Biology subjects

Tang, Y.

Publications and source records attributed to Tang, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Polyclonal-Monoclonal Transition in Lung Squamous Cell Carcinoma Evolution

The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1) and cytoskeletal regulators (e.g., KIF26A). Collectively, these findings established a polyclonal-monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

genomics↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

Involuntary facial muscle activity during imagined vocalisation contaminates EEG and enables emotion decoding

AO_SCPLOWBSTRACTC_SCPLOWDecoding imagined speech from electroencephalography (EEG) recordings is potentially useful for brain-computer interfaces. Previous studies have focused on decoding semantic information from EEG, leaving the decoding of emotion - an important component of human communication - largely unexplored. Here, we report two experiments involving participants tasked with overt (n = 14) or imagined (n = 21) emotional vocalisation in five different categories: anger, happiness, neutral, sadness, and pleasure. Throughout, we recorded 64-channel EEG; we computed time-frequency features and used a logistic-regression classifier to evaluate emotion decoding accuracy. In five participants, we also recorded facial surface electromyography (sEMG) during imagined vocalisation, and studied the contamination of EEG by sEMG. Our results show that emotion can be decoded from single-trial EEG recordings of both overt (78.1%, chance = 20%) and imagined vocalisation (36.4%). The high-gamma band (50 to 100 Hz) and lateral EEG channels (T7, T8, and proximal) were important for decoding. sEMG analysis indicated that involuntary facial muscle activity contributed to these spectral and spatial patterns during imagined vocalisation, especially during happy vocalisations. We conclude that involuntary facial muscle activity is associated with certain emotion categories (i.e., happiness), and drives above-chance decoding of emotion from single-trial EEG recordings of imagined vocalisation.

physiology↗

bioRxiv2026

A Long-Context Generative Foundation Model Deciphers RNA Design Principles

Programmable design of RNA sequences with defined functions remains a central challenge in biology. Despite recent advances, existing RNA generative models lack robust controllable design capabilities and are constrained by short context windows, limiting their capacity to model the complex evolutionary manifold of full-length transcripts. Here, we introduce EVA (Evolutionary Versatile Architect), a long-context generative RNA foundation model trained on over 114 million full-length RNA sequences spanning the full breadth of evolutionary diversity. By integrating a Mixture-of-Experts architecture with an 8,192-token context window, EVA learns a unified, evolution-consistent representation of RNA sequence space that captures both global transcript structure and fine-grained functional elements. EVA establishes a unified framework for a broad spectrum of RNA design tasks within a single architecture, ranging from mutational fitness prediction to context-aware sequence engineering. We demonstrate EVAs versatility through the de novo design and targeted optimization of diverse RNA classes, including tRNAs, aptamers, and CRISPR guide RNAs, as well as mRNA and circular RNA therapeutics. In systematic evaluations, EVA achieves state-of-the-art performance across seven of nine established benchmarks, improving structural modeling accuracy by up to an order of magnitude compared to existing approaches. EVA is fully open-source at the following repository: https://github.com/GENTEL-lab/EVA.

molecular biology↗

bioRxiv2026

Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease

Alzheimers disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2s function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology.

systems biology↗

bioRxiv2026

Optineurin is a gatekeeper of mitochondrial health and proteostasis in Alzheimer's disease vulnerable neurons

Alterations in autophagy-related pathways and in mitochondrial function have long been associated with the pathology of several neurodegenerative disorders, including Alzheimers disease (AD). However, the cascade of events that links these processes and how they contribute to the early degeneration of specific neuronal subpopulations remain to be understood. Here, we use a data-driven approach and identify Optn as a potential regulator of AD pathology that is highly enriched in vulnerable ECII neurons compared to neurons that degenerate later in the disease continuum. We show that Optineurin downregulation triggers early dysregulation of mitochondrial function, followed by alterations in AD-associated processes, including proteostasis, synaptic function, and neuroinflammation. This is accompanied by ECII neuron loss and astrocyte reactivity in EC neuron projecting areas in the hippocampus. Together our results suggest that Optineurin plays a central role in the maintenance of mitochondrial health and bioenergetics in AD vulnerable neurons and that pathological processes that impair this homeostasis may contribute to the early degeneration of vulnerable ECII neurons.

neuroscience↗

bioRxiv2026

Lipid monounsaturation confers cold tolerance and improves tissue viability during hypothermic storage

