Base by Base

Gao J et al., Nat Commun - H4 tail lysine residues drive liquid-liquid phase separation of 12‑mer nucleosome arrays, while H3 tail acetylation and the histone chaperone Nap1 increase internal dynamics and lower droplet viscosity. Key terms: Nap1, H3 acetylation, H4 acetylation, liquid-liquid phase separation, nucleosome arrays.

Study Highlights:
H4 tail lysine residues are the primary drivers of nucleosome array phase separation, and H4-tail acetylation prevents droplet formation. H3 tail acetylation mimic (H3KQ) and in situ H3 acetylation speed fluorescence recovery, indicating enhanced DNA–histone dynamics. Nap1 dissolves gel-like aggregates formed by tailless H3 arra...

️ Episode 252: Keratinocytes to cSCC: genetic steps

In this episode of PaperCast Base by Base, we explore Single-cell and spatial multi-omic profiling maps the genetic and transcriptional changes from normal keratinocytes through actinic keratoses to invasive cutaneous squamous cell carcinoma

Study Highlights:
Single-cell genotyping of 137 keratinocytes revealed most cells have low mutation burdens (median 1.14 mut/Mb) while keratinocytes with TP53 or NOTCH1 mutations carry substantially higher burdens. Deep panel sequencing of 16 paired actinic keratoses and adjacent cSCCs showed TERT promoter and CDKN2A mutations arise in actinic keratoses and additional events such as ARID2 loss an...

️ Episode 251: MuSCs, laminin-α2 and LAMA2 MD

In this episode of PaperCast Base by Base, we explore Activated muscle stem cells express and secrete laminin-α2 to remodel their niche, and loss of MuSC-derived laminin-α2 slows MuSC proliferation and delays regeneration in mouse models and human iPSC-derived precursors

Study Highlights:
Activated MuSCs upregulate Lama2 and deposit laminin-α2 around proliferating cells during early regeneration. MuSCs from Lama2-deficient dyW/dyW mice progress more slowly through S phase, accumulate in G1, and show reduced expansion ex vivo and in vivo. Transplantation of dyW/dyW MuSCs into wild-type muscle does n...

️ Episode 250: CIP2A–TOPBP1: Mitotic repair via MiDAS and MMEJ

In this episode of PaperCast Base by Base, we explore This study shows the CIP2A-TOPBP1 complex coordinates two mitotic double-strand break repair pathways, MiDAS and MMEJ, by recruiting SLX4/SMX components and Polθ to mitotic chromatin.

Study Highlights:
TOPBP1 BRCT1/2 binds SLX4 phosphorylated at Thr1260, a CDK1-dependent modification that promotes recruitment of SLX4, MUS81 and ERCC1 to mitotic chromatin to drive MiDAS. CIP2A is required for mitotic chromatin localisation of both TOPBP1 and Polθ, enabling Polθ-dependent MMEJ. Loss of CIP2A impai...

️ Episode 249: PCM1 links centrosome asymmetry to endosome dynamics

In this episode of PaperCast Base by Base, we explore In developing neural progenitors PCM1 localizes to the mother centrosome and to Notch ligand-containing endosomes, promoting Par-3/dynein assembly and Rab5-to-Rab11 trafficking to bias posterior-directed endosome segregation and preserve progenitor fate

Study Highlights:
Pcm1 is asymmetrically enriched at the posterior mother centrosome (Cep83+) in zebrafish radial glia progenitors and is also found on central-zone Notch ligand (Dld)-containing endosomes. In vivo time-lapse imaging and expansion microscopy show Pcm1 puncta move with Dld endosomes and promote po...

️ Episode 248: Disruption of PIKfyve triggers lysosomal repair and mitochondrial adaptation

In this episode of PaperCast Base by Base, we explore Disruption of the PIKfyve/Fig4/Vac14 complex drives ULK1-dependent trafficking of PI4KIIα and ATG9A to lysosomes, elevating lysosomal PI(4)P to promote membrane repair and induce mitochondrial fragmentation with increased respiration

Study Highlights:
PIKfyve complex disruption or pharmacological inhibition reduces mTORC1 signaling, activating ULK1 and driving ATG9A-dependent trafficking of PI4KIIα from the TGN to lysosomes. PI4KIIα accumulation elevates lysosomal PI(4)P, recruiting OSBP/ORP proteins to transfer cholesterol and p...

️ Episode 247: Genome graphs reveal structural variation in M. tuberculosis

In this episode of PaperCast Base by Base, we explore Long-read assemblies and a pangenome reference graph uncover widespread structural variants that shape Mycobacterium tuberculosis evolution and contribute to drug resistance

Study Highlights:
The authors built an M. tuberculosis pangenome reference graph from 859 high-quality long-read assemblies and identified 3,077 unique structural variants genome-wide. They developed miniwalk to genotype SVs from graph-mapped assemblies and showed higher precision for short-read SV genotyping (0.7 vs 0.46 for manta) at modest cost to recall. SVs cluster in GC-rich PE/PPE regions and in...

