:
Brown TR, Lee W-L, Ventimiglia J, et al. Genetics in Medicine (2025). doi: https://doi.org/10.1016/j.gim.2025.101451

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/genetic-testing-medicaid-asd-id-low-rates

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing (1) study design and cohort, (2) testing frequencies by diagnosis, (3) modality timeline, (4) disparities by race/urbanicity/sex, (5) age at first testing, and (6) barriers and implications discussed in the conclusion.
- transcript topics: Medicaid cohort construction and eligibility (2008-2016, 241,060 children, no private insurance); Genetic testing frequencies by diagnosis (ASD-only, ID-only, ASD+ID, random); Testing modality timeline (cytogenetics/Fragile X pre-2013; CMA and gene panels 2014-2016); Odds ratios and demographic disparities (race, urbanicity, sex); Age at first genetic testing; Clinical inertia and administrative barriers to testing

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:
- Cohort size and age range: 241,060 children aged 7-17 in 2016
- Genetic testing frequencies by diagnosis: ASD+ID 25.94%, ASD-only 16.86%, ID-only 13.09%, random 1.23%
- Testing modality timeline: cytogenetics/Fragile X predominant through 2013; CMA and gene panels increased 2014-2016
- Adjusted odds ratios: ASD+ID aOR 29.43 vs random sample; ASD-only aOR 16.66; ID-only aOR 12.82
- Racial disparities: Black children had lower odds of testing across cohorts; Hispanic children higher odds vs non-Hispanic White
- Urbanicity disparities: suburban aOR 0.93; rural aOR 0.84 vs urban

QC result: Pass.

Woo et al et al., Cell - This study shows that interferon-driven induction of the immunoproteasome subunit PSMB8 in neurons reduces proteasome β5 catalytic activity, causing accumulation of the glycolytic regulator PFKFB3. PFKFB3 accumulation shifts neurons from the pentose phosphate pathway to glycolysis, lowering NADPH/GSH, increasing ROS and lipid peroxidation, and sensitizing neurons to ferroptosis. Neuron-specific genetic deletion or pharmacologic inhibition of PSMB8 or PFKFB3 protected neurons in vitro and in mouse EAE models, highlighting new neuroprotective strategies for MS. Key terms: immunoproteasome, PSMB8, PFKFB3, ferroptosis, multiple sclerosis.

Study Highlights:
IFNγ induces neuronal PSMB8 expression in MS and EAE and PSMB8 replaces PSMB5 in the proteasome. PSMB8 incorporation decreases proteasomal β5 catalytic activity, impairing degradation of PFKFB3 and leading to its accumulation. PFKFB3 drives a metabolic switch to glycolysis, reduces PPP-derived NADPH and GSH, increases ROS and lipid peroxidation, and increases susceptibility to ferroptosis. Targeting PSMB8 or PFKFB3 genetically or pharmacologically protects neurons and reduces neurodegeneration in EAE.

Conclusion:
IFN-driven neuronal PSMB8 expression impairs proteasomal degradation, stabilizes PFKFB3 and triggers a glycolytic shift that depletes antioxidant defenses and promotes ferroptotic neurodegeneration, and PSMB8/PFKFB3 inhibition offers a promising neuron-targeted neuroprotective approach in MS.

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

Article title:
The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis

First author:
Woo et al

Journal:
Cell

DOI:
10.1016/j.cell.2025.05.029

Reference:
Woo et al., 2025, Cell 188, 4567–4585. https://doi.org/10.1016/j.cell.2025.05.029

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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/the-immunoproteasome-disturbs-neuronal-metabolism-and-drives-neurodegeneration-in-multiple-sclerosis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing IFN-γ–driven neuronal immunoproteasome remodeling (PSMB8), the proteasome shift affecting PFKFB3, PPP-to-glycolysis metabolic reprogramming, NADPH and glutathione depletion, ferroptosis susceptibility, and in vivo interventions (neuron-specific Psmb8 deletion; ONX-0914; Pfkfb3 inh
- transcript topics: IFN-γ–driven neuronal immunoproteasome remodeling (PSMB8); Proteasome core composition: 20S core vs immunoproteasome; PFKFB3 accumulation and PPP-to-glycolysis shift; NADPH and GSH depletion; ROS and lipid peroxidation; Ferroptosis as a neuronal death mechanism; In vivo interventions: neuronal Psmb8 deletion; ONX-0914; Pfkfb3 inhibition

