Base by Base

️ Episode 202: Stereo-seq V2: Spatial Total RNA Mapping in FFPE Tissues In this episode of PaperCast Base by Base, we explore how Stereo-seq V2 delivers high-resolution spatial mapping of total RNA in FFPE samples, from mouse brain to breast cancer and tuberculosis lung tissue. Study Highlights:The authors introduce Stereo-seq V2, a random-priming spatial transcriptomics platform that captures total RNA in situ on FFPE sections at single-cell resolution. By benchmarking against earlier Stereo-seq and other spatial methods in the mouse brain, they demonstrate improved gene detection, uniform gene body coverage, and robust profiling of non-coding RNAs and immune receptor transcripts. In long-stored triple-negative breast cancer blocks, Stereo-seq V2 maintains high sensitivity despite degraded RNA, enabling inference of copy-number alterations and spatially resolved alternative splicing events that distinguish tumor subtypes. Using Mycobacterium tuberculosis infection models in mice and human lung tissue, the study simultaneously maps host and pathogen transcriptomes and reconstructs spatial B cell receptor repertoires, revealing clonal expansion and affinity maturation around necrotic lesions. Conclusion:Stereo-seq V2 unlocks archival FFPE samples for high-resolution spatial total RNA and immune repertoire analysis, opening new avenues for translational research, infectious disease biology, and precision pathology. Music:Enjoy the music based on this article at the end of the episode. Reference:Zhao Y, Li Y, He Y, et al. (2025) Stereo-seq V2: Spatial mapping of total RNA on FFPE sections with high resolution. Cell 188, 6554–6571. https://doi.org/10.1016/j.cell.2025.08.008 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 201: Sex, Smoking, and Somatic Selection in the Bladder In this episode of PaperCast Base by Base, we explore how ultradeep duplex DNA sequencing of normal human bladder tissue reveals sex- and smoking-related biases in the selection of somatic mutations and cancer driver clones. Study Highlights:Researchers applied ultradeep duplex DNA sequencing at around 5,000× coverage to 79 normal bladder urothelium samples from 45 deceased donors, targeting 16 genes known to drive clonal expansions and bladder tumors. They identified more than 64,000 somatic mutations and thousands of clonal driver events, allowing precise estimates of positive and negative selection across genes such as TP53, RBM10, STAG2, ARID1A, CDKN1A, FGFR3, and the TERT promoter. Men showed markedly stronger positive selection for truncating driver mutations in RBM10, CDKN1A, and ARID1A than women, despite similar burdens of non-protein-affecting mutations, indicating sex-specific differences in clonal evolution of the normal urothelium. Activating TERT promoter mutations were strongly associated with older age and were far more frequent in donors with a history of smoking, suggesting that tobacco exposure promotes the expansion of telomerase-activated clones rather than simply increasing overall mutation burden. By approaching “natural saturation mutagenesis” in these genes, the study maps selection at individual residues and protein domains, providing an in vivo framework to assess the functional impact of somatic mutations directly in human tissues. Conclusion:These results show that sex and smoking history leave distinct imprints on the clonal architecture of the normal bladder and highlight ultradeep sequencing of normal tissues as a powerful tool for understanding cancer risk and mapping functionally important mutations in vivo. Music:Enjoy the music based on this article at the end of the episode. Reference:Calvet F, Blanco Martinez-Illescas R, Muiños F, Tretiakova M, Latorre-Esteves ES, Fredrickson J, et al. Sex and smoking bias in the selection of somatic mutations in human bladder. Nature. 2025;647:436–444. https://doi.org/10.1038/s41586-025-09521-x 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 200: Sperm Sequencing Reveals Extensive Positive Selection in the Male Germline In this episode of PaperCast Base by Base, we explore how ultra-accurate duplex sequencing of human sperm reveals widespread positive selection in the male germline and its consequences for mutation burden and disease risk in offspring. Study Highlights:This Nature study uses NanoSeq duplex whole-genome and exome sequencing on sperm and matched blood samples from healthy men aged 24 to 75 years to quantify how mutations accumulate in the male germline. The authors show that sperm acquire about 1.67 