The ends of human chromosomes are capped by specialized nucleoprotein structures, termed telomeres, which are essential for genome stability. Recent advances in long-read sequencing have enabled allele-specific telomere length measurements at nucleotide resolution, uncovering extreme heterogeneity in telomere length between alleles. The progressive telomere shortening over time makes steady-state telomere length in human somatic cells a promising biomarker for age-associated diseases. However, the mechanisms underlying allele-specific telomere maintenance and its stability remain poorly understood. Here, we developed a high-resolution workflow combining PacBio and Nanopore long-read sequencing platforms to map allele-specific telomere length in human blood samples as well as cultured cell lines. By tracing allele-specific telomeric sequence in family members across multiple generations, we show that the allele-specific telomeric variant sequences (TVSs) are heritable and underlie the extreme heterogeneity of telomere length between alleles. Continuous cell proliferation likely drives the slow but stochastic evolution of allele-specific TVSs, resulting in asymmetry in telomere inheritance from father and mother (p-value = 2.354e-7). Targeted deletion of allele-specific TVSs using CRISPR-Cas9 resets telomere length, further confirming their causal role in the control of allele-specific telomere maintenance. These results indicated that TVSs are heritable genetic elements underlying the allele-specific telomere length. The authors use long-read sequencing to map allele-specific telomere lengths and telomere variant sequences (TVS). They find that TVSs dispersed along the telomere repeat region are heritable genetic elements that account for the extreme heterogeneity of telomere length between alleles.
Asthma is an immune-mediated lung disease causing airway constriction that is fatal in rare cases, though the immune mechanisms underlying asthma severity are poorly understood. Here, we present a comprehensive immunological profiling of lymphoid organs, lungs, and intestines from human organ donors who died of fatal asthma (FA) compared to donors who died of unrelated causes with or without a history of asthma. Compared to control donors, FA donors exhibit elevated plasma IgE along with enhanced and aberrant immune responses in mucosal-associated lymph nodes (LN) and lungs, respectively. In particular, FA donors show increased memory T and B cells and decreased Treg cells with age in the gut- and lung-associated LN, increased Th2 and Th1 resident memory cells in the lungs, and increased associations between gut and lung immune responses compared to control donors. Our findings reveal mucosal immune dysregulation underlying asthma exacerbation through site-specific and inter-tissue disruption of immune homeostasis. Immune mechanisms driving severe asthma and fatal outcomes remain elusive. Through cross-tissue immune profiling of organ donors who died of fatal asthma versus other causes, the authors here reveal mucosal immune dysregulation marked by enhanced T- and B-cell memory, reduced Tregs, and increased lung Th2 and Th1 effectors linked to priming in gut-associated lymph nodes.
Abstract In the gastrointestinal tract, Wnt and BMP signals control Lgr5 ⁺ stem cell activity during homeostasis, whereas injury elicits an Lgr5 -independent, fetal-like regenerative program driven by YAP. Helicobacter pylori ( H. pylori ) infection activates YAP, but whether fetal-like reprogramming contributes to gastric pathology, and what drives it, has remained unclear. Here we show that H. pylori -induced gland hyperplasia is accompanied by YAP-dependent fetal-like transcriptional response and loss of epithelial BMP signaling. Epithelial BMP inhibition alone is sufficient to induce this program in vivo, through an epithelial–immune–stromal cascade: BMP-deficient epithelial cells secrete chemokines that recruit IL-1β-producing immune cells, and IL-1β drives enrichment of pro-regenerative fibroblasts producing prostaglandin E2. In gastric epithelial–stromal assembloids, IL-1β elicits stromal prostaglandin E2 production and subsequent epithelial YAP activation. Stromal deletion of the IL-1 receptor abrogates H. pylori -driven reprogramming and pathology. These data define a cascade that converts BMP loss into a fetal-like regenerative state and shapes H. pylori -associated gastric disease.
