️ Episode 190: Single-Cell Networks Reveal Cell Type–Specific Mechanisms in Type 2 Diabetes In this episode of PaperCast Base by Base, we explore how a network-based analysis of single-cell RNA sequencing from human pancreatic islets uncovers cell type–specific gene-regulatory changes that help explain type 2 diabetes pathophysiology. Study Highlights:The authors develop differential Gene Coordination Network Analysis (dGCNA) to compare gene–gene coordination between non‑T2D and T2D donors in Smart‑seq2 datasets covering >8,000 islet cells from 32 individuals. In beta cells, dGCNA resolves eleven networks with strong ontological specificity, revealing de‑coordination of mitochondria, glycolysis, cytoskeleton, cell cycle, unfolded protein response, and glucose‑response programs, while insulin secretion, lysosomal regulation, and ribosome-related programs show hyper‑coordination. Functional experiments validate predictions by showing that CEBPG modulates the unfolded protein response and insulin production/secretion, and that TMEM176A/B influences actin microfilaments and cAMP‑amplified exocytosis, with supportive phenotypes in knockout mice and human islets. Results replicate across independent datasets and outperform differential expression (DESeq2) in cross‑dataset reproducibility, and analysis of alpha cells reveals distinct T2D‑linked coordination changes involving secretory granules, glycolysis, mitochondria, and ribosomes. Conclusion:By focusing on networks of differentially coordinated genes rather than expression alone, dGCNA provides a robust framework to pinpoint cell type–specific mechanisms and nominate actionable targets for preserving islet function in type 2 diabetes. Reference:Nature Communications (2025). Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes. https://doi.org/10.1038/s41467-025-65060-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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug:  Keywords: single-cell RNA-seq, differential network analysis, pancreatic islets, beta cells, type 2 diabetes

️ Episode 189: DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms In this episode of PaperCast Base by Base, we explore how genome-wide DNA methylation profiling can pinpoint the organ of origin for neuroendocrine neoplasms (NEN), with a special focus on lesions detected in the liver and long-debated “primary hepatic NEN”. Study Highlights:Using two independent cohorts totaling 212 NEN tissues, the authors profiled methylation patterns and visualized them with dimensionality-reduction approaches, revealing distinct clusters for most organ sites. Hepatic NEN without a detectable extrahepatic primary did not form a unique liver-specific cluster and instead colocalized with extrahepatic subtypes, frequently showing foregut-like methylation signatures. A latent methylation component–based Random Forest classifier achieved high accuracy in predicting organ site from biopsy material and suggested that many presumed primary hepatic NEN are likely misclassified metastases of unknown primary. Copy-number analyses supported organ‑site–specific patterns and further differentiated grades and subtypes, including NET versus NEC. Conclusion:Methylome profiling offers a practical path to identify the primary site in neuroendocrine neoplasms—including liver-detected cases—supporting more precise diagnosis and treatment selection in real-world pathology workflows. Reference:Goeppert B, Charbel A, Toth R, et al. DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms. Nature Communications. 2025;16:9477. https://doi.org/10.1038/s41467-025-65227-8 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 188: Proteomics + Machine Learning for Lyme Neuroborreliosis Diagnosis In this episode of PaperCast Base by Base, we explore how large‑scale mass‑spectrometry proteomics of cerebrospinal fluid and plasma, paired with supervised machine learning, can distinguish Lyme neuroborreliosis from viral meningitis and non‑LNB controls in adults. Study Highlights:The authors analyzed 308 CSF and 207 plasma samples across development and validation cohorts to define host‑response protein signatures and train diagnostic classifiers. CSF proteomics yielded strong discrimination of LNB against viral meningitis and against controls, with independent‑cohort AUCs around 0.92 and 0.90, respectively, and highlighted immunoglobulin chains, complement factors, innate immune proteins, and cytoskeletal markers as key features. A plasma‑based model distinguishing LNB from controls achieved an AUC of about 0.80 in validation and captured systemic innate immunity, complement activation, lipid transport, and coagulation signatures. Across matrices, overlapping proteins illuminated compartmentalized immunity, with many immunoglobulins increased in CSF but relatively lower in plasma for LNB, and SHAP analyses prioritized features linked to humoral and innate responses as well as cell damage and migration. Conclusion:Machine‑learning‑assisted proteomics shows promise for less‑invasive diagnosis and monitoring of Lyme neuroborreliosis and could reduce reliance on lumbar puncture if validated prospectively. Reference:Nielsen AB, Fjordside L, Drici L, Ottenheijm ME, Rasmussen C, Henningsson AJ, Harritshøj LH, Mann M, Mens H, Lebech A‑M, Wewer Albrechtsen NJ. The diagnostic potential of proteomics and machine learning in Lyme neuroborreliosis. Nature Communications. 