substitutions per year per haploid genome, several-fold fewer than blood cells, with age-related signatures SBS1 and SBS5 dominating the mutation spectrum. By modeling nonsynonymous versus synonymous variants, they identify 40 genes under significant positive selection in spermatogonial lineages, many of which are classic cancer and developmental disorder genes enriched for activating and loss-of-function mutations. Aggregating variant allele fractions across these genes, they estimate that positive selection drives a two- to threefold enrichment of likely pathogenic mutations, such that roughly 3–5% of sperm from middle-aged to older men carry a potentially disease-causing coding variant. Conclusion:Positive selection in spermatogonial stem cells subtly reshapes the male germline over the lifespan, increasing the fraction of sperm that carry pathogenic mutations and refining how we think about paternal age, reproductive risk, and the shared genetic architecture of cancer and developmental disorders. Music:Enjoy the music based on this article at the end of the episode. Reference:Neville MDC, Lawson ARJ, Sanghvi R, Abascal F, Pham MH, Cagan A, et al. Sperm sequencing reveals extensive positive selection in the male germline. Nature. 2025;647:421–428. https://doi.org/10.1038/s41586-025-09448-3 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com Castos player https://basebybase.castos.com

️ Episode 199: PLD4 Deficiency and Lupus: When Nuclease Failure Ignites Autoimmunity In this episode of PaperCast Base by Base, we explore how loss-of-function mutations in the endolysosomal exonuclease PLD4 cause a monogenic form of systemic lupus erythematosus, reshaping our understanding of nucleic acid sensing and interferon-driven autoimmunity. Study Highlights:This study identifies biallelic loss-of-function PLD4 mutations in five patients with systemic lupus erythematosus, all presenting with severe lupus nephritis and hematologic involvement. Using whole-exome sequencing, structural modelling and biochemical assays, the authors show that these PLD4 variants markedly impair single-stranded DNA and RNA exonuclease activity, leading to accumulation of nucleic acid ligands in endolysosomes. Patient immune profiling with bulk and single-cell RNA sequencing, flow cytometry and CyTOF reveals hyperactivation of Toll-like receptor 7 and 9 pathways, with a strong type I interferon signature centered in plasmacytoid dendritic cells and monocytes. In Pld4-deficient mice, the team demonstrates lupus-like autoimmunity with nephritis, expansion of plasmacytoid dendritic cells and plasma cells, and upregulation of interferon-stimulated genes in kidney immune and parenchymal cells. Finally, pharmacologic JAK inhibition with baricitinib dampens type I interferon signalling, reduces autoantibody levels and renal inflammation in Pld4−/− mice, and suppresses interferon and NF-κB pathway activation in patient cells ex vivo. Conclusion:By defining PLD4 deficiency as a new monogenic cause of systemic lupus erythematosus and showing that JAK inhibition can reverse key interferon-driven features in experimental models and patient cells, this work points toward precision diagnostics and targeted therapies for a subset of patients with lupus driven by dysregulated endosomal nucleic acid clearance. Music:Enjoy the music based on this article at the end of the episode. Reference:Wang Q, Zhu H, Sun X, Zhang C, Ma S, Jin Y, et al. Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus. Nature. 2025;647:498–505. https://doi.org/10.1038/s41586-025-09513-x 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 Castos player - https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 197: Somatic Mutation and Selection at Population Scale In this episode of PaperCast Base by Base, we explore how ultra-accurate NanoSeq duplex sequencing reveals the hidden landscape of somatic mutations and clonal selection across blood and oral epithelium in over a thousand adults. Study Highlights:This study introduces improved whole-genome and targeted versions of NanoSeq, a duplex sequencing method with error rates below five mutations per billion base pairs, enabling reliable detection of single-molecule variants in highly polyclonal tissues. By applying targeted NanoSeq to 1,042 buccal swabs and 371 blood samples from a twins cohort, the authors map age-related somatic mutation rates and identify 46 genes under positive selection in oral epithelium, yielding more than 62,000 cancer-driver mutations. They also uncover negative selection