Biology subjects

Wang, R.

Publications and source records attributed to Wang, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

AI-like parallelogram geometry of word relations in the human neocortex

The same semantic relation (e.g., queen-king and woman-man) is encoded as a shared vector direction in language AI, forming parallelogram geometry, whereas its presence in the human brain remains unknown. Our fMRI analysis revealed similar geometry in the neocortex, particularly in higher-order language regions. Our findings link the brain and AI through a common geometry, advancing understanding of how abstract relational knowledge is organized and used in human language processing.

neuroscience↗

bioRxiv2026

A native single-transcript TnpB architecture enables efficient virus-induced genome editing and visual screening of heritable progeny harboring phenotypically silent edits

TnpB are ultra-compact RNA-guided nucleases, yet most reported systems require separate expression of the nuclease and cognate reRNA, eroding their size advantage and restricting viral delivery in plants. Here we demonstrate that ISDra2 TnpB harnesses its native overlapping architecture in which the reRNA sequence resides within the 3' coding region of TnpB, processing its own mRNA to generate functional reRNA and enabling single-transcript genome editing in plants. Only a 7-bp conserved motif followed by a 16-20 bp spacer directly downstream of the coding sequence suffices for editing, requiring no exogenous ribozymes or independent guide promoters. This ultra-compact design enables simultaneous packaging of the editing system and an NbPDS silencing module into a single TRV vector, achieving robust editing in systemic Nicotiana benthamiana tissues and establishing a dual VIGE-VIGS strategy for direct visual selection of heritable, transgene-free edited progeny via distinct albino phenotypes, reducing laborious large-scale genotyping even for targets lacking inherent visible traits.

plant biology↗

bioRxiv2026

Metagenomic and metabolomic analysis of a bryozoan-associated microbial complex from the Hanjiang River, China

Background Bryozoans are ancient colonial animals that have existed for over 470 million years and are widely distributed across aquatic environments. Recently, many spherical colloids (average diameter{approx}1 meter in diameter), containing bryozoans and diverse microorganisms, were found in the Hanjiang river in China. In this study, we investigated these bryozoan-dominated microbial complexes using metagenomic sequencing, metabolomic profiling, and complementary approaches. Results The results revealed that the microbial structure dominated by bryophytes included eukaryotes such as fungi, microalgae, and small parasites etc., as well as prokaryotes such as bacteria and viruses. All members form a highly integrated consortium that collaboratively maintains community function and stability, which displayed the shape and structure of a regular microbial complex and increased in size. Additionally, the results suggested the predominately presence of Proteobacteria were particularly abundant and are known to produce bryostatins in response to bryozoan signals. Interesting, it was implied that a decrease or even a loss in virulence occurs when pathogenic microorganisms become members of the complex. This is the first study focusing on the composition and metabolites of the unusual microorganism complex. The results discovered the close and intriguing connections within the microbial communities dominated by the ancient organism bryozoan through multi-omics technologies. It showed that both eukaryotes and prokaryotes can coordinate or compete, thereby forming a stable composite structure.

zoology↗

bioRxiv2026

siProGenA: Generative siRNA Candidate Construction via Position Proposal and Guide Generation

Small interfering RNAs (siRNAs) are short guide RNAs that recruit the RNA-induced silencing complex (RISC) to complementary target sites on messenger RNAs (mRNAs), triggering Ago2-mediated cleavage and gene silencing. siRNA design requires compact candidate sets that cover a target while preserving efficacy, specificity, and practical sequence constraints. Existing pipelines usually enumerate candidate windows, assign a canonical guide to each window, and then rank preconstructed siRNA--mRNA pairs. This has produced strong pairwise efficacy predictors, but leaves a candidate-construction gap: candidate positions and guide sequences are fixed before the model begins to rank them. We address this gap by decomposing siRNA candidate construction into two generative decisions: where to place candidates within an mRNA segment, and what constrained guide variants to consider at a candidate position. We instantiate this framework as siProGenA, using a Discrete Denoising Diffusion Probabilistic Model (D3PM) for mRNA-conditioned position proposal and a Bayesian Flow Network (BFN) for temperature-controlled guide generation. On 62 positive test segments, the diversity-aware final library reaches Hit@1 = 0.790 and Hit@5 = 0.903. In a measured-site controlled Stage~2 evaluation, seed- and cleavage-preserving variants outscore the canonical complement for 89.8% of measured sites, with supporting gains across additional computational scorers, random-mismatch controls, and biophysical diagnostics. Together, the results support a modular proposal--generation view of siRNA candidate construction for prioritizing compact candidate sets.