2025;16:9322. https://doi.org/10.1038/s41467-025-64903-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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 187: Gapped PARP + Tumor‑Targeted TOP1 in Advanced Tumors In this episode of PaperCast Base by Base, we explore a phase I dose‑escalation trial that pairs a tumor‑targeted topoisomerase I inhibitor (CRLX101, a nanoparticle camptothecin) with optimized, gapped scheduling of the PARP inhibitor olaparib to reduce toxicity while preserving efficacy in advanced solid tumors. Study Highlights:Twenty‑four adults with advanced solid tumors received CRLX101 every two weeks with olaparib started 48 hours later; the maximum tolerated and recommended phase 2 dose was CRLX101 12 mg/m² plus olaparib 250 mg twice daily on days 3–13 and 17–26 of each 28‑day cycle. Pharmacokinetics for both agents were consistent with their single‑agent profiles, and γH2AX pharmacodynamic assays in hair follicles showed higher DNA damage after adding olaparib compared with CRLX101 alone, supporting the mechanistic rationale. Among nineteen evaluable patients, two achieved confirmed partial responses and six had stable disease, with median overall survival of 6.06 months and progression‑free survival of 2.34 months; a patient with myxofibrosarcoma harboring a PALB2 truncation experienced a deep, durable response. Toxicities were manageable and mainly hematologic—leukopenia, anemia, neutropenia, and thrombocytopenia—while the gapped schedule mitigated dose‑limiting myelosuppression seen in prior PARP–TOP1 combinations and enabled higher olaparib dosing. Conclusion:Tumor‑targeted TOP1 delivery combined with gapped PARP inhibition appears to widen the therapeutic window for DDR‑chemotherapy combinations and merits biomarker‑informed expansion studies. Reference:Thomas A, Takahashi N, O’Connor LO, Redon CE, Mohindroo C, Sciuto L, Pongor L, Schmidt KT, Steinberg SM, Aladjem MI, Figg WD, O’Connor MJ, Pommier Y. Tumor‑targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. Nature Communications. 2025;16:9457. https://doi.org/10.1038/s41467-025-64509-5 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 186: TNFα–TGFβ Axis Disrupts Nasal Epithelium in Post‑COVID Syndrome In this episode of PaperCast Base by Base, we explore a single‑cell RNA‑seq study of nasal biopsies showing that persistent immune signaling—not residual virus—drives aberrant epithelial differentiation in people with post‑COVID syndrome. fileciteturn1file0 Study Highlights:Researchers profiled >56,000 cells from nasal tissue of individuals with moderate or severe post‑COVID syndrome, revealing marked depletion of proximal ciliated cells alongside expansion of basal and immune cell populations. Cell–cell communication and pathway analyses identified heightened TNFα and TGFβ signaling, with MIF–CD74 interactions and downstream NF‑κB/EGFR activity linking immune cells to epithelial remodeling. The team validated causality in air‑liquid interface cultures, where exposure to TGFβ and TNFα—alone and especially in combination—reduced ciliated‑cell differentiation and promoted basal‑cell skewing and EMT‑like programs. Viral RNA was undetectable in biopsies and inflammatory markers typical of acute infection were not elevated, indicating pathology independent of ongoing viral load. Conclusion:Targeting the TNFα–TGFβ inflammatory axis may help restore normal epithelial differentiation and mitigate respiratory comorbidities in severe post‑COVID syndrome. Reference:Reddy KD, Maluje Y, Ott F, Saurabh R, Schaaf A, Bohnhorst A, et al. scRNA‑seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post‑COVID syndrome. Nature Communications. 