The oxide path mechanism offers vision possibility from kinetics for the anodic oxygen evolution reaction, yet its universal activation remains elusive due to the difficulty of constructing globally appropriate interatomic distances. Here, we address this challenge in the integrated-screened Y0.1Ir0.2Ru0.7Ox by precisely regulating the Ru-Ru1 bond length and constructing locally ordered yet long-range disordered structures that dissipate lattice strain, thereby enabling homogeneous modulation of interatomic distances across the framework. In-situ infrared spectroscopy together with online mass spectrometry confirms that the catalyst consistently follows a universal pathway. Building on these structural and mechanistic advantages, the nanostructured catalyst achieves a low cell voltage of 1.75 V@3 A cm-2 with operational stability ( > 2800 h @ 3 A cm-2, 0.0625 mV h-1 decay rate) in proton exchange membrane water electrolysis. This work establishes a generalizable framework for pervasive dual-site catalysis, providing a paradigm for next-generation water electrolysis anodes and beyond. The elementary steps of oxygen evolution reactions challenge efficient water electrolysis. Here, the authors develop a scalable short-range ordered dual-site strategy that activates the universal oxygen-path mechanism, enabling stable acidic water electrolysis at high current densities.
We conducted a randomized surgical window-of-opportunity trial (NCT04606316) in recurrent, resectable glioblastoma. Between 2021 and 2024, 71 patients were screened, and 63 were randomized (intention-to-treat [ITT] population), and 58 received study treatment. Patients received pre-surgical immune checkpoint blockade (ICB) with dual anti-PD1 nivolumab + anti-CTLA4 ipilimumab (Arm 1), nivolumab alone (Arm 2), or placebo (Arm 3). Following surgery, Arms 1 and 3 received dual ICB, while Arm 2 continued nivolumab until progression or unacceptable toxicity. The primary endpoint, tumor-infiltrating lymphocyte (TIL) density, was met for Arm 1, as neoadjuvant dual ICB significantly increased TIL density compared with untreated control (Arm 3). As a secondary endpoint, median overall survival in the ITT population was 402 days (95% CI, 265–571) among patients who received dual ICB (Arms 1 and 3) and 273 days (95% CI, 166–506) for those assigned to nivolumab alone (Arm 2). No unanticipated toxicities were observed. Exploratory analyses showed that dual ICB elicited robust intratumoral and systemic immune activation, including increased interferon-related gene expression in blood. Higher TIL density and early systemic interferon-signature induction were associated with improved survival, whereas tumor mutational burden was not. Our results demonstrate pharmacodynamic activity of dual ICB in glioblastoma, with survival outcomes comparing favorably to similar studies. Here the authors report clinical and immunological outcomes of a randomized surgical window-of-opportunity trial designed to test whether dual immune checkpoint blockade targeting PD-1 and CTLA-4 could overcome the adaptive immune resistance previously reported with single-agent anti-PD-1 therapy in patients with surgically resectable recurrent glioblastoma.
Osteoclasts are mitochondria-rich cells that rely on oxidative phosphorylation to fuel differentiation and bone resorption. Oxidative phosphorylation generates reactive oxygen species (ROS), which support signaling but can also threaten mitochondrial integrity. Oxidation Resistance 1 (OXR1) is a redox-responsive regulator involved in antioxidant defense, but its role in osteoclasts remains unclear. Here, we show that OXR1 is upregulated during mouse osteoclastogenesis and OXR1 mRNA is enriched in human osteoclasts. Knockdown of Oxr1 in mouse osteoclast precursors causes excessive ROS accumulation, mitochondrial damage, and impaired autophagic flux. Accordingly, myeloid-specific loss of Oxr1 results in defective osteoclast formation and increased bone mass in mice. Mechanistically, OXR1 binds the antioxidant response regulator KEAP1 and promotes KEAP1 association with the autophagy adaptor P62/SQSTM1, thereby supporting mitochondrial ubiquitination and mitophagic clearance. In an ovariectomy-induced osteoporosis mouse model, intraosseous AAV9-shRNA-mediated Oxr1 silencing or pharmacological OXR1 inhibition suppresses osteoclast activity and attenuates bone loss. Thus, our findings suggest OXR1 to be a dual-function regulator that buffers ROS and simultaneously orchestrates the autophagic clearance of damaged mitochondria during osteoclastogenesis, hinting at OXR1 as a potential target for preventing osteoclast‑driven bone loss. Osteoclasts need to manage reactive oxygen species by coordinating redox control and mitochondrial quality maintenance. Here, the authors identify OXR1 as a regulator of osteoclastogenesis and mitophagy, and show that genetic or pharmacological targeting of OXR1 attenuates bone loss in an osteoporosis mouse model.