bioinformatics↗

bioRxiv2026

Chimeric Induced Cooperativity Opens the Design Space of Eukaryotic Gene Regulation

Predictive engineering of eukaryotic transcription is limited by the coupling of signal sensing, DNA binding, TF abundance and promoter output. Here we establish chimeric induced cooperativity (CIC), a modular architecture that separates LBD, DBD and AD functions and links them to promoters with tunable basal and maximal output. Module parameters can be recombined to predict new CIC-TF configurations and guide design before construction. Ligand-induced cooperativity reduces basal DNA occupancy while increasing induced occupancy, and effective DBDs combine low OFF-state activity with strong ON-state promoter occupancy rather than binding strength alone. Synthetic promoters independently control occupancy gain and output range. The same framework extends to repression and can be recalibrated with limited measurements in mammalian cells. In yeast, CIC-12 achieved a mean fold induction of 298-fold across 12 orthogonal sensors; an earlier CIC-10 chassis enabled model-guided optimization of an eight-gene vitamin B5 biosynthetic pathway. CIC establishes a programmable, model-guided design space for eukaryotic transcriptional control.

synthetic biology↗

bioRxiv2026

Flies evolved a gyrocompass to maintain navigational accuracy during rapid flight maneuvers

Halteres, the miniaturized hindwings of flies, function as biological gyroscopes that encode angular velocity during flight. Although their established role is to detect flight perturbations and trigger compensatory manoeuvers, here we show that halteres also function as a gyrocompass, maintaining an accurate estimate of heading during rapid turns. To overcome the incompatibility between rapid body rotations and two-photon imaging, we exploited the physics of haltere mechano-transduction to reproduce the inertial forces acting on the halteres during rapid body rotations using micron-scale oscillations of the thorax. Our experiments demonstrate that flies update their internal compass during rapid turns by integrating inertial measurements with predictions derived from efference copy signals. Because body saccades exceed the temporal bandwidth of visual motion processing, this inertial computation allows flies to maintain an accurate internal compass throughout these rapid manoeuvres. This capability may enable flies to compute critical parameters such as wind direction and ground speed by comparing measurements made before and after each saccade. Our findings suggest that an ancestral flight-stabilization system was evolutionarily co-opted into a biological gyrocompass, a new function that may have contributed to the adaptive radiation of flies.

neuroscience↗

bioRxiv2026

Mechano-Piezoelectric F-Peptide Hydrogels Enable In Situ Stem Cell and Immune Niche Modulation for Cartilage Regeneration

Osteoarthritis, characterized by cartilage degradation and synovial inflammation, has spurred interest in mechano-piezoelectric bio-hydrogel therapies that can both relieve symptoms and reverse progression. However, current approaches lack sufficient piezoelectric output and dual cartilage/inflammation targeting. To address this, we demonstrated a mechano-piezoelectric peptide hydrogel composed of nanofibers integrating piezoelectric cues with mesenchymal stromal cells (MSCs) recruitment and PIEZO2 mechanosignaling. Molecularly, the hydrogel's seed peptide incorporated four functions: COL2A1 targeting, MMP-13 responsiveness, MSCs homing, and self-assembly. Overexpressed MMP-13 in the osteoarthritis niche triggers gelation, promoting MSCs recruitment and drug retention. Fluorination modulates hierarchical nanofiber assembly, enhancing mechanical and piezoelectric properties, as confirmed by morphological, biophysical, and computational analysis. The trifluoromethyl-modified, 4-octyl itaconate (4-OI) loaded formulation reverses osteoarthritis via PI3K/AKT activation and Wnt/{beta}-catenin suppression, as shown by improved Osteoarthritis Research Society International (OARSI) scores, bone microarchitecture, and cartilage matrix. This synergy of mechano-piezoelectric cues and 4-OI offers a clinically promising strategy for osteoarthritis.