2025;16:9494. https://doi.org/10.1038/s41467-025-64778-0 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 185: Altered Milk Tryptophan in Women Living with HIV In this episode of PaperCast Base by Base, we explore a longitudinal metabolomics study of human milk that reveals how maternal HIV infection reshapes tryptophan metabolism across lactation, with potential implications for infant immunity, growth, and neurodevelopment. Study Highlights:The authors profiled the milk metabolome from hundreds of mothers over the first 18 months postpartum and found a robust, sustained decrease in milk tryptophan alongside higher kynurenine and an elevated kynurenine-to-tryptophan ratio in women living with HIV. Targeted quantification at four months confirmed lower tryptophan and higher kynurenine in milk, and paired plasma analyses mirrored these shifts, indicating systemic depletion rather than altered transfer into milk. An initially unknown metabolite was identified as 3’-deoxy-3’,4’-didehydro-cytidine (ddhC), the free base of an interferon‑inducible antiviral ribonucleotide, and cytosine and dimethylarginine were also elevated, consistent with interferon-driven inflammation. A validation cohort of treated women showed concordant directions of effect and a higher KT ratio, supporting generalizability of the signature beyond the primary cohort. Conclusion:Milk tryptophan depletion and interferon‑linked metabolic remodeling in mothers with HIV may contribute to adverse outcomes in HIV‑exposed, uninfected infants and point to testable interventions targeting the kynurenine pathway. Reference:Tobin NH, Li F, Zhu W, Ferbas KG, Sleasman JW, Raftery D, Kuhn L, Aldrovandi GM. Altered milk tryptophan and tryptophan metabolites in women living with HIV. Nature Communications. 2025;16:9437. https://doi.org/10.1038/s41467-025-64566-w 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 184: High-Accuracy Multiethnic XGBoost for Skin Cancer Identification In this episode of PaperCast Base by Base, we explore a large-scale study that builds a risk factor–based XGBoost model using the All of Us cohort to accurately identify patients with skin cancer across diverse ancestries. Study Highlights:Analyzing more than 400,000 participants, the authors quantify independent associations between genetic ancestry, lifestyle, social determinants of health, prior cancer history, and use of PDE5A inhibitors with skin cancer risk. They compare traditional logistic regression against gradient-boosted trees and show that logistic models have low precision for case identification, motivating a non-linear approach. The resulting multiethnic XGBoost model achieves high accuracy for identifying patients with any skin cancer, with F1 scores of 0.903 in individuals of European ancestry and 0.810 in non-European groups. SHAP importance and interaction analyses reveal strong non-linear effects of age and genotype principal components, and suggest that genetic and socioeconomic factors contribute more heavily to predictions in younger individuals. Conclusion:A multiethnic, non-linear model that integrates genetics, lifestyle, social determinants, and medication exposures can substantially improve early identification of skin cancer patients across ancestries, offering a precision-medicine tool to help reduce outcome disparities. Reference:D’Antonio M, Gonzalez Rivera WG, Greenes RA, Gymrek M, Frazer KA. A highly accurate risk factor–based XGBoost multiethnic model for identifying patients with skin cancer. Nature Communications. 2025;16:9542. https://doi.org/10.1038/s41467-025-64556-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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 183: The Genetic Lottery Goes to School: Better Schools Compensate for Genetic Differences In this episode of PaperCast Base by Base, we explore a large causal study from Norway asking whether school quality can offset genetic differences in students’ academic skills. Using parent–offspring genetic trios from the Norwegian Mother, Father, and Child Cohort (MoBa) and nationwide administrative data, the authors combine within-family polygenic indices for educational attainment with school value-added measures to test if better schools compensate for genetic disparities. Study Highlights:The researchers computed polygenic indices for educational attainment for children while controlling for parental indices to isolate random within-family genetic variation and paired these with causal value-added estimates of school quality derived from population registers. They found a negative gene–environment interaction for reading, indicating that higher-quality schools reduce the impact of polygenic differences on reading scores by about six percent per one standard deviation of school quality exposure in grade 8, with the effect driven by gains among students at the lower end of the polygenic index distribution. For numeracy, the interaction was null despite clear main effects of both genetics and school value-added, a pattern consistent with higher persistence of numeracy skills during this developmental period. Validation analyses supported exogeneity of the within-family genetic component and of the school value-added measures, and sensitivity checks suggested that the findings are not artifacts of test scaling or ceiling effects. fileciteturn0file0 Conclusion:In a causally identified framework, better schools can partially compensate for genetic differences in reading but not numeracy during lower secondary school, implying that investments in school quality may narrow genetically correlated gaps in foundational literacy. Reference:Cheesman R, Borgen N, Sandsør AMJ, Hufe P. The genetic lottery goes to school: Better schools compensate for the effects of students’ genetic differences. Proceedings of the National Academy of Sciences. 