Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 127 records · Page 7Linked to original sources

bioRxiv2026

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

cancer biology↗

bioRxiv2026

Neural Arming Niche in Tumor-Draining Lymph Nodes Programs CD8⁺T Cell Cytotoxicity via GZMB Norepinephrinylation

Lymph nodes are densely innervated neuro-immune hubs where naive T cells are primed and "armed" with cytotoxic machinery, yet how local neural cues in tumor-draining lymph nodes (tdLNs) set CD8 T cell effector reserves remains unclear. Here we show that tdLN-local sympathetic norepinephrine (NE) instructs CD8 T cell cytotoxic capacity by stabilizing the granzyme B (GZMB) pool through covalent norepinephrinylation. Exercise, used as a physiological perturbation, increases GZMB selectively in tdLN and tumor CD8 T cells without altering T cell abundance or cytokine output; tdLN sympathectomy abolishes these effects and reduces tdLN NE enrichment. Mechanistically, NE enters CD8 T cells and norepinephrinylates GZMB at Gln43, limiting UHRF1-mediated ubiquitination and proteasomal degradation. Genetic attenuation of norepinephrinylation destabilizes GZMB, impairs cytotoxicity, and accelerates tumor growth. Brief ex vivo NE conditioning increases GZMB reserves and improves adoptive tumor control.

cancer biology↗

bioRxiv2026

Mapping the North American Terrestrial Carbon Cycle: A Process-based Reanalysis Using State Data Assimilation (SDA)

AbstractThe ability to accurately assess ecosystem C budgets across scales from individual sites to continents is essential for C accounting, management, and ultimately mitigating climate change. State data assimilation (SDA) provides a framework for harmonizing observations with models, while robustly accounting for and reducing multiple sources of uncertainty. In this study, we employed a hybrid SDA framework that combines process-based terrestrial biosphere modeling, hierarchical Bayesian inference, and machine learning to harmonize bottom-up and remotely-sensed data streams for 8,000 pre-selected 1km2 locations across North America within a hybrid structure. Combining bottom-up soils data (SoilGrids) with spectral (MODIS and Landsat) and microwave (SMAP) remote sensing helps constrain the major C and water stocks through space and time. Machine learning is used both to identify and correct systematic errors in the process model (SIPNET) and to interpolate the pre-selected locations onto a 1km grid, making it computationally feasible to generate annual ensemble maps of the North American carbon budget. Furthermore, the uncertainties for each variable were reduced compared to those from observations or models alone. Spatiotemporal analysis showed a slight decrease in aboveground biomass (AGB) across the western US, a loss of leaf area across the boreal, and a slight greening of the Alaskan tundra. The uncertainty trends suggest a significant reduction in the uncertainty about soil organic carbon (SOC), the largest C reservoir. Validation results show that we accurately estimate C pools, compared to the assimilated data streams and held-out observations of AGB from GEDI, ICESat-2, and the US FIA, and SOC from the ISCN network. Our ML-debiasing algorithm further improved the accuracy of major C pools (AGB, SOC). In general, our continental SDA framework will facilitate global C MRV (monitoring, reporting, and verification) by providing accurate and precise C-cycle estimates, along with their corresponding spatiotemporal uncertainties.

ecology↗

bioRxiv2026

How Not to be Seen: Predicting Unseen Enzyme Functions using Contrastive Learning