High-frequency and fast-propagating antiferromagnetic magnons hold significant potential for ultrafast spintronic technologies, particularly at terahertz frequencies. While conventional electrical methods for exciting antiferromagnetic magnons are limited in coherence, frequency range, and wavevector control, optical approaches offer significant opportunities to overcome these constraints. Here, we report the first observation of nonreciprocal magnon propagation in a canted antiferromagnet α-Fe2O3 at sub-terahertz frequencies. Using ultrafast optical excitation and Bragg-selective magneto-optical Kerr detection, we reveal distinct propagation dynamics for quasi-ferromagnetic and quasi-antiferromagnetic magnons at room temperature. Notably, the quasi-ferromagnetic magnon exhibits pronounced nonreciprocity and a record-high group velocity (33 km s−1). The amplitude nonreciprocity arises primarily from the asymmetric dipolar interaction enhanced by the Dzyaloshinskii–Moriya interaction, as supported by theoretical calculations. These findings establish fundamental principles for ultrafast and directional control of antiferromagnetic magnons, paving the way for high-frequency spintronic applications. The authors demonstrate that optically excited subterahertz magnons in canted antiferromagnetic hematite propagate nonreciprocally at high group velocities, offering potential for ultrafast spintronic applications.
N-Acetylneuraminic acid (NeuAc) is a sialic acid valued in pharmaceuticals and infant nutrition, and microbial synthesis offers a scalable route once the pathway’s catalytic bottlenecks are relieved. We combine deep learning with metabolic engineering to build a high-titer NeuAc-producing E.coli strain. Modular pathway engineering reaches 1.25 g L−1 and pinpoints N-acetylglucosamine 2-epimerase (AGE) as the rate-limiting step. We develop DLCatalysis, a deep learning framework that predicts kcat Km−1 directly from protein sequence and substrate, and use it to mine AGEBf that lifts the titer to 6.84 g L−1. DLCatalysis-guided redesign of AGEBf and NeuBNm raises NeuAc to 9.27 g L⁻¹, and identifying and deleting exuT, a previously unannotated NeuAc transporter, blocks product reuptake. In 5-L fed-batch fermentation the optimized strain produces 85.5 g L−1, showing that AI-guided enzyme discovery can resolve the bottlenecks that have limited microbial NeuAc production. N-Acetylneuraminic acid (NeuAc) is a valuable pharmaceutical. Here the authors develop DLCatalysis, a deep learning framework that predicts kinetics from protein sequence and substrate, and use DLCatalysis to mine enzymes for NeuAc production in E. coli.
Electrocatalytic nitrate reduction (NO3RR) provides a sustainable approach for removing nitrate pollutants and producing valuable nitrogen chemicals. However, understanding catalytic behavior under realistic dilute conditions remains challenging, as conventional electrochemical measurements rely on ensemble-averaged signals that obscure dynamic interfacial processes at individual particles. Here we show an operando electrochemiluminescence (ECL) microscopy strategy that visualizes and evaluates apparent NO3RR kinetics at the single-particle level. Using Cu(111) nanosheets as a model catalyst, we convert reaction-induced optical responses into spatially resolved descriptors of nitrate adsorption and intermediate evolution. The time-dependent ECL response reveals the generation and diffusion of nitrite, a key intermediate in nitrate reduction. These descriptors provide apparent kinetic mapping, uncovering substantial kinetic heterogeneity of individual particles. Correlative imaging of intermediate diffusion demonstrates that interparticle coupling influences apparent catalytic performance by modulating intermediate accumulation and interfacial mass transport under dilute nitrate conditions. This approach provides an operando optical microscopy platform for visualizing dynamic catalytic interfaces and linking interfacial processes with apparent catalytic performance. Understanding catalytic dynamics at electrochemical interfaces is important, while reactions at individual particles remain difficult to observe. Here, the authors report an operando electrochemiluminescence microscopy approach to visualize nitrate reduction processes and monitor apparent kinetics.