2025;122(43):e2511715122. https://doi.org/10.1073/pnas.2511715122 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 182: Genotypic, Functional, and Phenotypic Characterization in CTNNB1 Neurodevelopmental Syndrome In this episode of PaperCast Base by Base, we explore a large cross-sectional cohort study that integrates genetics, cellular functional assays, and deep phenotyping to map the landscape of CTNNB1 neurodevelopmental syndrome. The authors analyze variant types across 127 individuals from 20 countries, probe Wnt/β-catenin signaling consequences in vitro, and connect genotypes to clinical trajectories and everyday function. Study Highlights:The cohort revealed 88 distinct CTNNB1 variants with a strong enrichment for predicted loss-of-function changes, and functional luciferase assays confirmed reduced Wnt/β-catenin pathway activity for most variants. A subset of truncating variants showed dominant-negative behavior, while a rare missense change (G575R) behaved as a gain-of-function with increased protein stability and signaling. Systematic clinical assessments documented frequent motor impairment, hypotonia, dysmorphic features, visual issues such as strabismus, and developmental delays including later independent walking. Missense variants tended to associate with comparatively milder phenotypes, with earlier walking and better communication, social, and feeding skills than frameshift, nonsense, splice, or deletion variants. Conclusion:By combining genomic curation, mechanistic assays, and standardized clinical measures, this study refines the natural history of CTNNB1 syndrome and highlights therapeutic avenues that may upregulate CTNNB1 expression while cautioning about variant-specific effects. Reference:Zakelj N, Gosar D, Miroševič Š, Sanders SJ, Ljungdahl A, Kohani S, Huang S, Leong LI, An Y, Teo MJ, Moultrie F, Jerala R, Lainšek D, Forstnerič V, Sušjan P, Lisowski L, Perez-Iturralde A, Orazem Mrak J, Chan HYE, Osredkar D. Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome. Human Genetics and Genomics Advances. 2025;6:100483. https://doi.org/10.1016/j.xhgg.2025.100483 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 181: Creatine Transporter SLC6A8: Conservation and Variant Impact In this episode of PaperCast Base by Base, we explore how the creatine transporter gene SLC6A8 (CRT1) is evolutionarily conserved across terrestrial mammals and how disease-associated variants alter creatine uptake in vitro, shedding light on genotype–phenotype relationships in creatine transporter deficiency. fileciteturn0file0 Study Highlights:The authors compared CRT1 amino acid sequences among multiple species and found striking conservation, with human transmembrane domains 1–10 identical across the mammals analyzed and most interspecies differences confined to terminal or loop regions. They curated benign and pathogenic missense variants from public databases and mapped them onto CRT1, observing that missense changes in N‑ and C‑termini are more often tolerated, whereas variants within core transmembrane domains and specific loop regions are frequently pathogenic. Functional assays in transfected cells demonstrated that eight of nine tested patient variants—most located in transmembrane segments—caused severe reductions in creatine transport, while a peripheral extracellular loop variant produced a more modest decrease. Integrating intolerance profiling with phylogenetic and experimental data, the study highlights a hotspot between amino acids 305–415 and underscores strong structural constraints that shape CRT1 function. Conclusion:Together, these results provide a practical framework for interpreting SLC6A8 variants in the clinic and suggest that domain-aware assessments can better predict which alterations are likely to impair creatine transport and contribute to neurodevelopmental disease. Reference:Diep T, Lipshutz GS. Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport. Human Genetics and Genomics Advances. 