MotivationPredicting enzyme function from its sequence is still an unsolved problem in the life sciences. Moreover, with the explosion of annotated genome data, we are inundated with potential enzymatic sequences that have not yet been biochemically characterized. While it is not possible to assign a not-yet-existing label to such a sequence, there is high value in placing the sequence as accurately as possible in known function space. Doing so can help provide more accurate falsifiable hypotheses for experimentalists wishing to characterize enzymes from specific functional families. ResultsHere we present a contrastive learning algorithm for predicting enzyme function from sequence. Our method, EnzPlacer, predicts the third, second, and first EC numbers for a protein whose fourth EC number is not in the training corpus. This novel prediction mechanism accurately places a protein sequence within a narrowed-down functional context, even if the precise function remains unknown. AvailabilityEnzPlacer is available from https://github.com/drxiangma/EnzPlacer under a GPL3 license. Contactqli@iastate.edu

bioinformatics↗

bioRxiv2026

Type 2 diabetes amplifies environmental Pb toxicity and intergenerational risk

Type 2 diabetes (T2D) and environmental lead (Pb) exposure intersect as prevalent global health challenges. Prior studies report elevated blood Pb in T2D, but the underlying mechanism and directionality remain unresolved. Here we show that T2D fundamentally alters Pb toxicokinetics, converting otherwise modest exposure into progressive organ injury and heritable risk. In a human cohort, elevated blood Pb in T2D specifically associated with impaired renal function rather than glycaemic control or adiposity. In db/db mice, diabetes increased oral Pb absorption through delayed gastrointestinal transit and epithelial barrier dysfunction, leading to enhanced systemic retention. With sustained exposure, renal Pb accumulation induced tubular stress that reduced effective clearance, creating a feed-forward loop in which diabetes promotes Pb retention and retained Pb accelerates kidney injury. Chronic Pb exposure exacerbated diabetic kidney injury without inducing hyperglycaemia, and short-course chelation attenuated renal stress markers. Beyond somatic toxicity, combined paternal T2D and Pb exposure programmed renal and neurobehavioral phenotypes across generations via sperm RNA. These findings redefine Pb from a passive environmental exposure to a context-dependent driver of disease, identify T2D as a vulnerability state that reshapes toxicant handling, and establish a mechanistic link between metabolic disease, environmental exposure and intergenerational risk. This work highlights the need for vulnerability-informed clinical management and environmental regulation in populations burdened by T2D.

genetics↗

bioRxiv2026

OT-knn: a neighborhood-aware optimal transport framework for aligning spatial transcriptomics data

Spatial transcriptomics (ST) measures gene expression while preserving spatial context within tissues, enabling detailed characterization of tissue organization. As ST technologies advance, aligning datasets across tissue sections, individuals, platforms, and developmental stages has become increasingly important but remains challenging due to sparse expression, biological heterogeneity, and geometric distortions between slices. We introduce OT-knn, a method for ST alignment that integrates local neighborhood information within an optimal transport framework. Rather than relying solely on single-spot expression, OT-knn reconstructs each spot using its spatial k-nearest neighbors, capturing microenvironment context that is more robust to noise and variability. These representations are then used to derive probabilistic correspondences between slices. We evaluate OT-knn using simulated data with known ground-truth alignment and real datasets from multiple ST platforms, including human dorsolateral prefrontal cortex data (10x Genomics Visium), mouse brain aging data with both within-donor and cross-donor comparisons (MERFISH), a multi-stage axolotl brain dataset (Stereo-seq), and a cross-platform analysis using mouse embryo datasets profiled by Stereo-seq and seqFISH. Across these settings, OT-knn achieves accurate and robust alignment, particularly in the presence of spatial deformation, donor heterogeneity, developmental variation and technological differences.

bioinformatics↗

bioRxiv2026

Endothelial PTBP1 Deletion in Transplanted Cardiac Tissue Limits Cardiac Allograft Vasculopathy

BackgroundCardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality following heart transplantation, with limited therapeutic options. Endothelial cells (ECs), at the interface between the donor graft and host immune system, play a central role in CAV development. However, the molecular mechanisms driving endothelial dysfunction and vascular remodeling in chronic heart transplant rejection remain poorly understood. MethodsTo characterize endothelial alterations associated with CAV, we isolated nuclei from cardiac tissues of four human donor groups: (1) early post-transplant CAV-negative surveillance biopsies, (2) CAV-negative explanted grafts with acute cellular rejection (ACR), (3) late-stage CAV-positive explanted grafts, and (4) naive non-transplanted control hearts. We applied intranuclear cellular indexing of transcriptomes and epitopes (inCITE-seq) to profile endothelial gene expression together with nuclear protein levels of splice factor polypyrimidine tract-binding protein 1 (PTBP1), a key post-transcriptional regulator of endothelial inflammatory responses. Functional relevance of PTBP1 was assessed using endothelial-specific deletion of Ptbp1 in an F1 hybrid murine model of CAV. ResultsIn human CAV, endothelial cells exhibited increased transforming growth factor-{beta} (TGF-{beta}) signaling and reduced oxidative phosphorylation (OxPhos) transcripts. Nuclear PTBP1 protein levels were markedly elevated in CAV endothelium and were associated with TGF-{beta}-responsive transcriptional programs and correlated with clinical indices of cardiac dysfunction. In murine heart transplants, endothelial-specific deletion of Ptbp1 markedly reduced hallmarks of CAV, including neointimal hyperplasia, fibrosis, and lymphocyte activation. At the molecular level, endothelial Ptbp1 deletion prevented suppression of mitochondrial transcripts and preserved mitochondrial content and integrity under hypoxic stress, attenuating interferon signaling in endothelial cells. ConclusionThese findings identify PTBP1 as a central endothelial regulator linking pro-fibrotic stress to mitochondrial dysfunction and immune activation in chronic cardiac allograft rejection. Targeting endothelial PTBP1 may represent a strategy to limit chronic graft injury while minimizing systemic immunosuppression.

immunology↗

bioRxiv2026

Unleashed condensation by recurrent mutations of an epigenetic regulator promotes cancer

The pathological mechanisms and significance for the prevalent hotspot mutations in disordered protein regions are poorly understood. ASXL1 is an obligate co-factor for BAP1 in H2AK119 deubiquitination. ASXL1 mutations are very frequent in myeloid malignancies, and are mostly C-terminal truncating mutations concentrated in a specific disordered region of ASXL1. ASXL1 truncations are gain-of-function mutations that promote myeloid malignancies, but the underlying mechanisms remain poorly understood. Here we show that the frequently truncated mutants of ASXL1 possess an intrinsic property of forming phase-separated biomolecular condensates, and this property is normally suppressed by the frequently deleted regions. A disease-mutant of the endogenous ASXL1 in leukemia cells forms dynamic nuclear co-condensates with other endogenous factors important for gene activation. The ASXL1 disease-mutants can greatly enhance H2A deubiquitination activity of BAP1 in cells and in vitro reconstituted system, enhance myeloid leukemia cell growth, and promote leukemogenesis in a mouse transplant model by turning on myeloid leukemogenic transcriptional programs. However, substitution of residues important for condensation disrupted or impaired all these abilities, suggesting that the condensation property is crucially important for the ASXL1 mutants in promoting cancer. Moreover, we discover that the conserved negative charges in the highly disordered and frequently deleted region on ASXL1 suppress the condensation of the wild type ASXL1. Charge-neutralizing mutations in this region restores condensation of the full-length ASXL1, and are sufficient to turn ASXL1 into a leukemogenic protein. Biochemical, biophysical, and simulation analyses suggest the intramolecular interactions normally mask the N-terminal region in engaging intermolecular interactions required for phase separation, and disease truncations escape from the regulatory interactions and unleash the phase separation property to form nuclear hubs to promote expression of tumorigenic gene programs. Finally, by showing a striking correlation of the mutation frequencies with the condensation properties and leukemogenesis activity for a series of human patient mutations, we suggest that dysregulation of condensation is a central mechanism for ASXL1 mutations in promoting myeloid malignancies. This suggests that dysregulation of condensation may be a key mechanism for some of the prevalent hotspot disease mutations in the disordered proteomes.

biochemistry↗

bioRxiv2026

Visualizing single base RNA mutations in living cells through DNA nanostructure mediated amplification