The continuous decreasing in the levelized cost of renewable electricity has promoted the accelerated development of electrocatalysis, particularly electrochemical CO2 reduction (CO2R) using dilute CO2 concentrations (5-15%), which offers a sustainable pathway to convert waste CO2 into fuels and chemicals. However, dilute CO2 introduces substantial concentration overpotentials, leading to unsatisfactory selectivity and energy efficiency. Here, we develop effective approaches (pH control, amine addition, gas compression) to enrich the interfacial CO2 availability, steering the CO2R selectivity towards the desired products. We further conduct techno-economic analysis and cradle-to-gate life cycle assessments to evaluate their economic and environmental performance. For instance, HCOOH production cost drops from 1.11 to 0.47 $ kg-1, lower than the 0.58 $ kg-1 of the pure CO2 scenario. Moreover, environmental burdens such as climate change and cumulative energy demand decrease by 38.2%-72.0% relative to the flue-gas scenario without these strategies. Overall, although variations in the electricity mix influence the absolute values reported in this study, our work provides critical implications and design principles for dilute CO2R. Direct electrochemical upgrading of dilute CO2 from flue gas is attractive but limited by poor local CO2 availability and selectivity. Here, the authors report interfacial engineering strategies to enrich local CO2 and improve selectivity, supported by technoeconomic and life-cycle assessments.
Hematopoietic stem cells (HSCs) self-renew to expand their pool but often differentiate upon division. Thus, it remains unclear how HSCs maintain their stemness during or after division. Here, we show that the suppression of glutamate dehydrogenase (Glud1), a key enzyme responsible for glutamate (Glu) catabolism, supports the maintenance of HSCs during division. We find that self-renewing mouse HSCs during hematopoietic regeneration exhibited lower intracellular Glu levels compared to HSCs differentiating during ex vivo culture. We therefore focus on the negative regulation of Glu catabolic reactions as a candidate factor to maintain HSCs during division, and find that treatment with the Glud1 inhibitor, R162, maintains a subset of HSCs that would otherwise differentiate during division under normal culture conditions. This treatment successfully results in an approximately 500-fold expansion of functional mouse HSCs that maintain expression pattern of conventional stem cell markers over a 30-day culture period. Importantly, this positive effect of Glud1 inhibition is independent of suppressing cell divisions and dependent on robust JAK2-STAT signaling. Overall, our findings propose that Glud1 inhibition, coupled with robust JAK2–STAT signaling, characterizes a functional HSC state during division, enabling ex vivo expansion of mouse HSCs under conventional culture conditions. The authors show that suppressing glutamate dehydrogenase (Glud1) maintains hematopoietic stem cell stemness during division. This approach achieves a 500-fold ex vivo expansion of functional stem cells under standard culture conditions.
Latin American populations remain underrepresented in genomic research. To help address this, we present an analysis of high-coverage whole-genome data from 1481 volunteers recruited as part of the oriGen Project. We identify over 47.2 million SNVs and 8.1 million short indels, including nearly 3 million non-singleton short variants absent from dbSNP and the Mexico City Prospective Study. Admixture analysis indicates that a Mexican training dataset is needed to more accurately estimate ancestry compositions by genetic similarity. Analysis of copy number variation associated with MX-AMR highlights several loci, including LCE1D and RHD. Interestingly, while 3.1% of participants carry homozygous deletions in the RHD gene, which determines the Rh blood group, this frequency dropped to 0.6% among individuals with high MX-AMR. Since the RHD deletion is rare in East Asians, and the Rh-negative phenotype is rare in Indigenous American populations, our results support the hypothesis that the Rh-negative blood group increased in frequency during the Spanish conquest rather than by genetic drift. We also find that 10% of volunteers are heterozygotes for the 22-42128945-C-T Loss of Function variant in CYP2D6, an enzyme involved in metabolizing painkillers, and tamoxifen. This work helps address the underrepresentation of Mexican populations in genomic research. Mexican populations remain underrepresented in genomics. Here, Aguilar-Ordoñez et al. report on 1,481 whole-genomes from the oriGen project, identifying key variants like a CNV driving the Rh-negative blood group.