️ Episode 246: SV2A structural pharmacology and allosteric occlusion

In this episode of PaperCast Base by Base, we explore High-resolution cryo-EM structures of human SV2A reveal that orthosteric ligands induce an occluded MFS conformation and a secondary allosteric pocket modulates ligand binding

Study Highlights:
The authors report sub-3 Å cryo-EM structures of human SV2A in the apo state and in complexes with levetiracetam, UCB-J, padsevonil, and the allosteric modulator UCB1244283. Levetiracetam and UCB-J bind the central cavity and drive inward movement of TM1 with Phe188 sealing the lumen, producing complete occlusion with levetiracetam and par...

️ Episode 245: Benchmarking DNA foundation models

In this episode of PaperCast Base by Base, we explore A comprehensive, unbiased benchmark compares five DNA foundation models across 57 datasets and multiple tasks, finding mean token embeddings improve classification and that model strengths vary by task and pre-training.

Study Highlights:
The study evaluated DNABERT-2, NT-v2, HyenaDNA, Caduceus-Ph, and GROVER on 57 datasets spanning sequence classification, gene expression prediction, variant effect quantification, and TAD recognition. Mean token embedding consistently and significantly outperformed summary-token and max pooling for sequence classification. Model performance was task-dependent: Caduceus-Ph excelled at human TFBS and promoter ta...

️ Episode 244: NEK7 couples SDHB to preserve mitochondrial electron transport and limit liver fibrosis

In this episode of PaperCast Base by Base, we explore Mitochondrial NEK7 is imported via MTS peptides, binds SDHB to stabilize complex II conformation, prevent reverse electron transport and ROS, and thereby protects against spontaneous and experimentally induced liver fibrosis

Study Highlights:
NEK7 localizes to hepatocyte mitochondria through two internal mitochondrial targeting signal peptides and co‑localizes with SDHB. NEK7 binds SDHB and stabilizes complex II spatial conformation without changing SDHB abundance or complex assembly. Hepatocyte NEK7 deficiency induces reverse electron tran...

️ Episode 243: Genome-wide UVB GxE study finds 162 vitamin D variants

In this episode of PaperCast Base by Base, we explore A GWIS of 338,977 UK Biobank White British participants using a cumulative weighted ambient UVB measure identified 307 independent loci for 25-hydroxyvitamin D, including 162 novel variants

Study Highlights:
The study linked a cumulative and weighted ambient UVB (CW-D-UVB) dose from TEMIS to each participant’s residence and blood draw date to model gene-environment interaction on standardized log-transformed 25OHD in 338,977 White British UK Biobank participants. Genome-wide marginal, interaction, and joint tests identified 307 independent variants associated with 25OHD, 162 of whic...

️ Episode 242: AAV9-fcMISv2 gene therapy prevents pregnancy in female cats

In this episode of PaperCast Base by Base, we explore A single intramuscular injection of an AAV9 vector encoding feline anti‑Müllerian hormone (fcMISv2) in prepubertal kittens produced sustained supraphysiological AMH, was well tolerated, and prevented breeding‑induced ovulation and pregnancy in adult females

Study Highlights:
Twelve 2–3 month-old kittens received a single IM dose of AAV9-fcMISv2 (low or high dose) or empty AAV9 and were monitored for up to 21 months for females and 10 months for males. Treated animals showed rapid viral clearance, no clinic...

️ Episode 241: Wagyu T2T reveals a cattle X neocentromere

In this episode of PaperCast Base by Base, we explore A telomere-to-telomere Wagyu assembly uncovers a natural neocentromere on the cattle X formed by inverted repeats and transposable element expansion, adds hundreds of new genes, and improves variant discovery

Study Highlights:
The UOA_Wagyu_1 haplotype-resolved assembly includes a complete X chromosome and four T2T autosomes, adding 431 Mb relative to the ARS-UCD2.0 reference and annotating 738 new protein-coding genes. The cattle X centromere spans ~12 Mb and is a natural neocentromere composed mainly of highly identical inverted re...

️ Episode 240: CYFIP1 controls cortical axon development by modulating calcium

In this episode of PaperCast Base by Base, we explore Reduction of CYFIP1 delays callosal axon growth and arborization by lowering intracellular calcium and impairing mitochondrial function

Study Highlights:
In vivo, Cyfip1+/- mice show delayed callosal axon growth at P5 and reduced axonal branching during P15 arborization that normalizes by P30. Cyfip1+/- cortical neurons have reduced cytosolic and mitochondrial calcium, larger and elongated mitochondria, increased mitochondrial density and motility, and decreased mitochondrial membrane potential and ATP at early stages. CYFIP1 associates with Hu pr...