Capturing RNA dynamics in living cells would provide critical insights into transcriptional control and cellular adaptation, but remains technically formidable -- particularly at single-base precision. Here, we introduce a DNA tetrahedron based three-dimensional catalytic hairpin assembly (3D@CHA) nanoplatform that couples target recognition with catalytic activation in a spatially organized framework. Three cascaded hairpins (H-AN, H1, and H2) then enable localized and efficient signal amplification. Without external carriers or transfection, the platform exhibits robust biocompatibility, distinguishing highly homologous insulin I (Ins1) and insulin II (Ins2) mRNAs in living cells and tracking their redistribution and intercellular transfer during metabolic changes. Introducing a single-base mismatch site into H1 and coupling it with a Forster resonance energy transfer (FRET) readout yielded a KRAS-3D@CHA probe capable of detecting KRASG12D mutations at the RNA level with single-base resolution. This platform establishes a programmable framework for precise RNA imaging and mutation discrimination, opening new avenues for RNA-level diagnostics and precision oncology.

cell biology↗

bioRxiv2026

Harnessing Tumor-Specific Transcript Diversity Uncovers a Shared Neoantigen Reservoir for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is refractory to immunotherapy due to its immunologically cold microenvironment and the scarcity of mutation-derived neoantigens. Here, we introduce NeoAPP, a computational tool designed to systematically decode neoantigens arising from tumor-specific transcripts (TSTs) generated by transcriptional dysregulation. Multi-cohort transcriptomic profiling of 413 PDAC samples using NeoAPP reveal a median of 351 neoantigens per sample derived from 56 neoantigen-encoding TSTs (neoTSTs), surpassing mutation-derived counterparts in both abundance and patient coverage. Mechanistic analyses show that non-canonical splicing junction and transposable element activation drive neoantigen generation, while FOXA2-regulated promoter usage constitutes a potential major source of neoTSTs. Tumor-derived neoTSTs are also detected in extracellular vesicles and cancer-associated fibroblasts, implicating stromal crosstalk in immune modulation. Vaccination with neoTSTs induce CD8+ T cell responses in HLA-A*02:01/A*11:01 transgenic mice and suppressed tumor growth in syngeneic PDAC models. Collectively, this work establishes TST-derived neoantigens as a dominant and therapeutically actionable antigen reservoir in PDAC, advancing a transcriptome-guided framework for neoantigen discovery with potential to overcome immune resistance in low-mutation cancers. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/705024v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@82ff31org.highwire.dtl.DTLVardef@401342org.highwire.dtl.DTLVardef@b0771corg.highwire.dtl.DTLVardef@15c03ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Unraveling β2-Adrenergic Receptor Signaling Bias Between Gαs and Gα15 in Shaping Macrophage Function

Myocardial infarction and heart failure are leading global causes of mortality. Chronic {beta}-adrenergic receptor ({beta}AR) activation in cardiomyocytes promotes heart failure via Gs signaling after myocardial infarction, whereas {beta}2AR activation may also provide cardiac protection and repair through alternative pathways. Macrophages play a pivotal role in cardiac repair, and {beta}2AR has been reported to signal via the hematopoietic-specific G15 in these cells. We aimed to characterize signaling bias between Gs and G15 downstream of {beta}2AR and to elucidate their roles in macrophage polarization. Using TRUPATH triple assays, we observed that several {beta}2AR agonists activate G15 with at least an order of magnitude greater potency than Gs in this system. In addition, clinically used {beta}-blockers may exhibit differential inhibition on these two pathways. Macrophages are briefly classified into M1 and M2 polarization according to their activating stimuli and functional properties. Transcriptomic profiling of THP-1-derived macrophage-like cells treated with the {beta}2AR agonist clenbuterol revealed enrichment of M1 transcriptional profile and repair-related hallmarks. Knockdown of Gs showed M1 enrichment, whereas G15 knockdown was associated with negative M2 enrichment as well as M1 enrichment. Loss of either Gs or G15 negatively affected repair-associated hallmarks. In contrast, pharmacological intervention of the Gs-cAMP signaling produced opposing M1/M2 transcriptional responses, while suppressing repair-associated hallmarks. These in vitro findings explore the distinct pharmacological profiles of {beta}2AR ligands toward Gs and G15 and reveal how {beta}2AR agonism may modulate macrophage function through dual-transducer signaling.