The rapid loss of tissue viability during hypothermic storage frequently results in organ failure and high discard rates in transplantation. In contrast, ectothermic animals can tolerate prolonged exposure to low temperatures in their natural environments. Elucidating the mechanisms underlying this cold tolerance may therefore inform improved strategies for tissue preservation. Here, we investigate proteomic and metabolomic responses to cold exposure in the livers of two frog species from distinct habitats: the cold-sensitive African clawed frog (Xenopus laevis) and the cold-tolerant Northeastern Asian brown frog (Rana dybowskii). Cold exposure induced lipid mobilization in X. laevis, whereas it promoted phospholipid mono-unsaturation in R. dybowskii. Notably, treatment with monounsaturated fatty acids (MUFAs) or overexpression of stearoyl-CoA desaturase (SCD) reduced cell death during cold storage. Moreover, MUFA infusion significantly improved cell viability in mouse liver tissue under hypothermic conditions. Together, these findings suggest that lipid mono-unsaturation, an adaptive feature of cold-tolerant frogs, can be leveraged to enhance tissue preservation during cold storage.

biochemistry↗

bioRxiv2026

Acoustic Modulation of Ion-Solvent Interactions: Microscopic Insights into Acoustoelectric Effect Modelling

The acoustoelectric (AE) effect, in which acoustic waves modulate the electrical properties of a conductive medium, holds significant potential for biomedical imaging. While classic models describe the phenomenon through conductivity modulation, a detailed understanding of its microscopic origins, particularly the role of ion behaviours, remains lacking. This study introduces a novel electrokinetic perspective by investigating how ultrasound modulates ion-solvent interactions, thereby bridging macroscopic AE signals with underlying ion dynamics. Through finite element simulations of a dilute NaCl solution, we demonstrate that acoustic pressure waves induce local variations in ion mobility and diffusion by altering ion hydration shells and solvent viscosity. These changes disrupt the balance among Coulombic, diffusive, and frictional forces on individual ions, leading to the local conductivity modulation. Furthermore, simulations reveal that acoustic perturbation of the electrode-electrolyte interface (EEI) significantly enhances AE signal generation, highlighting the EEIs critical role in AE-related applications. By linking acoustic modulation to fundamental ion-solvent interactions, this work not only provides a foundation for more accurate, microscopically grounded models of the AE effect but also connects AE effect modelling to the active research of solvation dynamics in physical chemistry.

bioengineering↗

bioRxiv2026

Orion Microbiome Database: mapping constellations in the microbiome universe

BackgroundPublicly available microbiome sequencing data have grown rapidly in scale and diversity, but secondary use remains limited by fragmentation across repositories, inconsistent annotations, heterogeneous processing pipelines, and incomplete metadata. These barriers complicate cross-study comparisons and restrict the reproducibility of large-scale microbiome research. ObjectiveThe Orion Microbiome Database was developed to overcome these challenges by providing a standardized, accessible, and reproducible resource for the integration and analysis of whole-genome shotgun (WGS) microbiome datasets. MethodsOrion aggregates raw metagenomic datasets from public repositories and harmonizes them into computed microbial profiles using automated and transparent analysis pipelines. Metadata are curated to ensure consistency and enable systematic cross-cohort comparisons. The platform provides interactive tools for data exploration, visualization, and downstream analysis, reducing redundancies in data preprocessing and lowering the barrier for both novice and expert users. Beyond research applications, Orion also serves as an educational resource, enabling microbiome data exploration in classroom settings. ConclusionBy unifying fragmented sequencing resources into a reproducible framework, Orion accelerates microbiome discovery, supports scalable cross-study investigations, and fosters integration of microbiome science into teaching and training. This database has the potential to serve as a model for future large-scale, community-driven platforms in microbiome research.

microbiology↗

bioRxiv2026

Acoustic features of emotional vocalisations account for early modulations of event-related brain potentials