️ Episode 239: Genomic Adaptations of the Svalbard Reindeer

In this episode of PaperCast Base by Base, we explore Comparative whole-genome analyses identify 150 differentiated genomic regions and candidate genes linked to fat metabolism, energy conservation, cold tolerance, reduced body size, fur morphology, and circadian rhythm that likely underpin Svalbard reindeer adaptation to the High Arctic

Study Highlights:
The authors sequenced and analyzed 62 reindeer genomes from Svalbard, mainland Norway, mainland Russia, and Novaya Zemlya using three complementary approaches: population branch statistic scans, annotation of high-frequency derived coding variants, and copy number variant analysis. They identified 150 genomic regions wi...

️ Episode 238: Germline polymorphisms shape antibody light chain repertoires

In this episode of PaperCast Base by Base, we explore Long-read sequencing of IGK and IGL paired with AIRR-seq shows that common germline SNVs, SVs, and alleles drive inter-individual differences in light chain gene usage and CDR3 properties

Study Highlights:
The authors combined targeted long-read genomic sequencing of IGK and IGL in 177 donors with matched AIRR-seq (IGK n=164, IGL n=168) to generate phased SNV, SV, and allele callsets and personalized germline databases. Cis guQTL analysis identified 2,352 variants in the unmutated IGK repertoire linked to usage changes in...

️ Episode 237: Tracing enteric pathogens in Africa with metagenomics and WGS

In this episode of PaperCast Base by Base, we explore This study combines whole-genome sequencing and metagenomics to map the diversity, abundance, and genomic relationships of enteric foodborne pathogens across human, animal, food and environmental samples in four African LMICs

Study Highlights:
The project sampled 3,417 items across Ethiopia, Mozambique, Nigeria and Tanzania between 2019 and 2023 and applied culture-based WGS and metagenomic sequencing. Of 446 recovered isolates, 380 high-quality genomes were analyzed (207 E. coli, 138 Salmonella spp., 24 Campylobacter spp., 11 Shigella spp.), and 139 metagenomes passed QC for community profiling. Pathogen di...

️ Episode 236: XPD translocation and genetic disease etiology

In this episode of PaperCast Base by Base, we explore Computational modeling reveals how ATP-driven conformational cycles of the XPD helicase drive directional 5′→3′ translocation on single-stranded DNA and how mutations disrupt this process to cause disease

Study Highlights:
The authors combined molecular dynamics, partial nudged elastic band path optimization, transition path sampling, and Markov state modeling to map seven metastable on-path states that define XPD’s ATPase cycle. ATP binding and hydrolysis drive reciprocal rotations of the RecA2 and Arch domains, transmitted via a spring helix and spindle he...

️ Episode 235: Maternal H3K9 methyltransferases control aRMAE in C. elegans

In this episode of PaperCast Base by Base, we explore Using dual-color reporters in C. elegans, the study shows maternal H3K9 methyltransferases MET-2 and SET-25 antagonistically regulate autosomal random monoallelic expression initiated in the early embryo

Study Highlights:
Dual-color fluorescent reporter alleles in C. elegans intestine cells enabled single-cell quantification of allele expression and a targeted screen for aRMAE regulators. MET-2/SETDB1, with LIN-65 and ARLE-14, acts maternally in the 8-cell E-cell to prevent monoallelic expression, while SET-25/SUV39 with HPL-2 and LIN-61 pr...

️ Episode 234: MTHFR genotype and methionine metabolism predict COVID-19 severity

In this episode of PaperCast Base by Base, we explore IMPACC longitudinal metabolomics and genomics analyses show that disruptions in one‑carbon/methionine metabolism together with MTHFR C677T genotype at hospital admission improve prediction of severe COVID‑19 and long COVID risk

Study Highlights:
IMPACC profiled plasma metabolites (global and targeted) from over 1,000 hospitalized COVID-19 patients and identified early alterations in one‑carbon metabolism, with emphasis on the methionine cycle. Methionine‑sulfoxide and S‑adenosylhomocysteine (SAH) were elevated in patients with more severe clinical trajectories and changed...

️ Episode 233: Mechanistic basis of NuA3 recognition and H3K14 acetylation

In this episode of PaperCast Base by Base, we explore Cryo-EM structures of the yeast NuA3 complex reveal how a cooperative Sas3–Nto1 binding cleft recognizes the H3 tail and directs acetylation of H3K14

Study Highlights:
The authors report cryo-EM structures of NuA3 in apo, acetyl-CoA-bound, and acetyl-CoA plus H3 tail-bound states at ~3.7, 3.1, and 3.2 Å resolution respectively. The histone H3 tail binding cleft is formed cooperatively by the catalytic subunit Sas3 and the non-catalytic subunit Nto1, with a hydrophobic pocket engaging H3 residues 9–12 and a polar...

