Base by Base

Martínez‑López JA et al et al., Nature Communications - This episode examines a Nature Communications study that introduces differential Gene Coordination Network Analysis (dGCNA) applied to deep Smart-seq2 single-cell RNA-seq of human pancreatic islets from 16 T2D and 16 non‑T2D donors. The method uncovers cell type‑specific networks altered in T2D, validates mechanistic roles for CEBPG and TMEM176A/B, and contrasts beta- and alpha-cell programs. Key terms: single-cell RNA-seq, type 2 diabetes, dGCNA, beta cells, TMEM176A/B.

Study Highlights:
The authors developed dGCNA to compare gene‑pair coordination between T2D and non‑T2D single cells and applied it to two merged Smart‑seq2 datasets. In beta cells dGCNA identified eleven networks (NDCGs) linked to processes such as mitochondria, glycolysis, UPR, cytoskeleton, insulin secretion and ribosomes, many reproducible across datasets. Functional validation showed CEBPG modulates the unfolded protein response and insulin transcription, while TMEM176A/B controls beta cell microfilament organization and influences insulin secretion and in vivo glucose responses. Alpha cells displayed four distinct NDCGs (secretory granules, glycolysis, mitochondria, ribosome), highlighting cell type‑specific T2D alterations.

Conclusion:
dGCNA leverages single‑cell variability to reveal reproducible, cell type‑specific regulatory network changes in T2D, pinpointing mechanistic genes and pathways that are not evident from standard differential expression alone.

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

Article title:
Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes

First author:
Martínez‑López JA et al

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65060-z

Reference:
Martínez‑López JA et al., Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes. Nature Communications (2025). doi:10.1038/s41467-025-65060-z

License:
Creative Commons Attribution 4.0 International License

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/dgcna-cell-type-specific-t2d

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-06.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited sections include: dGCNA methodology and NDCG identification in beta and alpha cells; functional validation of CEBPG and TMEM176A/B; cross-dataset replication and DESeq2 comparison; depth requirements (~1M reads/cell); and translational implications for therapy targets.
- transcript topics: Differential Gene Coordination Network Analysis (dGCNA) in islet cells; Beta-cell networks (NDCGs): Ribosome, Insulin secretion, Lysosome, UPR, Glycolysis, Mitochondria, Microfilaments, Microtubuli, Proliferation; Alpha-cell networks (NDCGs): Secretory granules, Glycolysis, Mitochondria, Ribosome; CEBPG as regulator of UPR and insulin transcription; knockout/knockdown effects; TMEM176A/B regulation of microfilament organization and insulin secretion; Deep sequencing depth requirement for dGCNA (~1M reads/cell)

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:
- dGCNA identified 11 beta-cell NDCGs with specificity to beta-cell dysfunction in T2D
- Beta-cell NDCGs hyper-coordinated: Ribosome, Insulin secretion, Lysosome; decoordinated: UPR, Microfilaments, Glycolysis, Proliferation, Glucose response, Microtubuli, Mitochondria
- Alpha cells show four NDCGs: Secretory granules, Glycolysis, Mitochondria, Ribosome
- CEBPG is a regulator of the beta-cell UPR; Cebpg KO/KD reduces UPR mediators and increases insulin transcription; Cebpg KD increases protein aggregation
- TMEM176A/B regulate beta-cell microfilament organization; TMEM176A/B KO/KD increases actin density and alters exocytosis-related genes
- dGCNA outperforms DESeq2 in identifying T2D-associated gene changes and shows replication across two datasets

QC result: Pass.

️ 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/

Nature Communications (2025) 16:9457 et al., Nature Communications - Phase I dose-escalation trial combining CRLX101 (nanoparticle camptothecin) with olaparib using a 48-hour gapped schedule in 24 patients with advanced solid tumors to determine MTD and assess pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy. Key terms: CRLX101, olaparib, PARP inhibitor, topoisomerase I, gapped scheduling.

Study Highlights:
This phase I study combined tumor-targeted CRLX101 with gapped olaparib dosing in 24 heavily pretreated patients to identify a tolerable regimen and probe PD effects. The MTD/RP2D was CRLX101 12 mg/m² every two weeks with olaparib 250 mg twice daily on days 3–13 and 17–26. Pharmacokinetics were consistent with single-agent profiles and γH2AX in hair follicles and PBMCs increased after olaparib, indicating augmented DNA damage. Among 19 evaluable patients there were two confirmed partial responses and six stable diseases with manageable myelosuppression.

Conclusion:
Tumor-targeted TOP1 delivery paired with a 48-hour gapped olaparib schedule established a recommended Phase 2 dose (CRLX101 12 mg/m² + olaparib 250 mg BID on specified days), produced additive DNA-damage pharmacodynamics, showed preliminary antitumor activity, and was tolerable with expected hematologic toxicity, supporting further evaluation.

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

Article title:
Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling

First author:
Nature Communications (2025) 16:9457

Journal:
Nature Communications

DOI:
10.1038/s41467-025-64509-5

Reference:
Nature Communications (2025) 16:9457; https://doi.org/10.1038/s41467-025-64509-5

License:
CC BY 4.0 (Creative Commons Attribution 4.0 International License)

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/gapped-scheduling-crlx101-olaparib-phase1

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections cover: DDR rationale, TOP1 and PARP inhibitors, CRLX101 nanoparticle delivery, gapped 48-hour scheduling, phase I trial design and dosing, pharmacodynamics (γH2AX) in surrogate tissues, pharmacokinetics, safety/toxicity, clinical efficacy signals (PR/SD), and exploratory genomic analyses.
- transcript topics: DNA damage response and PARP/TOP1 inhibitor synergy; CRLX101 nanoparticle delivery and tumor targeting via EPR; Gapped scheduling strategy with a 48-hour interval; Phase I trial design, dosing levels, and RP2D; Pharmacokinetics of CRLX101 and olaparib with no major interaction; Pharmacodynamics: γH2AX as a biomarker in hair follicles and PBMCs

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:
- MTD for CRLX101 and olaparib (RP2D) reported as 12 mg/m2 q2w and 250 mg BID on days 3–13 and 17–26
- 31-dose escalation with RP2D determined at DL4R
- 19 evaluable patients; 2 partial responses; 6 stable disease; median OS 6.06 months; median PFS 2.34 months
- γH2AX pharmacodynamics detected in hair follicles and PBMCs, increasing with combination treatment
- PK data show CRLX101 and olaparib with no major drug–drug interaction; CRLX101 half-life ~47 hours
- Gap scheduling mitigates bone marrow toxicity while allowing higher olaparib dosing

QC result: Pass.

️ 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/