Emotion is key to human communication, inferring emotion in a speakers voice is a cross-cultural and cross-linguistic capability. Electroencephalography (EEG) studies of neural mechanisms supporting emotion perception have reported that early components of the event-related potential (ERP) are modulated by emotion. However, the nature of emotions effect, especially on the P200 component, is disputed. We hypothesised that early acoustic features of emotional utterances might account for ERP modulations previously attributed to emotion. We recorded multi-channel EEG from healthy participants (n = 30) tasked with recognising the emotion of utterances. We used fifty vocalisations in five emotions - anger, happiness, neutral, sadness and pleasure - drawn from the Montreal Affective Voices dataset. We statistically quantified instantaneous associations between ERP amplitudes, emotion categories, and acoustic features, specifically, intensity, pitch, first formant, and second formant. We found that shortly after utterance onset (120-250 ms, i.e., P200, early P300) ERP amplitude for sad vocalisations was less than for other emotional categories. Moreover, ERP amplitude at around 180 ms for happy vocalisation was less than for anger, sadness, and pleasure. Our analysis showed that acoustic intensity explains most of these early-latency effects. We also found that, at longer latency (220-500 ms; late P200, P300) ERP amplitude for neutral vocalisations was less than for other emotional categories. Furthermore, there were also ERP differences between anger and happiness, anger and pleasure, anger and sadness, happiness and pleasure, as well as happiness and sadness in shorter windows during this late period. Acoustic pitch and, to a lesser degree, acoustic intensity explain most of these later effects. We conclude that acoustic features can account for early ERP modulations evoked by emotional utterances. Because previous studies used a variety of stimuli, our result likely resolves previous disputes on emotions effect on P200.

physiology↗

bioRxiv2026

Codon Deoptimization of Multispecific Biologics Reduces Mispairing During Transient Mammalian Protein Expression

Codon optimization is utilized in biologics design to maximize protein expression. Selecting the host organisms most frequently used codons for each amino acid can significantly enhance recombinant protein expression yields. However, non-optimal codons in mRNA can be critical for functional protein production through inducing pauses in or attenuating protein translation. In our study, we have investigated the effect of deoptimizing serine codons in biologics by shifting them from the five most frequently used codons to the least (TCG). Rare serine codons were strategically inserted into the coding sequences of the constant regions in a trispecific antibody (Protein 1), a bispecific antibody (Protein 2), and multiple non-proprietary bispecific antibodies. We observed that inserting 1-2 rare serine codons within an open reading frame led to expression changes that reduced the formation of mispaired 2x light chain and half-molecule species. Protein purity was drastically increased by incorporating two deoptimized serine codons into a single chain. Notably, we observed a negative correlation between total protein expression yield and final product purity. Taken together, our work demonstrates that incorporation of deoptimized serine codons into a single chain can significantly influence multispecific biologic pairing and enhance final product purity. Our findings align with existing literature showing that rare codon usage modulates translation kinetics and protein folding. Future investigation is warranted to enable a priori identification of the rate-limiting chain in multispecific biologics, thereby guiding strategic codon deoptimization prior to expression.

bioengineering↗

bioRxiv2026

Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids

Tumorigenesis typically follows a multi-hit trajectory, driven by accumulating oncogenic mutations. Colorectal cancer (CRC) has long served as a paradigmatic model of multi-hit tumorigenesis, characterized by adenoma-carcinoma transition accompanied by acquisition of specific oncogene and tumor suppressor mutations. However, how the temporal order of early mutations influences CRC initiation remains poorly understood. To address this, we established a CRC tumorigenesis model using murine intestinal organoids. By introducing defined combinations of key CRC driver mutations (Kras, Apc, and Trp53) in distinct orders, we systematically investigated how the order of mutation accumulation affects tumor initiation. Our results reveal that the mutation accumulation confers growth advantages in both in vitro and in vivo models. Strikingly, mutation order also influenced the tumorigenic properties of the organoids. Whereas organoids with Trp53 loss before or after Apc loss similarly affected organoid phenotypes in vitro or tumorigenicity in immunodeficient mice, organoids with Trp53 loss preceding Apc inactivation exhibited reduced tumor-forming potential in immunocompetent mice, likely due to their distinct immunological features. Collectively, our study reveals a critical role of ordered mutation accumulation in CRC initiation, an insight that may hold clinical relevance.

cancer biology↗

bioRxiv2026

Probiotic phage steering of disease suppressive rhizosphere microbiome

Current phage therapy approaches predominantly focus on targeting pathogenic bacteria, overlooking the vast potential of phages that interact with beneficial, plant growth-promoting (probiotic) bacteria. Here we tested if a single phage targeting a probiotic Stenotrophomonas maltophilia bacterium can steer the rhizosphere microbiome disease suppressiveness against Ralstonia solanacearum phytopathogen. We find that S. maltophilia quickly evolves resistance to its phage via mutations in ssb and TonB genes and by upregulating anti-phage defense systems. Crucially, evolution of phage resistance reprograms the bacterial transcriptome and metabolome, leading to unexpectedly enhanced antimicrobial activity against the R. solanacearum. Furthermore, exposing S. maltophilia to phage in the tomato rhizosphere increases the microbiota-wide disease suppressiveness by stabilizing bacterial diversity and facilitating pathogen suppression by other resident species. Our findings suggest that probiotic-specific phages could be used as ecological and evolutionary engineers to steer the rhizosphere microbiome disease suppressiveness through activation of antagonistic bacterial interactions.

