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Base by Base

Gustavo Barra

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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.
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️ Episode 225: VRK-1 and BAF-1 release meiotic chromosomes In this episode of PaperCast Base by Base, we explore VRK-1 phosphorylates BAF-1 to remove chromatin from the nuclear periphery during early meiotic prophase in C. elegans, and failure of this step impairs pairing and synapsis and generates heritable genome lesions Study Highlights: The aut…
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️ Episode 224: AntennAlive — wireless in-body sensing with engineered bacteria In this episode of PaperCast Base by Base, we explore A bio-hybrid, battery-free implant converts engineered bacterial activity into microwave backscatter signals by controlled degradation of a biodegradable antenna Study Highlights: The AntennAlive system uses a magnesi…
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️ Episode 223: Torsion Regulates DNA Replication Stalling and Restart In this episode of PaperCast Base by Base, we explore New single-molecule angular optical trap assays reveal that DNA torsion directly controls T7 replisome stalling and reactivation Study Highlights: A high-resolution, label-free angular optical trap (AOT) assay was developed to…
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️ Episode 222: snaR-A hijacks splicing to drive proliferation In this episode of PaperCast Base by Base, we explore This episode examines how the cancer-associated Pol III transcript snaR-A binds core splicing factors, localizes near nuclear speckles, perturbs U2-dependent splicing to increase intron retention, and promotes cell proliferation linke…
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️ Episode 221: Allele-resolved nanopore tour of the human placental methylome In this episode of PaperCast Base by Base, we explore Using phased long-read nanopore and short-read sequencing across eight trios, the study maps allele-specific DNA methylation and transcription in female human placentas, identifies hundreds of DMRs and novel imprinted …
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️Episode 220: The AML cellular state space reveals NPM1 immune evasion subtypes In this episode of PaperCast Base by Base, we explore Single-cell and bulk sequencing of 120 AML cases reveal two NPM1-mutated subtypes with distinct immune evasion mechanisms and divergent responses to hematopoietic stem cell transplantation Study Highlights: Bulk RNA-…
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️Episode 219: Multi-omic mapping of lipid dysregulation in Parkinson’s brain In this episode of PaperCast Base by Base, we explore Targeted multi-region lipidomics with proteomic and mitochondrial data reveals region- and stage-specific lipid alterations in Parkinson’s disease that converge on mitochondrial dysfunction Study Highlights: The study q…
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️Episode 218: SIM1 and the multi-ancestry genomics of erectile dysfunction In this episode of PaperCast Base by Base, we explore A large multi-ancestry GWAS meta-analysis identifies a dominant SIM1-linked locus and multiple genetic connections between electronic health record-defined erectile dysfunction and cardiometabolic, psychiatric, and substa…
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️Episode 217: Multiscale triads of meiotic crossover patterning In this episode of PaperCast Base by Base, we explore FFT and inverse-FFT analysis of Zip3/Zip2, Hop1 and Zip1 on yeast pachytene chromosomes reveals two interdigitated tiers of evenly spaced protein triads that correspond to canonical and minority crossovers and are differentially reg…
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️ Episode 216: 53BP1-RIF1 and DNA-PKcs: distinct interactions in chromosomal break repair In this episode of PaperCast Base by Base, we explore This episode reviews a study showing that 53BP1-RIF1 and DNA-PKcs have different genetic relationships across blunt end joining, deletion patterns, HDR, and radiosensitivity Study Highlights: Using EJ7-GFP …
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️ Episode 215: Protein Set Transformer for high-diversity viromics In this episode of PaperCast Base by Base, we explore Protein Set Transformer (PST) is a protein-based genome language model that represents genomes as sets of proteins to improve genome and protein representations across diverse viral datasets Study Highlights: PST embeds proteins …
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️ Episode 214: PI(4,5)P2 Asymmetry Enables Rapid FGF2 Secretion In this episode of PaperCast Base by Base, we explore This study shows that an asymmetric transbilayer distribution of PI(4,5)P2 lowers the energy barrier for lipidic pore formation and accelerates unconventional secretion of Fibroblast Growth Factor 2 Study Highlights: The authors gen…
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️ Episode 213: BRAIN-MAGNET: a functional atlas for non-coding variants In this episode of PaperCast Base by Base, we explore BRAIN-MAGNET couples a ChIP-STARR-seq atlas of 148,198 neural regulatory elements with a validated convolutional neural network to predict enhancer activity and prioritize disease-relevant non-coding variants Study Highlight…
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️ Episode 212: Zonal control of mutant β-catenin tumorigenesis This study shows that hepatic zonation determines whether mutant β-catenin drives proliferation and liver cancer by forcing differentiation to a non-permissive zone 3 fate or, when reversed, enabling MAPK- and mTOR-dependent growth Study Highlights: β-catenin exon 3 mutations cooperate …
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️ Episode 211: Retention Elements in Cancer Cells In this episode of PaperCast Base by Base, we explore the discovery of genetic elements that promote the retention of extrachromosomal DNA (ecDNA) in cancer cells, enhancing their survival and evolution. Study Highlights: Researchers identified a family of genomic elements known as retention element…