Crystallographic symmetry fundamentally governs the generation, propagation, and polarization of spin currents, which are the core processes in spin-orbit torque technology, yet harnessing this principle to realize field-free switching remains a critical challenge. Here, we propose a general symmetry-engineering strategy that tailors spin currents via tilting crystal axis. In epitaxial tilted MnTe (0001) thin films, all-electrical magnetization switching due to strong out-of-plane spin polarization was successfully observed, where spin propagation was reoriented. Remarkably, this approach yields an exceptionally high y-polarized spin-orbit torque efficiency (ξy = 0.58), together with a significant z-polarized component (ξz = 0.07). Our work proves crystal symmetry engineering as a powerful and versatile pathway for designing spin-source materials, opening new avenues for integrating high in-plane symmetry crystals into practical, energy-efficient spintronic devices. This work proposes a novel approach to achieve all-electrical magnetization switching by tilting the crystal structure of the spin source material, thereby manipulating the spin transport and polarization direction.
Abstract Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.
Copy number alterations (CNAs), gains or losses of genomic regions, contribute to malignant progression and tumor heterogeneity. Advances in spatial transcriptomics have expanded opportunities to study clonal structure in situ, but direct spatial genomic profiling remains difficult in practice, motivating the increasing use of computational methods to infer CNAs from spatial transcriptomics data. However, their performance across diverse spatial transcriptomics settings remains unclear. Here, we present a benchmark of nine CNA inference methods across 69 spatial transcriptomics tissue sections from six cancer types and four spatial transcriptomics platforms. By evaluating these methods across four key tasks, we show that no single method consistently outperforms all others, with performance depending on the analytical goal and data characteristics. We therefore provide task-specific and data-aware guidance to help users select appropriate methods in practical settings. More broadly, this benchmark provides a basis for the future development and optimization of CNA inference methods. Copy number alteration inference from spatial transcriptomics remains challenging. Here, the authors benchmark nine methods across a variety of tissue sections, showing that no method dominates across all tasks and providing practical guidance for method selection.
In-situ intraparticle mineralization of widespread metalloids in groundwater is challenging but critical for global freshwater security. However, electronic and steric hindrances of complex oxygen-containing configurations prevent efficient oxygen dissociation and mineralization. Here, arsenic oxyanions are selectively and stably mineralized within d-orbital-modulated nanoscale Fe0 particles following enhanced d-p orbital-coupled oxygen dissociation, yielding ~100% removal efficiency, ~100% electron utilization, and ~94% metalloid intraparticle mineralization as resolved from thousands of single nanoparticles. Universal As, Sb, and Se intraparticle mineralization demonstrate excellent long-term stability (up to 98-fold of conventional nanoscale Fe0) in various groundwater matrices, where σ-bonded species show preferential intraparticle mineralization over π-bonded configurations. Field deployment is verified through macroscale material synthesis, minimal leaching of Fe and S in permeable reactive barriers, and economic advantages. This work establishes targeted d-p orbital-coupled bond dissociation as a transformative paradigm for metalloid-contaminated groundwater remediation and proposes a scalable in-situ remediation strategy that bridges atomic-level precision with field-ready practicality. Toxic arsenic, antimony and selenium in groundwater are mineralized inside lattice-modified iron nanoparticles with a 98-fold greater stability during long-term aging in groundwater, offering an economic in-situ remediation strategy.
Today’s self-driving vehicles have achieved impressive driving capabilities, nonetheless, safety concerns arising from ambiguous traffic laws, rare long-tail events, etc., still pose a significant challenge to their practical deployment. Therefore, human drivers are necessitated to take over in certain cases. Here, we present a human-guided continual learning method that leverages these human guidance data to continually improve self-driving performance, thereby enabling better handling of similar cases in the future. Our technique facilitates performance improvement by merely using the new data collected during driving, without requiring lengthy re-training from scratch. We evaluate the proposed technology through both simulations and real-world experiments, showing that it enables continual improvement by incrementally acquiring small amounts of human guidance. After each learning stage, the updated policy matches or outperforms the previous self-driving policy in terms of social compliance, rare case handling, etc. These findings highlight the potential of this technology to continually improve self-driving vehicles across multiple dimensions and to support broader human-in-the-loop autonomous systems. This study presents a human-guided continual learning method that leverages small amounts of driving guidance to incrementally improve self-driving performance across multiple dimensions, such as social compliance and rare case handling.