2025;6:100489. https://doi.org/10.1016/j.xhgg.2025.100489 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 180: Leveraging Global Genetics Resources for Equitable Polygenic Prediction In this episode of PaperCast Base by Base, we explore how multi-ancestry genome-wide association study resources and modern polygenic score methodologies can improve prediction accuracy across African, East Asian, and European populations, with a focus on practical, computationally efficient strategies that work even when individual-level data are unavailable. Study Highlights:This article systematically benchmarks leading single-source and multi-source polygenic score methods across 10 complex traits using GWAS summary statistics from Ugandan Genome Resource, Biobank Japan, UK Biobank, and the Million Veteran Program. The authors show that combining ancestry-aligned and European GWAS improves prediction in non-European targets and that independently optimized multi-source approaches often outperform jointly optimized methods while being far more computationally efficient. They introduce a generalizable use of the LEOPARD framework to estimate optimal linear combinations of population-specific scores using only summary statistics, achieving performance comparable to individual-level tuning in many settings. All methods are implemented in the GenoPred pipeline, providing an accessible, reference-standardized workflow for equitable polygenic prediction across diverse populations. Conclusion:Multi-source, summary-statistics–friendly approaches implemented in GenoPred offer a practical path to more accurate and equitable polygenic prediction, particularly when leveraging diverse GWAS resources and efficient tuning frameworks like LEOPARD. Reference:Pain O. Leveraging global genetics resources to enhance polygenic prediction across ancestrally diverse populations. Human Genetics and Genomics Advances. 2025;6:100482. https://doi.org/10.1016/j.xhgg.2025.100482 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 178: TP53 Reduced Penetrance: Predictive Features and Clinical Implications In this episode of PaperCast Base by Base, we explore how a large ClinVar-anchored analysis integrates functional assays, computational predictors, immunogenicity estimates, allele frequencies, and clinical presentation to identify TP53 variants with reduced penetrance relative to classic Li-Fraumeni syndrome. Study Highlights:The authors reviewed ClinVar to assemble a set of TP53 variants flagged by diagnostic labs as reduced penetrance and compared them with benign and standard pathogenic reference sets using four independent functional assays and multiple in silico tools. Reduced penetrance variants tended to show intermediate activity in functional assays—most prominently in the Kato yeast transactivation readout—and had deleterious predictions by BayesDel and AlphaMissense, but with lower scores than standard pathogenic variants. These variants occurred at higher population frequencies than standard pathogenic variants, and carriers presented with cancer at later ages and with attenuated enrichment for classic Li-Fraumeni core cancers, although early-onset breast cancer and pediatric sarcomas remained associated. A random forest model using functional scores, predictors, immune fitness, and allele frequency prioritized 106 additional TP53 variants of uncertain or conflicting significance as potential reduced penetrance candidates for future study. Conclusion:The work outlines measurable features that distinguish reduced penetrance TP53 variants from both benign and standard high-penetrance variants, supporting refined classification and personalized surveillance strategies for carriers. Reference:Fortuno, C., Richardson, M. E., Pesaran, T., McGoldrick, K., James, P. A., & Spurdle, A. B. (2025). Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53. *Human Genetics and Genomics Advances*, 6, 100484. https://doi.org/10.1016/j.xhgg.2025.100484 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 179: Mosaicism for Autosomal Trisomies: Maternal Age, UPD, and Reproductive History in 1,266 Cases In this episode of PaperCast Base by Base, we explore a comprehensive literature analysis of 1,266 reported cases of autosomal trisomy mosaicism, contrasting prenatal cohorts—true fetal mosaicism and confined placental mosaicism—with postnatal diagnoses to clarify how maternal age and reproductive history relate to outcomes and uniparental disomy. Study Highlights:The authors screened 596 publications and assembled 948 prenatal and 318 postnatal mosaicism cases to compare outcome patterns and demographics. They found that advanced maternal age was more common in pregnancies with normal outcomes than in those with abnormal outcomes (73% vs 56%), while pregnancies ending in fetal loss showed a 50% advanced maternal age rate. Mosaic carriers with concomitant uniparental disomy of chromosomes 7, 14, 15, or 16 had markedly higher advanced maternal age than those with biparental disomy overall (78% vs 48%), suggesting age-associated biases in trisomy rescue. Reporting of reproductive history was limited, but prior fetal loss was nearly twice as frequent among mothers in the postnatal cohort compared with the