cell biology↗

bioRxiv2026

The BELL-type homeobox transcription factor RLC3/OsBLH4 controls leaf rolling and drought tolerance via KNOX-BELL-lignin regulatory network in rice

O_LIModerate leaf rolling in rice is crucial for plant architecture and stress adaptation, but its molecular regulation remains unclear. We investigated the role of RLC3/OsBLH4, a BELL-type homeobox transcription factor, in controlling leaf rolling and drought tolerance, addressing gaps in lignin biosynthesis and cell wall development mechanisms. C_LIO_LIWe used gene map-based cloning (rlc3-1, rlc3-2), CRISPR/Cas9 knockout lines (rlc3-ko#11, rlc3-ko#12), and allelic complementation to validate RLC3s function. Additionally, we employed biochemical assays, gene expression analysis, and protein interaction studies to explore its regulatory network. C_LIO_LIRLC3 mutations impaired lignin biosynthesis and secondary cell wall formation, reducing bulliform cells area and causing midrib defects. These structural abnormalities accelerated water loss, leading to excessive leaf rolling and compromised drought tolerance. Mechanistically, RLC3 directly activates lignin synthesis genes (OsPAL5, OsCOMT5, OsCCR4, OsCAld5H1) and interacts with KNOX transcription factors (OSH1, OSH45, OSH71) to form a KNOX-BELL complex, further regulating lignin content and cell wall development. C_LIO_LIRLC3 orchestrates lignin deposition and secondary cell wall development to control leaf rolling, water transport, and drought tolerance. This study reveals a novel KNOX-BELL-lignin regulatory module governing leaf morphology and stress adaptation, offering targets for crop improvement under drought conditions. C_LI

plant biology↗

bioRxiv2026

The Structural History of Eukarya

Comparative genomics has traditionally relied on sequence-based markers, yet the global evolutionary landscape of protein architecture remains largely unexplored. We present the Structural History of Eukarya (SHE), a phylogeny derived from all-vs-all structural comparisons of 1,542 eukaryotic proteomes, encompassing nearly 300 trillion protein-protein alignments. This proteome-scale analysis reveals a bipartite model of eukaryotic evolution: a rigid Strict Core dominated by cytoskeletal architecture, supporting a more plastic Operational Engine centred on translational machinery. We identify lineage-specific accelerations of structural evolution in species such as birds and ants that are decoupled from proteome expansion, and show that aggregate structural topology provides a quantitative diagnostic of reference proteome quality. Finally, we demonstrate that proteome-wide structural fidelity enables a data-driven framework for model organism selection, replacing heuristic choices with quantitative matching to human biological processes. SHE is freely accessible as an interactive portal: https://she-app.serve.scilifelab.se/

evolutionary biology↗

bioRxiv2026

Ophiuchus-Ab: A Versatile Generative Foundation Model for Advanced Antibody-Based Immunotherapy