️Episode 232: Lamin A/C steers fork restart via H3K9me3 and PARylation

In this episode of PaperCast Base by Base, we explore Nucleoplasmic Lamin A/C, together with LAP2α, enforces active replication fork slowing during mild replication stress by promoting local H3K9me3 and ADP-ribosylation to restrain RECQ1-mediated restart and protect genome stability

Study Highlights:
Lamin A/C dynamically associates with replication factories throughout the nucleus and its acute depletion abolishes stress-induced fork slowing and increases chromosomal breakage. Loss of nucleoplasmic Lamin A/C or LAP2α reduces poly-ADP-ribosylation (PAR) at nascent DNA...

️Episode 231: Transcription start sites as a germline mutational hotspot

In this episode of PaperCast Base by Base, we explore This study identifies a pronounced germline mutational hotspot centered on transcription start sites (TSSs) driven in part by early embryonic mosaic variants and transcription-associated DNA damage

Study Highlights:
Extremely rare variants show a localized excess of non(CpG > TpG) mutations around TSSs extending several hundred base pairs, reaching ~35% enrichment at the 100-bp scale and ~14% at 1 kb. The hotspot is largely absent from de novo mutation calls because early mosaic variants are significantly enriched downstream of th...

️Episode 230: MIDEAS Y654S hyperactivates MiDAC in a dominant neurodevelopmental syndrome

In this episode of PaperCast Base by Base, we explore A recurrent de novo MIDEAS p.Tyr654Ser variant disrupts an autoinhibitory loop in the MiDAC complex, increasing HDAC1 deacetylase activity and causing a multisystem neurodevelopmental disorder

Study Highlights:
Two unrelated probands carry the same de novo heterozygous MIDEAS p.Tyr654Ser variant and present with speech delay, progressive joint contractures, facial dysmorphism and gastrointestinal dysmotility. A 2.9 Å cryo-EM structure shows Y654 lies in a conserved loop of MIDEAS that covers the HDAC1 active sit...

️Episode 229: Inhibiting PCBP2 condensates in Alzheimer’s

In this episode of PaperCast Base by Base, we explore Elevated PCBP2 forms liquid-like condensates that sequester mitochondrial and RNA-binding proteins, stabilize BACE1 mRNA, and promote amyloid pathology while the small molecule CN-0928 reduces PCBP2 via INTS1 to lower Aβ and improve cognition in AD models

Study Highlights:
PCBP2 protein is increased in AD patient brains and AD mouse models and forms enlarged, dynamic cytoplasmic condensates that undergo LLPS in vitro and in cells. PCBP2 condensates concentrate mitochondrial proteins and RNA-binding/NMD factors including UPF1, correlating with disru...

️ Episode 228: Two non-competing H3N2 stem antibodies reveal evolving antigenicity

In this episode of PaperCast Base by Base, we explore Structural and functional characterization of two group 2 H3 HA stem antibodies, 2F02 and AG2-G02, shows distinct non-overlapping epitopes, protection in mice, and antigenic changes driven by HA2 position 32 that limit AG2-G02 binding

Study Highlights:
Cryo-EM structures show 2F02 targets the central stem epitope while AG2-G02 targets the lower stem epitope and the two can bind concurrently to an HA trimer. Both antibodies neutralize diverse H3 strains in vitro and provide prophylactic pr...

️ Episode 227: 1q gain enables rescue of aneuploid hESCs during RPE differentiation

In this episode of PaperCast Base by Base, we explore This study shows that spontaneous RPE differentiation eliminates most aneuploid human pluripotent stem cells but permits expansion of cells with chromosome 1q gains when they are co-cultured with wild-type cells

Study Highlights:
Large-scale single-cell genomics revealed pervasive low-grade mosaicism in genetically balanced hPSC cultures, with 3–6% of cells carrying various aneuploidies. During undirected RPE differentiation most aneuploid lineages are purged, except for cells bearing gains of chromosome arm 1q which persist. 1q-gain cells only comp...

️ Episode 226: FGF4 protects podocytes in diabetic kidney disease

In this episode of PaperCast Base by Base, we explore This study shows that podocyte-derived FGF4 is reduced in DKD and that recombinant FGF4 preserves podocyte survival and glomerular function in diabetic models via FGFR1-AMPK-FOXO1 signaling

Study Highlights:
FGF4 expression is downregulated in kidneys from DKD patients and diabetic mouse models and localizes predominantly to podocytes. Podocyte-specific deletion of Fgf4 worsened albuminuria, reduced GFR, increased oxidative stress and podocyte loss in diabetic mice. Systemic treatment with a non-mitogenic recombinant FGF4 improved glucose in db/db mi...