prenatal cohort (30% vs 16%), and prior chromosomal abnormalities in earlier pregnancies appeared substantially enriched relative to non-mosaic series. Conclusion:These findings challenge assumptions drawn from non-mosaic trisomies and indicate that maternal age and reproductive history shape both outcomes and the likelihood of uniparental disomy in autosomal trisomy mosaicism, motivating better standardized reporting and registry-based studies. Reference:Kovaleva, N. V.; Cotter, P. D. Mosaicism for Autosomal Trisomies: A Comprehensive Analysis of 1266 Published Cases Focusing on Maternal Age and Reproductive History. Genes 2024, 15, 778. https://doi.org/10.3390/genes15060778 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 177: Biallelic MCM8/MCM9 Variants: From Hypogonadism to Cancer Predisposition In this episode of PaperCast Base by Base, we explore a multi‑cohort clinical–genomic study that delineates the phenotype of individuals with biallelic germline variants in MCM8 or MCM9, clarifying links to polyposis and early‑onset cancers in addition to the long‑recognized association with hypogonadism. Study Highlights:Using population datasets (100,000 Genomes Project, UK Biobank, and gnomAD), a curated case series, and tumor sequencing, the authors assessed cancer and reproductive phenotypes among carriers of predicted deleterious variants. They found significant enrichment of biallelic MCM9 variants among participants with colonic and rectal polyps and with gastric cancer in the 100,000 Genomes Project, whereas no similar enrichment was seen for MCM8 or in UK Biobank. Across the aggregated case series (26 biallelic MCM8 and 28 biallelic MCM9 carriers), MCM9—but not MCM8—was associated with polyposis and early‑onset colorectal cancer, while both genes were linked to hypogonadism and to female germ cell tumors presenting in early adolescence. Tumor mutational‑signature analysis predominantly showed clock‑like processes without a consistent pattern of mismatch‑repair or homologous‑recombination deficiency, suggesting that many tumors in carriers are not defined by a distinctive repair‑defect signature. The authors recommend inclusion of MCM8/MCM9 on diagnostic panels for relevant clinical contexts and propose surveillance considerations for biallelic carriers. Conclusion:Biallelic MCM9 variants confer risk for polyposis, gastric cancer, and early‑onset colorectal cancer, and biallelic variants in either MCM8 or MCM9 are consistently linked to hypogonadism and early germ cell tumors, supporting panel inclusion and individualized surveillance strategies. Reference:Helderman, N. C., Yang, T., Palles, C., Terlouw, D., Mei, H., Vorderman, R. H. P., Cats, D., Díaz‑Gay, M., Jongmans, M. C. J., Ramdien, A., van de Beek, I., Eleveld, T. F., Green, A., Hes, F. J., van den Heuvel‑Eibrink, M. M., Van Der Kelen, A., Kliesch, S., Kuiper, R. P., Lakeman, I. M. M., Lashley, L. E. E. L. O., Looijenga, L. H. J., Oud, M. S., Steingröver, J., Tenenbaum‑Rakover, Y., Tops, C. M., Tüttelmann, F., de Voer, R. M., Westra, D., Wyrwoll, M. J., Golubicki, M., Antelo, M., Bonjoch, L., Terradas, M., Valle, L., Alexandrov, L. B., Morreau, H., van Wezel, T., Castellví‑Bel, S., Goldberg, Y., & Nielsen, M. (2025). Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9. *Human Genetics and Genomics Advances*, 6, 100480. https://doi.org/10.1016/j.xhgg.2025.100480 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 176: FAHD1 and the Pyruvate-Driven Evolution of Hepatocellular Carcinoma In this episode of PaperCast Base by Base, we explore how multi-omics integration—spanning single-cell transcriptomics, spatial mapping, and causal genetic inference—uncovers a pyruvate-hyperactive epithelial subpopulation in hepatocellular carcinoma and identifies FAHD1 as a central regulator linked to poor prognosis and immune evasion. Study Highlights:The authors harmonized six single-cell metabolic scoring methods across tens of thousands of tumor microenvironment cells and uncovered PyHighEpi cells with elevated pyruvate metabolism, stemness, and proliferation that concentrate in tumor cores. Spatial transcriptomics traced evolutionary trajectories from stromal transition zones into malignant foci and showed that pyruvate activity scales with spatial progression. Summary data-based Mendelian randomization pinpointed FAHD1 as a causal driver of HCC susceptibility, and FAHD1+ epithelial cells engaged cancer‑associated fibroblasts via ITGB2 to sculpt a TGF‑β/VEGF‑enriched niche consistent with immune escape. Functional knockdown experiments reduced proliferation, migration, and invasion, while an eight‑gene FAHD1‑derived risk score stratified survival and predicted responsiveness to PD‑1 blockade; in silico docking also suggested tivozanib as a potential FAHD1‑targeting compound. Conclusion:By linking