Antibodies exhibit extraordinary specificity and diversity in antigen recognition and have become a central class of therapeutics across a wide range of diseases. Despite this clinical success, antibody design remains fundamentally challenging. Antibody function emerges from intricate and highly coupled interactions between heavy and light chains, which complicate sequence-function relationships and limit the rational design of developable antibodies. Here, we reveal that modeling antibody sequence space at the level of paired heavy and light chains is essential to faithfully capture inter-chain dependencies, enabling a deeper understanding of antibody function and facilitating antibody discovery. We present Ophiuchus-Ab, a generative foundation model pre-trained on largescale paired antibody repertoires within a diffusion language modeling framework, unifying antibody generation and representation learning in a single probabilistic formulation. This framework excels diverse antibody design tasks, including CDR infilling, antibody humanization, and light-chain pairing. Beyond generation, diffusion-based pre-training yields transferable representations that enable accurate prediction of antibody properties, including developability, binding affinity, and specificity, even in low-data regimes. Together, these results establish Ophiuchus-Ab as a versatile foundation model for modeling antibodies, providing a foundation for next-generation antibody-based immunotherapy.

bioinformatics↗

bioRxiv2026

Nanobody MET CAR T cells show efficacy in solid tumors

BackgroundMET overexpression is associated with poor prognosis in many solid tumors due to its central role in tumor survival, invasion, metastasis, and chemoresistance. While targeting MET with antibody-drug conjugates has shown promising results, engineered cellular immunotherapeutic approaches have not been extensively explored. Compared to conventional single-chain variable fragments (scFv), naturally occurring single-domain antibodies consisting of variable heavy chains only (VHH or nanobodies) are smaller, retain high specificity, and exhibit remarkable biochemical stability. In this study, we tested the efficacy of MET-targeting VHH-CAR-T (chimeric antigen receptor T cells). MethodsWe generated a panel of VHH-CAR-Ts using mRNA electroporation. VHH-CAR-T cells were evaluated in functional assays including cell binding avidity, cytokine production profiles, hydrogel microwell-based cellular kinetics, and in vitro cytotoxicity. We also assessed the therapeutic efficacy of VHH-CAR-T in an in vivo mouse model of metastatic triple negative breast cancer (TNBC). ResultsAmong the tested VHH, we identified those with intermediate avidity as most effective for in vitro tumor killing. VHH-CAR-Ts with CD28 costimulatory domains demonstrated augmented cytotoxicity with favorable selectivity, requiring a minimum antigen density threshold for activation. Mechanistically, VHH-CAR-Ts demonstrated low tonic signaling, high avidity, potent cytokine production, and rapid tumor killing kinetics. When administered in an mRNA format, VHH-CAR-Ts exhibited potent and prolonged control of tumor growth in an in vivo metastatic model of TNBC. ConclusionTaken together, these results demonstrate that VHH-CAR-Ts exhibit robust MET specificity and potent therapeutic efficacy both in vitro and in vivo. Thus, VHH-CAR-T cell therapy represents a promising immunotherapeutic strategy for targeting MET-overexpressing solid tumors. What is already known on this topicMET signaling is an important contributor to the aggressiveness of many solid tumors, and targeting MET by antibody-drug conjugates has shown efficacy and safety. Targeting MET by CAR-T cells has been under study, though with limited potency. What this study addsThis study is the first to demonstrate effectiveness of anti-MET VHH-CAR-T cells. Compared with other antigen binding domains, VHH-incorporated CAR-T cells show low tonic signaling, a favorable cytokine profile, and potent tumor killing. How this study might affect research, practice or policyWith the multiple advantages of VHHs including small size, stability, and low potential for tonic signaling, VHH-CAR-T cells represent a promising approach for CAR-T design against solid tumors.

immunology↗

bioRxiv2026

Functional In-Context Learning in Genomic Language Models with Nucleotide-Level Supervision and Genome Compression