biophysics↗

bioRxiv2026

Spatially-restricted metabolic delivery of auxin for selective adventitious root induction

Auxin impacts on nearly every aspect of plant growth and development. Its exogenous application therefore results in pleiotropic growth responses. Exploiting this activity for plant propagation requires avoiding or minimizing such off-target effects and is generally achieved as a trade-off between toxicity and organogenetic efficacity. We recently identified the compound HYSPARIN (HYS) with potent, and uniquely selective adventitious root inductive activity. Unlike other root-inducing compounds, HYS preferentially activates auxin responses in the shoot via an unknown mechanism. Here, we show that HYS acts as a shoot-specific proauxin. Rather than acting through auxin homeostasis, we found that HYS is hydrolysed in planta independently of ILR1/ILL amidohydrolases to release the synthetic auxin MCPA. Structure-activity relationship analysis confirmed a strong dependence on its MCPA moiety for activating auxin responses, and identified its promoiety as a determinant of shoot-specificity and activity. Selective application of MCPA also potently induces AR is consistent with a model in which HYS metabolism produces a spatially restricted, AR inductive auxin signal. The activation mechanism of HYS thus provides a conceptual framework for tissue-specific metabolic delivery of auxin and may enable the programmable delivery of other xenobiotics in plants.

plant biology↗

bioRxiv2026

Human parietal retrieval states prioritize an absent temporal reference to reconstruct event order

How the brain judges when something happened is thought to involve reconstruction--deriving temporal judgments from information recovered from memory rather than simply reading out a fixed temporal code. Testing this has been difficult because conventional tasks present both compared items at retrieval, so reinstatement could reflect cue processing as much as memory recovery. Here we dissociated what a judgment requires from what its cue supplies: during fMRI scanning, participants (n = 55) judged a targets temporal position relative to a milestone that was never shown at retrieval. We found that retrieval patterns in the precuneus and angular gyrus resembled the absent milestone more than the target, a bias strongest in the precuneus. Moreover, trial-by-trial similarity to the encoded path linking milestone to target--rather than to either alone--predicted correct judgments independently of retrieval activation. Human parietal retrieval is thus configured more by what a judgment requires than by what the cue supplies, providing content-specific representational evidence for reconstructive temporal-order memory.

neuroscience↗

bioRxiv2026

MiRNA let-7a-5p Ameliorates Pulmonary Fibrosis by Suppressing TGFBR1-Mediated Endothelial-to-Mesenchymal Transition

Background Idiopathic Pulmonary Fibrosis (IPF) is a fatal chronic lung disease with limited therapeutic options. While alveolar epithelial injury and fibroblast activation are well-studied, endothelial-mesenchymal transition (EndoMT) is emerging as a critical pathogenic mechanism. The regulatory role of exosomal miRNAs in pulmonary fibrosis remains unclear. This study investigates serum exosomal miRNAs, particularly let-7a-5p, in modulating EndoMT during the onset of pulmonary fibrosis. Methods Clinical cohorts of IPF patients and healthy controls were enrolled. Serum exosomal miRNAs were profiled, followed by differential expression and functional enrichment analyses. In vitro experiments involved human pulmonary artery endothelial cells (HPAECs) transfected with let-7a-5p mimic or inhibitor. Dual-luciferase reporter assays confirmed the binding between let-7a-5p and TGFBR1. HPAECs were co-cultured with lung epithelial cells to examine paracrine signaling. In vivo studies used a bleomycin-induced mouse model with let-7a-5p agomir administration. Assessments included histopathological staining, hydroxyproline content, Western blot, qPCR, micro-CT, and pulmonary function tests. Results Let-7a-5p was significantly downregulated in serum exosomes from IPF patients, correlating with clinical indicators. Mechanistically, let-7a-5p directly bound the TGFBR1 3'UTR to inhibit its expression. Inhibition of let-7a-5p upregulated -SMA, FN1, smad2/3 phosphorylation, and collagen I, while downregulating CD31 and VE-cadherin. Therapeutically, let-7a-5p mimic reversed bleomycin-induced EndoMT and suppressed epithelial-mesenchymal transition (EMT) via paracrine signaling. Mice administered agomir showed reduced fibrosis, improved lung function, and suppressed TGF-{beta}/Smad signaling. Conclusion Serum exosomal let-7a-5p suppresses pulmonary fibrosis by targeting TGFBR1 to inhibit EndoMT. Its downregulation in IPF patients correlates with disease progression, highlighting its biomarker potential.