mitochondrial pyruvate control to stromal crosstalk and immune suppression, the study positions FAHD1 as a therapeutic entry point and proposes risk-guided, metabolism‑plus‑immunity strategies for difficult‑to‑treat HCC. Reference:Huang, J., Liang, S., Sun, J., & Chen, H. (2025). FAHD1‑mediated pyruvate metabolism in hepatocellular carcinoma: Multi‑omics and causal genetic evidence. *Human Genetics and Genomics Advances*, 6, 100494. https://doi.org/10.1016/j.xhgg.2025.100494 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 175: Predictive Prioritization of Pancreatic Enhancers Linked to Disease Risk In this episode of PaperCast Base by Base, we explore how enhancer–promoter 3D chromatin maps from five primary human pancreatic cell types were transformed into graph “tree” models to quantify enhancer connectivity and prioritize elements most critical for cell-type-specific gene expression, creating a framework to connect noncoding variants to function in pancreatic disease. Study Highlights:The authors profiled H3K27ac HiChIP and ATAC‑seq across 28 donors, building enhancer–promoter tree models that capture direct and indirect loops and reveal modular “forests” centered on promoter–promoter hubs.They developed EPIC, a k‑nearest‑neighbors model using chromatin features and tree topology to rank enhancers by their predicted effect on cell‑type‑specific transcription and validated top predictions in primary human cells using CRISPRa/i with single‑cell RNA FISH readouts.Direct E1 enhancer loops predominated and multiple enhancers additively boosted expression of lineage‑defining genes, while EPIC‑prioritized enhancers overlapped germline risk variants for type 2 diabetes and pancreatic ductal adenocarcinoma.GWAS integration pointed to unexpected enrichment of PDAC‑associated variants in acinar enhancers and experimental perturbation at the XBP1 locus reduced transcripts in line with predicted effect sizes. Conclusion:Enhancer tree models coupled with the EPIC prioritization algorithm provide a scalable route to nominate and validate functional noncoding elements and their target genes in the human pancreas, sharpening variant‑to‑function studies and disease mechanism discovery. Reference:Wang L, Baek S, Prasad G, Wildenthal J, Guo K, Sturgill D, Truongvo T, Char E, Pegoraro G, McKinnon K, The Pancreatic Cancer Cohort Consortium, The Pancreatic Cancer Case‑Control Consortium, Hoskins JW, Amundadottir LT, Arda HE. Predictive prioritization of enhancers associated with pancreatic disease risk. Cell Genomics. 2026;6:101040. https://doi.org/10.1016/j.xgen.2025.101040 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 174: TMEM217–SLC9C1: Wiring the cAMP Switch for Sperm Motility and Male Fertility In this episode of PaperCast Base by Base, we explore a PNAS study revealing how TMEM217 forms a complex with the sperm-specific Na+/H+ exchanger SLC9C1 to organize cAMP signaling, sustain motility, and enable fertilization in mice. Study Highlights:Using phylogenetic profiling and interactomics, the authors identified TMEM217 as a conserved partner of the exchanger SLC9C1 and showed that both proteins localize to the principal piece of the sperm flagellum. Knockout of Tmem217 produced severe motility defects and infertility with hairpin flagellar bending, accompanied by loss of SLC9C1 and full-length soluble adenylyl cyclase, reduced cAMP levels, and dampened PKA and tyrosine phosphorylation. Co-immunoprecipitation and AlphaFold3 modeling demonstrated that TMEM217 binds the voltage-sensing domain of SLC9C1, supporting a mechanism that assembles the SLC9C1–sAC–cAMP axis during spermiogenesis. Pharmacologic boosting of cAMP paired with membrane-conditioning media restored motility and fertilization in vitro, yielding viable offspring after embryo transfer. Conclusion:Dissecting the TMEM217–SLC9C1 interface and local cAMP control suggests diagnostics and mutation-agnostic therapeutic strategies for asthenozoospermia and male infertility. Reference:Iida-Norita R, Miyata H, Ninomiya A, Emori C, Kamoshita M, Pan C, Wang H, Ikawa M. Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. Proceedings of the National Academy of Sciences. 