AO_SCPLOWBSTRACTC_SCPLOWGenomic foundation models aim to learn general-purpose representations directly from DNA sequence, enabling sequence understanding, generation, and probabilistic reasoning across a wide range of biological tasks. Scaling such models to genomic lengths, however, remains challenging due to the tension between long-range context, nucleotide-level resolution, and practical computational efficiency. Architectural innovations have enabled increasingly long nominal inputs, but often struggle to translate additional context into meaningful performance gains, particularly in the presence of sparse functional signal along eukaryotic genomes. In this work, we revisit the design of long-context genomic foundation models from the perspective of training objective and data construction. We introduce Factorized Nucleotide Supervision (FNS), which reconciles efficient k-mer tokenization with single-nucleotide likelihoods through probability marginalization, and Genome Compression Pretraining (GCP), which reshapes the training distribution by concentrating on gene-centric and regulatory regions. Together, these techniques enable standard transformer-based models to perform functional in-context learning without sacrificing nucleotide-level fidelity or computational efficiency. Building on these ideas, we present a family of autoregressive genomic foundation models supporting contexts of up to 98k base pairs across eukaryotic and prokaryotic genomes. Across training-free evaluations and downstream fine-tuning benchmarks, our models consistently improve over prior approaches and match or exceed state-of-the-art baselines while enabling substantially more efficient inference. Together, these results demonstrate that aligning supervision and data regimes with the biological structure of genomic sequence provides a principled and effective path toward scalable and biologically faithful genomic language modeling. Models, data, and scripts for downstream analyses are publicly available at https://huggingface.co/GenerTeam.

genomics↗

bioRxiv2026

Microstructural Disruption of the Forceps Minor in Schizophrenia: A Potential Clinical Imaging Biomarker Using Translational DTI

Schizophrenia is one of the most complex brain disorders, arising from multidimensional pathophysiological processes that span genetic vulnerability, neurotransmitter dysregulation, structural brain damage, and large-scale brain network dysfunction. Large-scale neuroimaging studies have consistently demonstrated the critical role of frontal brain regions in schizophrenia. Despite substantial progress, the precise localization of structural damage within these regions and the neurobiological mechanisms linking such alterations to disease pathology remain poorly understood. In this study, we included a total of 115 subjects from two sites of the B-SNIP dataset, comprising 60 healthy controls and 55 individuals with schizophrenia. We employed diffusion tensor imaging (DTI) to precisely characterize specific structural alterations in the frontal brain regions associated with schizophrenia. Our findings reveal significant microstructural abnormalities in the forceps minor, a major commissural white-matter tract that serves as a critical interhemispheric bridge between the bilateral frontal lobes. Network-level mapping further demonstrates that the forceps minor is closely integrated with large-scale brain networks, particularly the default mode network, and maintains strong structural connectivity with orbitofrontal regions-both of which are known to exhibit dysfunction in schizophrenia. Moreover, converging evidence suggests that the forceps minor plays an important role in the regulation of social behavior, a core domain of impairment in schizophrenia. Collectively, these findings identify the forceps minor as a promising structural imaging biomarker for schizophrenia and provide novel insights into the microstructural mechanisms underlying the disorder.

neuroscience↗

bioRxiv2026

Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia

The central apparatus of motile cilia, consisting of central microtubules and various protein projections, is essential for dictating the ciliary movement. Although three proteins (FAP65, FAP147, and FAP70) have been localized to the C2a projection in Chlamydomonas reinhardtii, the full protein composition and functional roles of the vertebrate C2a remain inadequately defined. Here, we use three knockout mouse models corresponding to their respective homologs (Ccdc108, Mycbpap, and Cfap70) to systematically investigate their functions in vertebrates. Notably, all three knockout strains exhibit distinct phenotypes related to primary ciliary dyskinesia (PCD), including hydrocephalus and sinusitis. The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one anothers stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules and ultimately alters the ciliary movement pattern. Furthermore, we significantly expand the vertebrate C2a proteome by identifying ARMC3 and MYCBP as additional C2a components. Collectively, our findings illuminate the proteomic composition and strict physiological requirements of the vertebrate C2a projection, providing new insights into the molecular pathogenesis of PCD. Impact StatementDeficiency in any of the interdependent C2a proteins (CCDC108, MYCBPAP, and CFAP70) collapses this central pair microtubule-associated projection, disrupting vertebrate ciliary movement and causing primary ciliary dyskinesia phenotypes in mice.

cell biology↗