Antibiotic resistance has become a critical public health problem, rendering many antibiotics ineffective. In particular, the evolution of extended-spectrum β-lactamases (ESBLs) threatens β-lactams, the cornerstone of bacterial infection treatment. We investigated the evolution of Escherichia coli TEM-1 β-lactamase into ESBLs by constructing a combinatorially complete library of all 55,296 TEM-1 variants from 18 clinical mutations across 13 residues. We obtained over 9,000,000 fitness measurements under native (ampicillin) and non-native (aztreonam) selection. Graph-theoretic and epistatic analyses revealed that ampicillin selection produced weak epistasis and predictable evolutionary trajectories, whereas aztreonam selection induced extensive higher-order epistasis, increasing phenotypic unpredictability. Machine learning identified interpretable epistatic rules shaping these landscapes. Evolutionary statistics, including direct coupling analysis and latent generative landscapes, showed that top-performing ESBL variants followed conserved epistatic patterns observed in natural β-lactamases. Our integrated experimental–computational framework provides a foundation for predicting ESBL evolution and quantifying mutational contributions to ESBL variants. Authors investigate the evolution E. coli TEM-1 β-lactamase into ESBLs with a complete library of 55,296 TEM-1 β-lactamase variants, showing that adaptation to a non-native antibiotic is driven by higher-order epistasis, making resistance evolution far less predictable than to the native substrate.
Mutations in the Plasmodium falciparum genes, pfdhfr and pfdhps, drive antifolate resistance and threaten malaria control in regions where sulfadoxine-pyrimethamine (SP) is the primary chemoprevention strategy. The spatial patterns and evolutionary dynamics of these mutations in high-transmission settings remain incompletely understood. Here we genotyped 11 resistance-associated mutations in pfdhfr and pfdhps in 4,725 P. falciparum isolates collected from 16 Ugandan health facilities as part of annual surveillance between 2016 and 2022. Notably, we show that the frequency of PfDHFR I164L, which confers higher pyrimethamine resistance, increased over time from 19.4% to 32.4%. Using identity-by-descent, haplotype structure, and extended haplotype homozygosity analyses, we show that PfDHFR I164L is present on multiple haplotype backgrounds and undergoes localised expansions, without detectable signatures of recent positive selection at all but one site. Our results suggest that the evolution of antifolate resistance, driven by PfDHFR I164L, is spatially heterogeneous and complex in regions that primarily use SP chemoprevention programmes. PfDHFR haplotypes involving I164L are known to strongly influence antifolate resistance in Plasmodium falciparum. In this study, Asua and colleagues examine the frequency of antifolate-resistance conferring mutations in over 4,700 parasite samples collected in Uganda over a 6-year period. They report that markers conferring antifolate resistance during this time, which may impact chemotherapeutic strategies that are reliant on sulfadoxine-pyrimethamine (SP).
Rare diseases often remain unsolved because causal genetic changes can be complex and thus missed by standard sequencing or difficult to prioritize. Long-read sequencing can reveal structural variants, repeat expansions, DNA methylation and inherited haplotypes, but trio sequencing of an affected child and both parents remains costly. Here we show that phenotype-driven Trio-barcoded Oxford Nanopore Adaptive Sequencing (TBAS) enables cost-efficient long-read analysis of rare-disease trios on one flow cell. TBAS workflow uses clinical features to select broad disease-gene panels, barcodes all three family members and enriches these regions during sequencing rather than targeting a known causal locus. In benchmark regions, TBAS increased coverage and accurately detected small variants, structural variants, tandem repeat expansions, methylation and read-backed phasing, while reducing estimated sequencing consumable costs to 32.2% of conventional three-flow-cell trio long-read sequencing. Across 13 trios, TBAS recovered all five known diagnoses and prioritized candidates in five of eight unresolved cases. Here the authors present Phenotype-driven Trio-barcoded Adaptive Sequencing (TBAS) that enables cost-efficient long-read sequencing of rare-disease trios on a single flow cell, detecting diverse genetic variants while cutting costs to 32% of standard trio sequencing.