molecular biology↗

bioRxiv2026

A Practice on Antibody Hydrophobic Interaction Chromatography Retention Time Prediction using Pre-Trained Large Language Model Fine-Tuning

Hydrophobicity is a critical property associated with the risk of non-specific binding, and it is commonly assessed using hydrophobic interaction chromatography retention time. Several computational approaches have been developed to predict antibody developability based on pre-trained language models. Such models can be fine-tuned with limited labeled antibody sequences and, in principle, do not require structural information, which is often challenging to obtain. Nevertheless, few studies have achieved strong performance in hydrophobicity prediction without incorporating structural features. Here, we present a case study of fine-tuning the pre-trained model IgBert to predict antibody hydrophobicity. Using Herceptin as a reference, we performed hydrophobic interaction chromatography retention time experiments and generated Herceptin-adjusted datasets. The fine-tuned model achieved a best R2 of 0.916, underscoring the critical role of rigorous data quality control. We also synthesized and validated 20 commercially available antibody sequences, and the results showed that the predicted hydrophobic properties were correctly reflected. Our findings provide practical guidance and highlight considerations for future applications of fine-tuned pre-trained language models in antibody hydrophobicity prediction.

bioinformatics↗

bioRxiv2026

Paternal Metabolic Reversal Remodels Sperm RNA Profiles and Ameliorates Intergenerational Metabolic Disorder in Mice

Paternal obesity increases metabolic risk in offspring, but whether this risk can be reduced by restoring paternal health before conception remains unresolved. We developed a within-sire induction-and-reversal model in outbred CD1 mice in which high-fat diet (HFD)-exposed males generated offspring before and after transition to an ingredient-matched control diet with voluntary exercise. HFD caused obesity, glucose intolerance, insulin resistance, and extensive remodeling of sperm mRNA, lncRNA, and sncRNA profiles, together with transcriptomic changes in metabolic tissues. Diet and exercise reversal normalized paternal metabolic indices and broadly restored tissue RNA profiles, although sperm retained a limited transcriptional memory of prior HFD exposure. Offspring sired before reversal developed sex-dependent metabolic dysfunction despite control-diet rearing, whereas offspring sired after reversal showed substantial improvement. These findings show that paternal metabolic risk is modifiable before conception and that this reversibility is linked to remodeling of sperm RNA. (140 words) HighlightsO_LIPaternal HFD-Ex induces obesity, glucose intolerance and insulin resistance in CD1 males C_LIO_LISperm shows much stronger RNA response than four metabolic organs profiled C_LIO_LIDiet and exercise reversal restores metabolism and RNA profiles in sperm and four metabolic organs analyzed C_LIO_LIOffspring metabolic risk is reduced when sires conceive after reversal through diet and exercise intervention C_LI eTOC BlurbChen, Magalhaes, et al. show that paternal metabolic recovery before conception remodels sperm RNA and reduces transmission of HFD-associated metabolic risk to offspring in a within-sire mouse model.

genetics↗

bioRxiv2026

Catch-bond engineering surpasses high-affinity maturation for T cell receptor therapies against solid tumors