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️ Episode 210: Tumour-Reactive CD8 T Cell Clusters in Human Melanoma In this episode of PaperCast Base by Base, we explore how tumour-reactive CD8 T cells organize into stable clusters with melanoma cells and antigen-presenting cells, and how these structures can be isolated from patient samples to boost anti-tumour immunity. Study Highlights: The …
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️ Episode 209: PERT: Prime Editing tRNAs for Nonsense Mutations In this episode of PaperCast Base by Base, we explore how prime editing can reprogram endogenous tRNAs into potent suppressor tRNAs, enabling a single therapeutic strategy to rescue many different genetic diseases caused by premature stop codons. Study Highlights: The authors introduce…
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️ Episode 208: ZAK, Collided Ribosomes, and the Stress Switch In this episode of PaperCast Base by Base, we explore how collided ribosomes activate the MAP3K ZAK to drive the ribotoxic stress response and shape cell fate decisions under translational stress. Study Highlights: Using biochemistry, cryo-electron microscopy and crosslinking-based RNA m…
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️ Episode 207: Semantic Design of de novo Genes with Evo In this episode of PaperCast Base by Base, we explore how a genomic language model called Evo can use genomic context to design entirely new DNA sequences that encode functional genes and multi-component defence systems. Study Highlights: Researchers trained the Evo genomic language model on …
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️ Episode 206: Wild Birds and the North American H5N1 Epizootic In this episode of PaperCast Base by Base, we explore how wild migratory birds have shaped the ecology and spread of the 2021–2023 highly pathogenic H5N1 epizootic across North America, and what this means for wildlife conservation and poultry health. Study Highlights: Using 1,818 haem…
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️ Episode 205: Ancient RNA Expression Profiles from the Woolly Mammoth In this episode of PaperCast Base by Base, we explore how ancient RNA preserved in permafrost can reveal tissue-specific gene expression and regulatory dynamics in the extinct woolly mammoth. Study Highlights: Researchers analyzed skeletal muscle and skin from ten Late Pleistoce…
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️ Episode 204: StealTHY CRISPR: Revealing Hidden Metastasis Regulators In this episode of PaperCast Base by Base, we explore how the StealTHY CRISPR platform sidesteps Cas9 immunogenicity to uncover metastasis drivers in immunocompetent and humanized cancer models. Study Highlights: Researchers show that standard CRISPR-Cas9 tools and xenogeneic re…
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️ Episode 203: Divergent Evolutionary Dynamics of Benign and Malignant Tumors In this episode of PaperCast Base by Base, we explore how benign and malignant tumors follow different evolutionary trajectories across birds and mammals, and what this reveals about cancer defenses across the tree of life. Study Highlights: The authors combine necropsy d…
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️ 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…
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️ 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 …
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️ 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 …
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️ 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…
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️ Episode 198: Mechanical Confinement and the Shape-Shifting Life of Melanoma Cells In this episode of PaperCast Base by Base, we explore how physical forces in the tumor microenvironment can push melanoma cells to switch from a pigment-producing, proliferative state into an invasive, drug-tolerant one, focusing on new work that links mechanical co…
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️ 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…
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️ 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: T…
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️ 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 …
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️ 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 …
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️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…
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️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 Mic…
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️ 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 dat…
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️ 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 Highlig…
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️ 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…
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️ 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. St…
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️ 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 ef…
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️ 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 High…
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️ 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…
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️ 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 p…
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️ 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,…
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️ 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 anal…
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️ 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 relationship…
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️ 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 practic…
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️ 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 postnat…
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️ 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 penet…
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️ 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 lo…
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️ 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 F…
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