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:
- IFN-γ drives neuronal expression of immunoproteasome subunit PSMB8.
- PSMB8 incorporation into neuronal proteasomes reduces proteasomal activity (β5) in neurons.
- PSMB8 expression leads to accumulation of PFKFB3 in neurons.
- PFKFB3 accumulation shifts metabolism from PPP toward glycolysis, reducing NADPH and GSH antioxidant capacity.
- The metabolic switch increases ROS and lipid peroxidation, sensitizing neurons to ferroptosis; neuron-specific Psmb8 deletion or ONX-0914 reduces disease severity; Pfkfb3 inhibitio

QC result: Pass.

Fu Q et al., Cell - Recovery of mitochondrial DNA from dental calculus links the Late Middle Pleistocene Harbin cranium to Denisovans and demonstrates dental calculus as a source of ancient host DNA. Key terms: Denisovan, mitochondrial DNA, Harbin cranium, dental calculus, Middle Pleistocene.

Study Highlights:
Researchers recovered mitochondrial DNA from dental calculus of the >146,000-year-old Harbin cranium after tooth and petrous bone yielded no DNA. The Harbin mtDNA falls within Denisovan mtDNA variation and clusters with early Denisovan individuals from Denisova Cave. Recovery relied on short, deaminated fragments and stringent filtering to reduce modern contamination. This association connects a nearly complete cranium to Denisovans and implies a broad Middle Pleistocene Denisovan geographic range in Asia.

Conclusion:
Mitochondrial DNA from Harbin dental calculus places the cranium within Denisovan mtDNA variation and highlights dental calculus as a viable source of ancient host DNA when bone preserves little or no DNA.

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

Article title:
Denisovan mitochondrial DNA from dental calculus of the >146,000-year-old Harbin cranium

First author:
Fu Q

Journal:
Cell

DOI:
10.1016/j.cell.2025.05.040

Reference:
Fu Q., Cao P., Dai Q., Bennett E.A., Feng X., Yang M.A., Ping W., Pääbo S., Ji Q. (2025). Denisovan mitochondrial DNA from dental calculus of the >146,000-year-old Harbin cranium. Cell 188, 1–8. https://doi.org/10.1016/j.cell.2025.05.040

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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-55-jozt

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing dental calculus DNA retrieval, surface decontamination, ancient DNA authentication via damage patterns, mitochondrial placement within Denisovan lineage, Harbin dating and geographic implications, and explicit limitations.
- transcript topics: Dental calculus as a source of host ancient DNA; Decontamination methods (UV exposure and bleach); Ancient DNA authentication through cytosine deamination and fragment-length filtering; Mitochondrial DNA analysis and Denisovan placement; Harbin cranium dating and Middle Pleistocene Denisovan range; Study limitations and future nuclear DNA considerations

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:
- Harbin cranium mtDNA retrieved from dental calculus (>146 ka) and clusters within Denisovan mtDNA variation
- Dental calculus acts as a dense, crystalline vault that can preserve host DNA when bone preserves poorly
- Surface decontamination used (UV exposure followed by 5% bleach) reduces surface modern DNA but does not penetrate the calculus core
- Estimated modern human contamination levels in the dataset were substantial (56–67% depending on method)
- Ancient DNA authentication relies on cytosine deamination signatures at fragment ends and preferential short fragment lengths (<60 bp)
- Harbin mtDNA shows affinity to older Denisovan mtDNAs (Denisova 2, 8, 19, 20, 21) more than to younger Denisovans (Denisova 3, 4)

QC result: Pass.

Stephenson E et al., Cell Genomics - Longitudinal single-cell multi-omics profiling of PBMCs from 61 end-stage kidney disease (ESKD) patients with COVID-19 (580,040 cells) reveals distinct temporal immune trajectories in severe versus mild disease, emergence of a dexamethasone-associated monocyte population, and expanding T cell clones enriched for SARS-CoV-2 specificity. Key terms: COVID-19, end-stage kidney disease, single-cell multi-omics, T cell receptors, glucocorticoids.