against truncating variants in essential genes, generating in vivo saturation mutagenesis maps that distinguish activating hotspots from deleterious loss-of-function sites. Mutational signature analyses reveal a ubiquitous clock-like process and an alcohol-associated signature whose burdens vary widely between individuals and correlate with lifestyle factors such as tobacco use, alcohol consumption, and poor oral health. Twin-based and germline analyses further suggest that inherited variants, including a locus near ALDH2, can modulate somatic mutation signatures and driver landscapes. Conclusion:Accurate single-molecule sequencing at population scale shows that normal tissues are mosaics of tiny driver-mutant clones shaped by age, environment, and germline background, opening a path toward mechanistic cancer epidemiology and new biomarkers for early carcinogenesis. Music:Enjoy the music based on this article at the end of the episode. Reference:Lawson ARJ, Abascal F, Nicola PA, et al. Somatic mutation and selection at population scale. Nature. 2025;647:411–419. https://doi.org/10.1038/s41586-025-09584-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.com/  

️ Episode 196: Impact of Chromatin Accessibility QTLs Across Immune Contexts In this episode of PaperCast Base by Base, we explore how single-cell chromatin accessibility QTLs (caQTLs) reshape the interpretation of immune disease genetics by mapping regulatory variation across major immune cell types and disease-relevant states. Study Highlights:The authors harmonized ∼280,000 PBMC scATAC-seq profiles from 48 individuals—including healthy donors and COVID-19 patients—to build a unified chromatin accessibility atlas. Topic modeling uncovered continuous cell-state programs, including a CD8 effector-memory continuum associated with COVID-19, and enabled the discovery of 37,390 caQTLs plus thousands of dynamic, state-dependent effects. Compared to eQTLs, caQTLs explained roughly 50% more GWAS loci and highlighted that many regulatory variants act through chromatin without detectable steady-state expression changes in current datasets. Extensive sharing of caQTLs across immune cell types contrasted with the context specificity of eQTL colocalizations, underscoring the need to integrate chromatin, expression, enhancer–promoter links, and disease-relevant cellular states to pinpoint causal mechanisms. Conclusion:Chromatin accessibility QTLs substantially expand the fraction of disease loci with molecular support, but reliable causal gene mapping requires convergence of caQTL and eQTL signals within the same cellular context and along relevant cell-state trajectories. Music:Enjoy the music based on this article at the end of the episode. Reference:Mu Z, Randolph HE, Aguirre-Gamboa R, Ketter E, Dumaine A, Locher V, Brandolino C, Liu X, Kaufmann DE, Barreiro LB, Li YI. Impact of disease-associated chromatin accessibility QTLs across immune cell types and contexts. Cell Genomics. 2026;6:101061. https://doi.org/10.1016/j.xgen.2025.101061 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.com/

️ Episode 195: Tiny Shields: Lymphoid Microglia in Alzheimer’s Disease In this episode of PaperCast Base by Base, we explore how a subset of brain immune cells adopts a lymphoid-like program that helps contain inflammation and protect neural circuits in Alzheimer’s disease models. Study Highlights: Using mouse models of amyloid pathology and human Alzheimer’s brain tissue, the authors identify plaque-associated microglia with reduced PU.1 expression that cluster around deposits and express an unexpected set of lymphoid receptors, including CD28. By genetically tuning PU.1 levels specifically in microglia, they show that lowering PU.1 is sufficient to trigger this lymphoid-like transcriptional program, remodel chromatin and generate microglia that compact amyloid plaques, limit tau aggregation and preserve synapses, plasticity and behaviour. These PU.1low microglia display fewer type I interferon and complement signatures, accumulate fewer lipid droplets and extend survival in Alzheimer’s model mice, indicating a broadly neuroprotective state. In contrast, microglia-specific deletion of CD28 amplifies amyloid burden and drives a widespread pro-inflammatory interferon response in the microglial pool, suggesting that a small CD28+ subset exerts outsized control over brain inflammation. Human genetic data further link a PU.1-lowering SPI1 allele with increased abundance of lymphoid-like microglia, supporting the relevance of this protective program in people with Alzheimer’s disease. Conclusion: This work positions PU.1-tuned, CD28-expressing microglia as critical regulators of neuroinflammation and suggests that selectively boosting their lymphoid-style “checkpoint” signals could inspire new immunotherapy strategies for Alzheimer’s disease. Music: Enjoy the music based on this article at the end of the episode. Reference: Ayata P, Crowley JM, Challman MF, et al. Lymphoid gene expression supports neuroprotective microglia function. Nature. 