️ 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 authors used an auxin-inducible VRK-1 depletion system and genetic perturbations to show that VRK-1 phosphorylates BAF-1 (Ser4) to release chromatin–nuclear periphery contacts during leptotene–zygotene. VRK-1 loss or a BAF-1 Ser4 phospho-mutant increases chromatin tethering at the nuclear envelope, delays homolog pairing, slows...

️ 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 magnesium split-ring passive implant antenna coupled with genetically engineered Escherichia coli that accelerate metal degradation to convert molecular detection into an electromagnetic signature. E. coli BL21 engineered to express the CcmA–H cytochrome c maturation pathway degraded the magnesium prototype faster (≈8 h) than non-engineered cells (≈14 h), causing a controlled structural transition...

️ 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 track T7 replisome-driven DNA rotation and torsional slowing in real time. The combined helicase–DNA polymerase (DNAP) replisome generates ∼22 pN·nm of stall torque, about twice that of E. coli RNA polymerase, while helicase or DNAP alone produce minimal positive torque. Loss of the helicase C‑terminal...

️ 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 linked to poorer patient outcomes

Study Highlights:
Proteomic pull-downs and CLIP analyses reveal snaR-A interactions with RNA chaperones (La, ILF3) and multiple splicing factors, with PAR-CLIP and CLIP-qPCR supporting a direct interaction with the U2 snRNP subunit SF3B2. HCR-RNA-FISH and SON TSA-seq place snaR-A in subnuclear fo...

️ 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 genes, and reports somatic placental variants

Study Highlights:
The authors combined >20x Oxford Nanopore whole-genome sequencing with Illumina WGS and RNA-seq in eight mother–father–placenta trios to phase reads into maternal and paternal alleles. They catalogued 723 differentially methylated regions, finding a strong bias toward paternal demeth...

️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-seq profiles are strongly confounded by variable mature cell-type signatures that can conceal subtype-specific blast programs. Single-cell multimodal sequencing of AML identified four main clusters of immature leukemic cells and separated NPM1-mutated cases into NPM1class I and NPM1class II. NPM1class I is...

️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 quantified 146 lipid species across eight anatomically distinct post-mortem brain regions in controls and mid- and late-stage Parkinson’s disease using targeted LC-MS/MS and integrated proteomics and mitochondrial assays. Control brains showed distinct regional lipid signatures and age-associated increases in hexosylceramides, while PD brains exhibited cortical elevations of ganglios...

️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 substance-use traits

Study Highlights: Meta-analysis of 913,194 European and 125,315 African ancestry individuals (136,867 and 51,599 cases respectively) identified 40 independent variants in Europeans, two in Africans, and 51 lead SNPs in cross-ancestry analyses.

The strongest associations mapped to a non-coding region regulating SIM1, led by rs78677597 in Europeans and rs17185536 in Africans and in th...

️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 regulated by Pch2/TRIP13 Study

Highlights: Quantitative fluorescence profiles and Fourier analysis identify two dominant spatial periodicities centered near 0.5 µm and 1.0 µm for Zip3/Zip2, Hop1 and Zip1 along pachytene chromosomes. Inverse FFT reconstructs narrow and broad peaks that colocalize into triads of the three prot...

️ 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 and MA-del reporters in HEK293 cells, loss of 53BP1 alone did not reduce blunt No Indel EJ but amplified the decrease caused by DNA-PKcs kinase inhibition (M3814) or PRKDC knockout. Disruption of 53BP1 or RIF1, and DNA-PKcs inhibition or loss, each caused a similar sh...

️ 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 with ESM2, concatenates positional and strand vectors, contextualizes proteins with a multi-head attention encoder, and produces genome embeddings via a learnable weighted decoder pooling. The foundation PST-TL models were pretrained on >100k dereplicated viral genomes encoding >6M proteins using a triplet-loss objective with PointSwap augmentation an...

️ 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 generated asymmetric LUVs and GUVs by enzymatically converting outer-leaflet PI(4)P to PI(4,5)P2 using PIP5K1C and validated PI(4,5)P2 presence with FGF2-GFP and FGF2-Halo binding assays. GUV reconstitution assays revealed that outer-leaflet enrichment of PI(4,5)P2 shortened mean FGF2-dependent po...

️ 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 Highlights:
The authors generated an activity-ranked functional genomics atlas of 148,198 non-coding regulatory elements in human neural stem cells. Comparative ChIP-STARR-seq revealed many elements are epigenetically primed in embryonic stem cells for later neural activity. BRAIN-MAGNET, a convolutional neural network trained on the atlas, predicts enhancer activity from DNA sequence an...

️ 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 with exogenous MYC to produce a proliferative translatome that supports tumour outgrowth. Differentiation to an extreme zone 3 GLUL+Lgr5+ hepatocyte fate suppresses the pro-growth translatome and is refractory to WNT/MYC-driven tumorigenesis. Early proliferative lesions that progress show reduced WNT activation, elevated MAPK signalling and engagement of an IGFBP2–mTOR–cyclin D1...