2025;122(42):e2513924122. https://doi.org/10.1073/pnas.2513924122 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 173: Bottlebrush Block Copolymer Shields Muscles and Prevents DMD Onset In this episode of PaperCast Base by Base, we explore a PNAS study showing how a synthetic bottlebrush block copolymer can act as a powerful membrane stabilizer to protect dystrophin-deficient muscle in Duchenne muscular dystrophy. Study Highlights:Researchers engineered and tested an amphiphilic bottlebrush diblock polymer, B–PEO43_10–PPO15_5, as a membrane stabilizer in the mdx mouse model of Duchenne muscular dystrophy. At nanomolar doses, the polymer rapidly restored twitch contractility in single dystrophin‑deficient fibers and showed ~150,000‑fold greater potency than optimized linear PEO–PPO copolymers. Early systemic dosing from postnatal day 1 to 21 prevented the surge of serum creatine kinase and blocked histologic hallmarks of damage in tibialis anterior and diaphragm while routine liver and kidney panels remained normal. In adult mice, pretreatment prevented IgG entry into myocardium during isoproterenol stress and significantly improved survival during combined handling and β‑adrenergic stress tests. Conclusion:This work positions bottlebrush block copolymers as fast‑acting, mutation‑agnostic membrane stabilizers with potential to preserve skeletal, respiratory, and cardiac muscle when deployed early and to complement gene‑based therapies. Reference:Cohen H, Bez Batti Angulski A, Quick JD, Kuebler TS, Thompson BR, Bauer J, Hahn D, Townsend D, Hassler JF, Hackel BJ, Lodge TP, Sham YY, Bates FS, Metzger JM. Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy. Proceedings of the National Academy of Sciences. 2025;122(42):e2513599122. https://doi.org/10.1073/pnas.2513599122 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 172: When Random DNA Fights Back: De Novo Gene Birth as Antiphage Defense In this episode of PaperCast Base by Base, we explore a PNAS study showing that short, previously nongenic DNA sequences can quickly evolve into genes that help bacteria survive phage attack, illuminating early steps of gene birth and the host–virus arms race. fileciteturn2file0 Study Highlights:The authors screened two massive libraries totaling ~100 million (semi-)random open reading frames in Escherichia coli and recovered thousands of sequences that improved survival during T4 phage challenge. A set of short proteins, dubbed Random Inhibitors of Phage infection (Rips), broadly protected cells by activating the Rcs envelope-stress pathway and triggering colanic-acid capsule production that physically blocks adsorption. A second class of hits, Random T4 Inhibitor Products (rtp1–4), acted with specificity by reducing expression of the OmpC outer-membrane receptor, thereby limiting T4 and other OmpC-dependent phage entry; for some rtp genes the protective molecule was RNA rather than protein. Transcriptomics, reporter assays, and adsorption measurements supported these mechanisms while showing minimal growth penalties, and evolved T4 variants rapidly gained baseplate mutations that restored adsorption and infectivity. Conclusion:Random sequence space harbors many routes to immediate fitness gains, with de novo protein- and RNA-based functions rewiring bacterial envelopes and receptors in ways that both reveal mechanisms of gene birth and suggest new antiphage strategies. Reference:Frumkin I, Vassallo CN, Chen YH, Laub MT. Emergence of antiphage functions from random sequence libraries reveals mechanisms of gene birth. Proceedings of the National Academy of Sciences. 2025;122(42):e2513255122. https://doi.org/10.1073/pnas.2513255122 fileciteturn2file0 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 171: Virulence Hierarchies in the Tuberculosis Complex—What Makes Some Lineages Deadlier? In this episode of PaperCast Base by Base, we explore a new PNAS study that directly compares the virulence of Mycobacterium tuberculosis, M. bovis, and M. orygis across natural and laboratory hosts to uncover why animal-adapted lineages can be so devastating. Study Highlights:The authors performed side-by-side infections in Holstein calves and C57BL/6 mice, showing that M. bovis and M. orygis consistently caused more severe disease, faster mortality, and higher bacterial burdens than M. tuberculosis. Comparative proteomics identified ESAT‑6/CFP‑10 and the SigK‑regulated antigen MPT70 as prominent secreted factors in animal-adapted lineages, and gene deletions reversed the lethal phenotype for M. bovis but not for M. orygis. Disease outcomes depended on infection route and immune history, with oral priming, BCG vaccination, and a multisubunit vaccine (H107e) markedly prolonging survival after aerosol challenge. Together, the data establish a clear virulence hierarchy within the MTBC and point to lineage‑informed antigen choices for future vaccines and control strategies. Conclusion:Animal-adapted MTBC members can be hypervirulent compared with M. tuberculosis, and their distinct antigenic profiles and route‑dependent biology offer actionable clues for next‑generation zoonotic and human TB vaccines. Reference:Danchuk SN, Duffy SC, Sullivan J, Rufai SB, McIntosh FA, Lupien A, Harrison LB, et al. Virulence hierarchies within the Mycobacterium tuberculosis complex. Proceedings of the National Academy of Sciences. 2025;122(42):e2507104122. https://doi.org/10.1073/pnas.2507104122 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/