The sensitivity of T cell receptors (TCRs) has traditionally been attributed to their affinity, a principle that has long underpinned both T cell biology and TCR engineering. Currently, high-affinity maturation remains the predominant strategy employed to enhance TCR sensitivity; however, this approach has been associated with severe off-target toxicities in clinical settings. In this study, using the only FDA-approved TCR-T therapy as a clinical reference, we demonstrate that force-induced catch bonds, rather than static affinity, primarily determine TCR sensitivity and facilitate the development of more effective TCR engineering strategies. Among polar and charged amino acids, histidine was determined to be the most effective residue for pinpointing engineering hotspots. TCRs engineered to form catch bonds exhibited superior performance compared to the FDA-approved TCR subjected to high-affinity maturation, improving the efficacy of TCR-T cell therapies against solid tumors without eliciting off-target toxicity or alloreactivity. Mechanistically, a correlation was observed between TCR sensitivity and the strength of catch bonds, whereas no such relationship was found with affinity. The duration of T cell-tumor cell interactions, immunological synapse formation, and the intensity of subsequent signaling are governed by catch bonds rather than by affinity. Structural and computational investigations have demonstrated that force-induced reconfiguration of the ligand-receptor interface, along with the formation of a novel hydrogen bond network, augments the specificity of interactions between the TCR and antigenic peptides. Furthermore, bispecific T cell engagers utilizing the TCR scaffold also formed catch bonds with tumor antigens, indicating intrinsic mechanosensory properties of the extracellular domains of TCRs and suggesting a novel therapeutic modality based on catch-bond-engineered TCRs.

immunology↗

bioRxiv2026

Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC

Bulk transcriptomic classifiers stratify pancreatic ductal adenocarcinoma (PDAC) into classical and basal-like subtypes with prognostic and therapeutic relevance, yet increasing evidence indicates that these epithelial programs frequently coexist within individual tumors. How these intermediate states affect the local tumor microenvironment remains poorly defined. Here, we integrate multiplexed ion beam imaging (MIBI) with bulk RNA sequencing to resolve epithelial subtype identity at the level of spatially contiguous cancer nests and quantify their associated microenvironments. Across 47 primary tumor samples from 34 patients, we identified classical, intermediate, and basal cancer cell states at single-cell resolution and delineated discrete cancer nests with mixed or dominant subtype compositions. Distance-resolved spatial analysis reveals that basal-rich cancer nests are surrounded by locally immunosuppressive microenvironments characterized by reduced expression of MHC class II and co-stimulatory molecules in proximal myeloid cells, independent of myeloid abundance. These regions are enriched in fibroblast-dominated neighborhoods and distinct cell-cell interaction architectures. Using EcoTyper analysis of two independent bulk RNA-seq cohorts, including an OHSU discovery cohort (N = 277 patients) and TCGA as a validation cohort (N = 147 patients), we identified poor-prognosis tumor ecotypes enriched for basal epithelial states that similarly exhibited depleted myeloid antigen presentation signatures, linking spatial niche phenotypes to transcriptional ecotypes and patient outcomes. Together, these findings demonstrate that epithelial subtype programs in PDAC are organized at the level of spatially defined cancer nests and that basal cancer programs reside within localized niches of myeloid antigen presentation dysfunction, linking intratumoral architecture to immune suppression and clinical prognosis.

cancer biology↗

bioRxiv2026

Beyond Temporary Scaffolding: Persistent Hippocampal Engagement and Brain-Wide Network Reorganization in Remote Memory Consolidation

The standard model of memory consolidation posits a temporary role for the hippocampus. We challenge this view by combining a novel face-name associative memory task with cross-modal decoding of fMRI data. We demonstrate that the hippocampus remains persistently engaged in representing both recent and remote memories, with distinct subregional contributions: recent memories were represented in the right posterior hippocampus, whereas remote memories additionally recruited the left anterior hippocampus. This sustained hippocampal involvement occurred alongside a large-scale network reorganization. Remote memory retrieval was accompanied by increased global connectivity among semantic regions, yet the hippocampus itself did not emerge as a major hub. Instead, network hubs shifted from the medial prefrontal cortex (mPFC) for recent memories to the mPFC and bilateral inferior parietal lobule for remote memories. These findings reveal a dynamic process in which the hippocampus preserves long-lasting representational functions while the broader memory network undergoes extensive reorganization.

neuroscience↗

bioRxiv2026

AINN-Express: A Leakage-Aware, Sequence-Only Predictor of VHH Antibody Expression Built on the AINN-P1 Protein Foundation Model