Study Highlights:
Longitudinal single-cell CITE-seq and paired TCR/BCR sequencing of PBMCs from ESKD patients show divergent temporal gene-expression trajectories in severe/critical versus mild/moderate COVID-19. An early and stronger interferon response is seen in severe disease with a steeper decline over time, and HLA class II expression falls over time in severe cases. The fastest-expanding T cell clones are enriched for known SARS-CoV-2-specific TCRα sequences and form public motifs with inferred MHC class II restriction. Glucocorticoid treatment (dexamethasone) is associated with the rapid emergence of a distinct CD163-high, dexamethasone-related monocyte population.

Conclusion:
This multi-omics longitudinal study delineates time-dependent immune differences between mild and severe COVID-19 in a high-risk ESKD population, identifies steroid-associated monocytes, and documents shared SARS-CoV-2-directed T cell clonotypes; findings are observational and do not prove causality.

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

Article title:
Temporal multi-omics analysis of COVID-19 in end-stage kidney disease

First author:
Stephenson E

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100918

Reference:
Stephenson E, Macdonald-Dunlop E, Dratva LM, et al. Temporal multi-omics analysis of COVID-19 in end-stage kidney disease. Cell Genomics. 2025;5:100918. doi:10.1016/j.xgen.2025.100918

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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at 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-54-corrupted-pdf

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing time-resolved multi-omics methodology, interferon dynamics, TNF expression vs protein uncoupling, dexamethasone-induced monocytes, expanding SARS-CoV-2–specific T cell clones and public TCR motifs, baseline TGF-β signaling in ESKD, HLA class II changes with severity, and Mendelian
- transcript topics: Time-resolved multi-omics methodology (CITE-seq, VDJ, Olink); Interferon response dynamics in COVID-19; TNF gene expression vs TNF-α protein uncoupling; Dexamethasone-associated monocytes (dex. monos); Public SARS-CoV-2–specific T cell clones and TCR motifs; Baseline TGF-β signaling across immune cells in ESKD

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:
- IFN response peaks in week 1 and wanes in weeks 2–3, with greater early IFN signaling in severe cases
- TNF gene expression downregulated in monocytes while TNF-α protein is elevated in plasma
- Dexamethasone treatment leads to emergence of a dexamethasone-related monocyte population (dex. monos) absent in the 2020 cohort
- Fastest expanding T cell clones enriched for SARS-CoV-2–specific sequences and form public TCR motifs shared across patients
- Baseline TGF-β signaling upregulated across all immune cell lineages in ESKD, irrespective of COVID-19 status
- HLA class II gene expression downregulated over time in severe/critical COVID-19

QC result: Pass.

Siena LM et al., The American Journal of Human Genetics - A systematic review of 24 full economic evaluations assessing polygenic risk score (PRS)–based clinical strategies across cancer, cardiovascular disease, and other conditions, summarizing methods, cost components, and evidence on cost-effectiveness. Key terms: polygenic risk scores, economic evaluation, cost-effectiveness, screening, implementation.

Study Highlights:
The authors reviewed 24 cost-utility analyses (16 cancer, 5 cardiovascular, 3 other) and assessed study quality with the QHES instrument. Most analyses used hypothetical cohorts and decision models (Markov or microsimulation) and focused on PRS-informed screening or eligibility for preventive therapy. Results show a general positive trend toward cost-effectiveness—most consistently for cardiovascular applications—but studies often omitted implementation costs, indirect costs, and real-world data. Key gaps include limited representativeness across ancestries and sparse evaluation of delivery models and long-term non-health benefits.

Conclusion:
PRS-based approaches show a promising trend toward cost-effectiveness, particularly for cardiovascular prevention, but robust real-world pilot studies and explicit accounting for implementation, equity, and long-term benefits are needed before wide-scale clinical adoption.