️ 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 elements that tether ecDNA to mitotic chromosomes, facilitating its transmission to daughter cells during division. The study utilized a novel genome-scale assay called Retain-seq, revealing thousands of retention elements that enhance the persistence of ecDNA. These elements are primarily located at gene promoters and are ch...

️ 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 authors used conventional and imaging flow cytometry to identify heterotypic clusters in which CD8 T cells were physically conjugated to tumour cells and antigen-presenting cells across 21 human melanoma metastases. Single-cell RNA and TCR sequencing showed that clustered CD8 T cells were more clonally expanded an...

️ 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 PERT, a prime editing-mediated strategy that permanently converts selected endogenous tRNAs into optimized suppressor tRNAs capable of reading through premature termination codons. Through large-scale screening of thousands of engineered tRNA variants and careful tuning of promoter, leader, terminator and tRNA sequence elements, they identify su...

️ 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 mapping, the authors define how ZAK is constitutively recruited to ribosomes and how this engagement changes upon stress-induced ribosome collisions. They show that ZAK contacts the 40S subunit through a C-terminal eS27 pin and rRNA patches and anchors to RACK1 via a RACK1-interacting helix, wh...

️ 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 long prokaryotic and phage DNA sequences and used genomic neighbourhoods as prompts to autocomplete new genes whose functions mirror those of their neighbours. They experimentally validated Evo-designed toxin–antitoxin systems and type III toxin–antitoxin modules, discovering novel protein toxins, protei...

️ 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 haemagglutinin gene sequences from wild birds, domestic birds, and mammals collected across North America, the authors reconstruct the timing and routes of highly pathogenic H5N1 spread using Bayesian phylogeographical and phylodynamic models. They show that North America experienced around nine separate viru...

️ 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 Pleistocene woolly mammoths preserved in Siberian permafrost, extracting both ancient DNA and RNA to assess the authenticity and quality of the recovered molecules. Using alignment strategies optimized for short, damaged transcripts and mapping primarily to the Asian elephant genome, they identified characteristic damage patterns, exonic en...

️ 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 reporters provoke strong T cell responses in syngeneic and humanized mice, reshaping clonal architecture and suppressing metastasis.
To overcome this, they develop StealTHY, a “hit-and-run” knockout strategy that pairs species-autologous Thy1 reporters with transient delivery of Cas9 protein, eliminating persistent immunogenic transgenes while preserving sgRNA library complexity.
Across...

️ 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 data on tumor prevalence from hundreds of bird and mammal species with Bayesian multivariate phylogenetic generalized linear mixed models to test how benign and malignant tumors relate to macroevolutionary processes. They show that prevalence of both benign and malignant tumors increases with body mass, confirming th...

️ 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 RN...

️ 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 suc...

️ 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 bl...

️ 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, le...

️ 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 confinement, chromatin remodeling, and neuronal-like programs in cancer.

Study Highlights:
Using a zebrafish model of BRAFV600E-driven melanoma together with human tumor samples and single-cell transcriptomics, the authors identify a subpopulation of tumor cells at the tumor–microenvironment interface that displays elongated nuclei and...

️ 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 ma...

️ 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...

️ 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...

️ 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 tar...

️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, wi...

️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 high...

️ 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...

️ 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, cy...

️ 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 coloca...

️ 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, comp...

️ 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...

️ 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 inter...

️ 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 hi...

️ 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...

️ 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 contro...

️ 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...

️ 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 m...

️ 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 co...

️ 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 tho...

️ 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 in...

️ 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 varia...

️ 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 transi...

️ 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–prom...

️ 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 infe...

️ 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 co...

️ 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 Ran...

️ 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...

️ Episode 170: Maternal Age, Meiotic Recombination Failure, and Triploidy in Humans

In this episode of PaperCast Base by Base, we explore how maternal age and failures of meiotic recombination shape the origins of triploid conceptions in humans, drawing on large-scale preimplantation genetic testing datasets from ICSI-derived embryos.

Study Highlights:
Drawing on 96,660 embryo biopsies with an independent validation cohort of 44,324, the authors quantify the burden of ploidy-level abnormalities in ICSI-derived blastocysts and show that triploidy is about five times more frequent than haploidy at the blastocyst stage. Genotyping and sex-chromosome modeling reveal that nearly all triploid em...

️ Episode 169: Deep mutational scanning of the insulin receptor guides precision therapy for insulin resistance

In this episode of PaperCast Base by Base, we explore how a comprehensive deep mutational scan of the human insulin receptor ectodomain maps the effects of ~14,000 missense variants on surface expression, insulin binding, and downstream signalling, creating a sequence–function atlas to improve diagnosis and treatment of severe insulin resistance.