2025. https://doi.org/10.1038/s41586-025-09662-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.com/ On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 194: Bayesian History of Science: Watson and Crick and the Structure of DNA In this episode of PaperCast Base by Base, we explore how Bayesian reasoning can be used to reconstruct the famous discovery of the DNA double helix by James Watson and Francis Crick, following the sequence of structural models proposed in the early 1950s and the evolving evidence that supported or undermined each hypothesis. Study Highlights:The author applies a naïve Bayes framework to four competing models of DNA proposed by Watson, Crick, and Linus Pauling, treating each model as a target theory evaluated against multiple lines of historical evidence such as X-ray diffraction patterns, base pairing rules, symmetry constraints, and stereochemical feasibility. Conditional probabilities for how well each model accounts for each piece of evidence are manually estimated from historical sources using a simple five-point scale ranging from strongly inconsistent to strongly consistent, and combined with prior probabilities to calculate posteriors and likelihood ratios. By updating priors model by model, the study reconstructs how initial triple-helix proposals were progressively disconfirmed, while intermediate double-helix attempts with incorrect base pairing achieved only modest support despite offering a plausible replication mechanism. A dramatic jump in posterior probability and in the likelihood ratio is observed for the final Watson–Crick model with complementary purine–pyrimidine base pairing, consistent bond geometry, compliance with Chargaff’s rules, and correct symmetry, which the author interprets as a form of “Bayesian surprise” that matches scientists’ retrospective sense of having made a genuine discovery. The analysis also shows how “soft” considerations, such as analogy to Pauling’s alpha helix and the promise of an explanatory replication mechanism, can be incorporated alongside hard experimental data within a Bayesian account of theory choice in the history of science. Conclusion:This work argues that Bayesian analysis provides a coherent way to track how evidence and prior expectations jointly shaped the path from early speculative DNA models to the accepted double-helix structure, offering a quantitative complement to narrative histories of scientific discovery. Reference:Small H. Bayesian history of science: The case of Watson and Crick and the structure of DNA. Quantitative Science Studies. 2023;4(1):209–228. https://doi.org/10.1162/qss_a_00233 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.com/

️Episode 193: SARM1, DNA, and the Death Signal In this episode of PaperCast Base by Base, we explore how the axon-degenerating enzyme SARM1 acts as a double-stranded DNA sensor that triggers NAD+ loss, cell death, and chemotherapy-induced neuropathy, opening up new possibilities for neuroprotective therapies. Study Highlights:The authors show that the immune adaptor SARM1 directly binds double-stranded DNA via its TIR domain and, once activated, rapidly degrades cellular NAD+ in a sequence-independent but length-dependent manner. Using a combination of biochemical assays and structural analyses, they demonstrate that SARM1 forms multimeric complexes with linear DNA, with optimal activation occurring when DNA fragments are long enough to engage multiple SARM1 molecules. In cells, cytosolic DNA introduced by transfection or released during chemotherapy colocalizes with SARM1, driving NAD+ depletion and promoting cell death, whereas mutations that disrupt DNA binding or complete knockout of SARM1 blunt this response. In mouse models, loss of SARM1 protects against chemotherapy-induced neuropathy, linking DNA sensing by SARM1 directly to treatment-related neurotoxicity and positioning this pathway as a therapeutic target. Conclusion:By revealing SARM1 as a double-stranded DNA sensor that couples cytosolic DNA to NAD+ degradation, cell death, and