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

Article title:
Weighing the evidence on costs and benefits of polygenic risk-based approaches in clinical practice: A systematic review of economic evaluations

First author:
Siena LM

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.05.012

Reference:
Siena LM, Baccolini V, Riccio M, Rosso A, Migliara G, Sciurti A, Isonne C, Iera J, Pierri F, Marzuillo C, DeVito C, La Torre G, Villari P. Weighing the evidence on costs and benefits of polygenic risk-based approaches in clinical practice: A systematic review of economic evaluations. Am J Hum Genet. 2025;112:1735–1753. doi:10.1016/j.ajhg.2025.05.012.

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/ep53-prs-economics-review

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the systematic review's scope, disease-category results, modeling approaches, uptake assumptions, ancestry considerations, and implementation costs, and compared them with the canonical article.
- transcript topics: Overview of PRS economic evaluations; Study counts by disease: cancer, cardiovascular disease, other; PRS use in cancer screening and treatment decision-making; PRS use in cardiovascular disease: statin eligibility; Modeling approaches (Markov, microsimulation); Real-world data vs hypothetical cohorts

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:
- There were 24 full economic evaluations included in the review (not just abstracts).
- Cancer: 16 studies; Cardiovascular disease: 5 studies; Other diseases: 3 studies.
- PRS used to optimize cancer screening; PRS used to refine eligibility for preventive therapies (e.g., statins) in CVD; one cancer study used PRS to guide chemotherapy decisions.
- Most evaluations used hypothetical cohorts; real-world data were limited; several studies scored highly on quality checklists.

QC result: Pass.

Keener R et al., Cell Genomics - A method-focused excerpt describing LIZS6-related experiments across multiple conditions (NoSk, LSFM) with quantitative readouts and protocol detail. Key terms: LIZS6, NoSk, LSFM, tzqom�t{z, moww.

Study Highlights:
The provided text documents experiments centered on LIZS6 across multiple platforms and experimental conditions such as NoSk and LSFM. Quantitative measurements and numeric readouts appear throughout the excerpt (for example values like 4.333 and 43.5359), and the manuscript emphasizes assay workflows and imaging approaches. The excerpt is rich in methodological detail but does not present explicit mechanistic interpretation in the available text.

Conclusion:
The excerpt details protocols, comparative conditions, and quantitative outputs for LIZS6-related experiments but does not provide a clear mechanistic or clinical conclusion in the truncated text.

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

Article title:
Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis

First author:
Keener R

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100917

Reference:
Keener R.M., Shi S., Dalapati T., Wang L., Reinoso-Vizcaino N.M., Luftig M.A., et al.. Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis. Cell Genomics, 5, 100917. (2025). https://doi.org/10.1016/j.xgen.2025.100917

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/ep52-lizzs6-methods-measurements

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describe the host receptor mechanism (FCRL3 binding to Ig-like domain 1), the RS2282284/N721S variant and its effect on signaling, in vitro assays (Gentamicin protection with GFP-tagged bacteria and flow cytometry), and evolutionary/clinical implications including hepatitis C association and autoimmune
- transcript topics: FCRL3 as lymphocyte receptor for Yersinia pestis; RS2282284 / N721S SNP in FCRL3 and signaling disruption; Ig-like domain 1 binding and extracellular interactions; SYK recruitment and actin-mediated engulfment; FCRL5 redundancy in bacterial entry; High-throughput genome-wide association screen in LCLs

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:
- FCRL3 mediates entry of Yersinia pestis into B cells via binding to the extracellular Ig-like domain 1, triggering intracellular signaling that leads to engulfment.
- The RS2282284 SNP (N721S) in FCRL3 disrupts the intracellular signaling cascade, blunting SYK recruitment and actin polymerization, thereby reducing bacterial internalization.
- The same N721S variant is associated with a markedly reduced risk of chronic hepatitis C infection.
- The protective allele is present at about 6% frequency in humans, suggesting balancing selection due to trade-offs with autoimmunity.
- Other variations in FCRL3 that alter signaling capacity are linked to autoimmune diseases such as rheumatoid arthritis and Graves disease.
- Limitations acknowledged: the mechanism was studied in immortalized B cells and in vitro systems; in vivo validation is needed.

QC result: Pass.