Study Highlights:
The authors constructed a saturation mutagenesis library across residues 28–955 of INSR and used barcoded, pooled cell-based assays to quantify variant effects on receptor expression, insulin or antibody binding, and ma...

️ Episode 168: Low circulating miR-190a-5p predicts progression of chronic kidney disease

In this episode of PaperCast Base by Base, we explore how unbiased small RNA sequencing and multi-cohort validation identify circulating miR-190a-5p as a prognostic marker of chronic kidney disease that reflects tubular health and points to a potential therapeutic strategy.

Study Highlights:
Using small RNA-sequencing of plasma from people with and without CKD in the context of type 2 diabetes, the authors found miR-190a-5p to be significantly reduced in those with impaired kidney function.
In an independent prospective CK...

️ Episode 167: DeepScence: Detecting Senescent Cells at Single-Cell and Spatial Resolution

In this episode of PaperCast Base by Base, we explore a Cell Genomics study introducing DeepScence, a deep-learning autoencoder that leverages a compact “CoreScence” gene set to identify senescent cells across single-cell and spatial transcriptomics data, outperforming marker- and gene set–based approaches.

Study Highlights:
The authors systematically compared nine published senescence gene sets and distilled a consensus 39‑gene CoreScence panel that is consistently associated with senescence across tissues and conditions. DeepScence models expression counts with a zero‑inflated negative binomial autoencoder whose bottleneck s...

️ Episode 166: Molecular Squeezing: How Coronin, Cofilin, and AIP1 Rapidly Disassemble Actin Filaments

In this episode of PaperCast Base by Base, we explore a Cell study that uses single-particle cryo-EM to reveal the stepwise, synergistic mechanism by which coronin, cofilin, and AIP1 drive rapid actin filament disassembly in eukaryotic cells.

Study Highlights:
The authors solve a series of cryo-EM structures showing that coronin binds cooperatively to F-actin, opens a molecular backdoor to accelerate inorganic phosphate release, and undertwists the filament to prime it for cofilin binding. Cofilin then binds in a strand-restricted cooperative manner th...

️ Episode 165: Protist Genomics: Key to Understanding Eukaryotic Evolution

In this episode of PaperCast Base by Base, we explore how accelerating protist genomics—spanning single-cell approaches, metagenomics, and long-read assemblies—unlocks deep insights into eukaryotic evolution, symbiosis, organelle origins, ecosystem dynamics, and the methodological shifts needed to go beyond plant/animal-centric standards.

Study Highlights:
This review argues that protists encompass most eukaryotic diversity yet remain severely underrepresented in genome databases, creating blind spots in phylogenomics and models of eukaryotic evolution. It synthesizes emerging wet-lab and computational strategies—such as FACS-enabled single-cell sequencing, nuclei extraction for high...

️ Episode 164: m6A in the coding sequence: linking deposition, translation, and decay

In this episode of PaperCast Base by Base, we explore how N6-methyladenosine (m6A) marks within coding sequences orchestrate a fast, translation-coupled route to mRNA decay, and how splicing- and chromatin-linked mechanisms shape where those marks are placed across transcripts.

Study Highlights:
The authors synthesize recent mapping and mechanistic studies to show that exon-junction complexes restrict METTL3 activity in coding regions, helping define the mature m6A landscape. They describe CDS–m6A decay (CMD), a translation-dependent pathway in which m6A wi...

️ Episode 163: Animal origins: looping back in time

In this episode of PaperCast Base by Base, we explore how chromatin folding mechanisms emerged alongside animal evolution, focusing on a Spotlight article that synthesizes high-resolution 3D genome maps across unicellular relatives of animals and early-branching metazoans to probe when enhancer–promoter looping first appeared.

Study Highlights:
This Spotlight reviews evidence from micro-C datasets spanning ichthyosporeans, filastereans, choanoflagellates, sponges, ctenophores, placozoans, and cnidarians, showing that broad A/B-like chromatin compartments and, crucially, enhancer–promoter chromatin loops are features that arise within animals rather than in their unicellular relati...

️ Episode 162: Spatially Resolved microRNA Expression in Tissues: Technologies, Challenges, and Opportunities

In this episode of PaperCast Base by Base, we explore how emerging “spatial miRNomics” methods map microRNA expression directly within intact tissues, revealing cell- and region-specific regulatory patterns that bulk and even single-cell assays can miss.

Study Highlights:
This review charts the field from established singleplex imaging with LNA probes and miRNAscope to early multiplex strategies and sequencing-based workflows that add poly(A) tails in situ to capture small RNAs. It explains how spatial total RNA sequencing (STRS) and Patho-DBiT adapt commercial spatial transc...