chemotherapy-induced neuropathy, this study highlights a druggable axis for preserving neural function during cancer treatment. Reference:Wang L, Liu Q, Li S, et al. SARM1 senses dsDNA to promote NAD+ degradation and cell death. Cell. 2025;188:1–18. https://doi.org/10.1016/j.cell.2025.09.026 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 192: At Base-Pair Resolution: Chromatin’s Cis-Regulatory Conversations In this episode of PaperCast Base by Base, we explore how base-pair resolution maps of chromatin contacts reveal a unified, biophysical model of communication between enhancers, promoters, and other cis-regulatory elements in mammalian cells. Study Highlights:Using Micro Capture-C ultra (MCCu), the authors generate multidimensional chromosome conformation maps with single base-pair pixels, allowing them to resolve contacts between individual transcription factor motifs within cis-regulatory elements in mouse embryonic stem, hematopoietic progenitor, and erythroid cells. They show that nucleosome-depleted regions partition chromatin into nanoscale domains and form highly localized contacts with one another, while surrounding nucleosomes produce distinct patterns of linker spacing that mark inactive regions. By acutely degrading Mediator complex subunits with degron systems, they find that Mediator is critical for fine-scale promoter architecture and transcription complex stabilization but has only minor effects on large-scale enhancer–promoter contacts. Integrating MCCu data with coarse-grained molecular dynamics simulations and super-resolution imaging, they demonstrate that the physicochemical properties of chromatin itself can recapitulate observed contact patterns and help explain how transcription factor binding and nucleosome positioning coordinate cis-regulatory interactions. Conclusion:This work provides a high-resolution framework for linking chromatin biophysics to gene regulation, offering a roadmap for dissecting how specific protein complexes and nucleosome landscapes shape enhancer–promoter communication across the genome. Reference:Li H, Dalgleish JLT, Lister G, et al. Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions. Cell. 2025;188:1–19. https://doi.org/10.1016/j.cell.2025.10.013 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 191: CATphishing: Synthetic Learning as an Alternative to Federated Learning in MRI In this episode of PaperCast Base by Base, we explore a Nature Communications study that proposes CATphishing—an approach that uses latent diffusion models to generate site-specific synthetic 3D brain MRIs for collaborative training without sharing raw data. The work spans seven institutions and 2,491 patients and evaluates whether models trained on synthetic data can match those trained via centralized data sharing or federated learning. Study Highlights:The authors train latent diffusion models locally at each site to capture dataset-specific MRI distributions and then aggregate only synthetic multi-contrast MRIs and tumor masks for downstream model training across centers. In IDH mutation status classification, models trained solely on synthetic data achieved performance comparable to centralized and federated approaches, with overall accuracy around 95.5% and AUC near 0.966, versus 96.2% and 0.979 for centralized training. A two‑stage tumor‑type pipeline—separating glioblastoma from IDH‑mutated tumors and then classifying oligodendroglioma versus astrocytoma—likewise showed similar end‑to‑end accuracy for synthetic versus real‑data strategies, landing near 90–92% overall. Fidelity and privacy were examined with FID and no‑reference image‑quality metrics and by a membership‑inference analysis that performed at chance, supporting the case for synthetic data as a viable, privacy‑preserving alternative in multi‑center AI development. Conclusion:CATphishing demonstrates that high‑fidelity synthetic MRI can enable cross‑institutional modeling with accuracy close to real‑data training while reducing privacy, communication, and coordination burdens in multi‑center collaborations. Reference:Truong NCD, Yogananda CGB, Wagner BC, Holcomb JM, Reddy DD, Saadat N, Bowerman J, Hatanpaa KJ, Patel TR, Fei B, Lee MD, Jain R, Bruce RJ, Madhuranthakam AJ, Pinho MC, Maldjian JA. Categorical and phenotypic image synthetic learning as an alternative to federated learning. Nature Communications. 2025;16:9384. https://doi.org/10.1038/s41467-025-64385-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 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/