Expression -- whether an antibody can be produced at usable yield -- is one of the earliest and most expensive filters in therapeutic discovery. We present AINN-Express, a sequence-only predictor of VHH single-domain antibody (nanobody) expression built on AINN-P1, Ainnocences protein foundation model. AINN-Express encodes a VHH with a frozen AINN-P1 encoder and scores it with a lightweight gradient-boosted classifier: it takes only an amino-acid sequence, returns an expression probability, and needs no structure and no per-task model training. Under a leakage-safe, leave-program-out evaluation, AINN-Express reaches ROC-AUC 0.87 within known antibody programs and 0.81 on entirely new programs -- well above the majority baseline -- making it a practical tool for prioritizing candidates before wet-lab work. We further justify the encoder choice with a controlled, leakage-aware benchmark against general-purpose protein language models: on this task, AINN-P1 (167 M parameters) generalizes to unseen programs far better than a general-purpose ESM2 (650 M) -- 0.81 versus 0.68 new-program ROC-AUC -- and matches a domain-finetuned ESM2 (0.83) with no task-specific finetuning, at roughly one-quarter of the parameters. The gap is invisible under a random split, where all encoders score [~]0.88; only leave-program-out evaluation reveals that general-purpose embeddings largely encode program identity rather than transferable determinants of expression. Purpose-built representation quality, not parameter count, is what makes AINN-Express generalize.

bioinformatics↗

bioRxiv2026

Constructing a full-length single-nucleus transcriptomic atlas of the obese mouse by UURNA-seq

Single-nucleus RNA-seq (snRNA-seq) offers advantages in sample preparation for atlas construction and data mining of gene regulation. However, current snRNA-seq protocols struggle to balance sensitivity and throughput. Here we present ultra-throughput and ultra-sensitivity single-nucleus total RNA sequencing (UURNA-seq), a platform that enables large-scale atlas construction in a single day. UURNA-seq outperforms existing single-cell and single-nucleus protocols, with reduced coverage bias, higher gene detection efficiency, and greater throughput at lower per-cell cost. This performance extends to primary tissues and is consistent in fresh and frozen samples, supporting flexible workflows for clinical and archival specimens. Notably, UURNA-seq also detects substantially more non-coding RNAs, including lncRNAs and sncRNAs, alongside mRNAs at single-nucleus resolution, uncovering previously inaccessible layers of cellular regulation in complex tissues. Leveraging these capabilities, we constructed the first comprehensive multi-tissue atlas of obesity and characterized RNA dynamics at atlas scale, revealing both conserved and tissue-specific transcriptional alterations and identifying critical dysregulation of hormone signaling and metabolic pathways. Together, these results establish UURNA-seq as a sensitive, scalable, and cost-effective platform that provides a route to dissect the molecular basis of complex diseases such as obesity.

genomics↗

bioRxiv2026

Enkephalin constrains fear learning via volume transmission to the lateral amygdala

Fear learning involves the formation of associations between cues and aversive outcomes, a process that must be tightly regulated to prevent excessive or generalised fear. Dopamine release in the lateral amygdala (LA) drives fear acquisition, whereas endogenous opioids constrain it. However, whether opioids are dynamically released within the amygdala circuits during learning, and how they exert this control remain unclear. Here we show that met-enkephalin is locally released within the amygdala during auditory fear conditioning, with signals shifting from the aversive outcome to its predictive cue as learning progresses. The amygdalo-striatal transition zone (ASt), is the principal source of this enkephalin, released from medium spiny neurons receiving strong auditory thalamic input. This enkephalin spreads from the ASt to the LA via volume transmission. Selective knockdown in the ASt abolished opioid signals and enhanced fear learning, demonstrating that this diffuse signal constrains fear memory formation. We further show that enkephalin suppresses dopamine release in both the ASt and LA via {micro}-opioid receptors, identifying the ASt as a neuromodulator hub coordinating opioid and dopaminergic signalling across amygdala fear circuits. Although demonstrated here for auditory fear learning, the ASt receives multimodal sensory input, suggesting a broader mechanism through which sensory experience recruits enkephalin release to gate associative learning

neuroscience↗