️ Episode 161: Decoding Genomic Landscapes of Introgression

In this episode of PaperCast Base by Base, we explore how modern population genetics dissects the genomic footprints of introgression across species, reviewing summary statistic approaches, probabilistic modeling, and supervised learning, and showing how these methods reveal adaptive and ghost introgression and the functional roles of introgressed loci.

Study Highlights:
The authors organize the field into three complementary pillars: summary statistics for fast exploratory scans, probabilistic models for principled inference of local ancestry and selection, and supervised deep learning for scalable, high‑resolution predictions. They explain why windowed stat...

️ Episode 160: The Long‑Read Leap in Single‑Cell Omics

In this episode of PaperCast Base by Base, we explore how long‑read, single‑molecule sequencing has collided with single‑cell technologies to illuminate “dark” regions and events in the genome, epigenome, and transcriptome that short reads routinely miss.

Study Highlights:
This review maps the rapid maturation of Pacific Biosciences and Oxford Nanopore platforms alongside single‑cell methods, showing how full‑length isoform sequencing reveals complex alternative splicing at single‑cell resolution. It details single‑cell long‑read genome assays such as SMOOTH‑seq and dMDA that sensitivel...

️ Episode 159: The Untapped Potential of Short‑Read Sequencing in Biodiversity Research

In this episode of PaperCast Base by Base, we explore how modern short‑read sequencing and genome skimming are reshaping biodiversity science—from rapid species identification and biomass estimation to scalable phylogenomics and holobiont studies—while keeping costs and sample requirements low.

Study Highlights:
This review synthesizes how low‑coverage short‑read data can recover organellar genomes and high‑copy nuclear markers, enabling robust taxonomic identification and phylogenetic inference across diverse taxa. It explains assembly‑free and mapping approaches that extract universal single‑copy orthologs or k‑...

️ Episode 158: Interruptions in Repeat Expansion Diseases: How Are They Gained and Lost?

In this episode of PaperCast Base by Base, we explore how small sequence changes—“interruptions”—within expanded tandem repeats shape the onset and severity of repeat expansion disorders, and a new mechanistic model that may explain how these interruptions are gained and lost across generations.

Study Highlights:
Interruptions within repeat tracts can dampen somatic expansion and shift clinical trajectories, helping to explain variability in age at onset and phenotype across disorders such as Huntington’s disease, myotonic dystrophy type 1, spinocerebellar ataxias, and fragile X. A...

️ Episode 157: Synthetic gametes and the non-identity problem: the babies of tomorrow

In this episode of PaperCast Base by Base, we explore how synthetic DNA technologies may enable the creation of synthetic gametes and why this possibility forces a rethinking of identity, harm, and responsibility in human reproduction.

Study Highlights:
The authors argue that while building a full human genome remains infeasible today, engineering haploid genomes for gametes is a nearer-term and more tractable objective, drawing on advances such as synthetic chromosomes in yeast. They analyze how synthetic gametes differ ethically from embryo editing an...

️ Episode 156: RAEFISH: Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution

In this episode of PaperCast Base by Base, we explore RAEFISH, a reverse-padlock amplicon-encoding FISH method that delivers whole-transcriptome imaging at single-molecule resolution without sequencing. The study demonstrates genome-scale coverage across cells and intact tissues and extends to direct readout of CRISPR guide RNAs, enabling high-content functional screens with spatial context.

Study Highlights:
RAEFISH introduces a “reversed” padlock design with splint-assisted ligation, rolling-circle amplification, and MERFISH-style sequential readouts to barcode >20,000 transcripts while remaining compatible with cost-efficient oligo pool amplification. In A549 cells, the authors report an ave...

️ Episode 155: EIF3A/EIF3B Loss-of-Function: A Cardiocraniofacial Neurodevelopmental Syndrome

In this episode of PaperCast Base by Base, we explore how loss-of-function variants in EIF3A and EIF3B—core components of the eIF3 translation initiation complex—cause a multisystem disorder marked by congenital heart defects, craniofacial differences, and mild neurodevelopmental features. The study brings clinical genetics together with functional zebrafish models to establish gene–disease validity and illuminate developmental mechanisms.

Study Highlights:
An international cohort of eighteen individuals was assembled with de novo or loss-of-function variants in EIF3A (n=4) or EIF3B (n=14), r...

️ Episode 154: Multiple-testing corrections in selection scans using identity-by-descent segments

In this episode of PaperCast Base by Base, we explore how Temple and Browning develop principled genome-wide significance thresholds for IBD-based scans of recent positive selection by explicitly modeling correlation along the genome.

Study Highlights:
The authors model standardized IBD-rate scan statistics as an Ornstein–Uhlenbeck process and derive both an analytical threshold and a fast simulation-based alternative that control the family-wise error rate while adapting to genetic-map spacing and autocorrelation. In extensive coalescent simulations, the approach achieves approximate FWER control and shows that Bonferroni can...