evolutionary biology↗

bioRxiv2025

A generalized test of genotype-phenotype causality in population-sampled nuclear families

We recently developed a causal inference framework and test -- the Transmission Mean Test (TMT) -- to identify causal genotype-phenotype relationships in population-sampled parent-child trios, where one child per family is observed. Here, we establish the generalized TMT (gTMT) for population-sampled nuclear families, allowing multiple offspring per family. This extension focuses on detecting genetic loci with non-zero average causal effects (ACE) on child phenotypes, taking into account that siblings share similar random family-specific effects. We construct a potential outcomes trait model that considers both individual-level and family-level heterogeneity, captures additive and non-additive genetic effects, and accommodates both quantitative (continuous or count) and dichotomous traits. We design an unbiased estimate dgTMT of the ACE and develop a sampling variance estimate [Formula] to form a statistic testing the null hypothesis of no causal effect. We provide both theory and empirical evidence demonstrating that gTMT is robust to confounding factors such as the population structure and family-specific effects. We analyze nuclear families in the UK Biobank as an illustrative example of the gTMT in action. When parental genotypes are missing, we propose to further extend gTMT by using Bayesian calculations on child genotypes to model parental genotypes as intermediate random variables.

genetics↗

bioRxiv2025

Molecular insights into Profilin1-dependent regulation of cellular phosphatidylinositol-(4,5)-bisphosphate

Phosphatidylinositol (4,5)-bisphosphate (PIP2), the most abundant cellular poly-phosphoinositide (PPI) class of phospholipid, is a central plasma membrane (PM)-associated signaling hub that controls many cellular processes. In this study, we demonstrate that either deletion of the gene encoding actin-binding protein profilin1 (Pfn1) or disruption of Pfn1-actin interaction leads to downregulation of PM PIP2 content in cells. This is also phenocopied when F-actin is depolymerized implying that Pfn1-dependent PIP2 alteration is related to its actin-regulatory function. Phospholipase C (PLC) activity is critical for Pfn1-deficient cells to exhibit the PIP2-related phenotype. These findings, taken together with biochemical signatures of elevated PIP2 hydrolysis (higher baseline PM diacylglycerol-to PIP2 ratio and protein kinase C activity) exhibited by Pfn1-deficient cells, imply that PLC-mediated PIP2 hydrolysis plays a role in Pfn1-dependent regulation of PM PIP2. Furthermore, we unexpectedly found that Pfn1 loss leads to dramatic alterations in several other important forms of lipids, revealing a previously unrecognized role of Pfn1 as a broad regulator of cellular lipid environment that extends beyond PPI control. In conclusion, our study establishes Pfn1 as an important regulator of cellular lipid homeostasis. SUMMARY STATEMENTThis study uncovers a mechanism of how functional loss of Profilin1, a key regulator of actin cytoskeleton, can trigger downregulation of plasma membrane content of PIP2, an important class of phospholipid, in cells.

cell biology↗

bioRxiv2025

Wnt-presenting materials sustain H3K14-acetylation in human skeletal stem cells for tissue engineering and bone repair

Engineering functional tissues for transplantation requires insight into epigenetic mechanisms that regulate stem cell fate. We have developed the Wnt-induced osteogenic tissue model (WIOTM), a platform that recapitulates human osteogenesis, and identified acetylation of histone H3 at lysine 14 (H3K14ac) as a critical epigenetic regulator in human skeletal stem cells (hSSCs). In WIOTM, localized Wnt signals drive asymmetric cell division (ACD), yielding a proximal hSSC with high H3K14ac and a distal daughter with reduced H3K14ac that migrates into the 3D collagen matrix and initiates osteogenic differentiation. Disrupting H3K14ac in hSSCs abrogates ACD and WIOTM formation. To test whether hSSCs maintain H3K14ac in vivo, we formed the WIOTM on Wnt-functionalized polymer bandages and transplanted them into calvarial defects. The WIOTM contributed to bone repair, and human cells adjacent to the bandages retained high H3K14ac despite the injury environment. These findings establish WIOTM as both a mechanistic and translational platform for regenerative medicine.

cell biology↗

bioRxiv2025

Spatial 5mC-seq profiling of embryos and decidua after implantation in mammal

DNA methylation plays key roles in development and diseases. However, no spatial DNA methylation profiling technology has been reported until now. Here, we developed a spatial 5mC-seq method (SmC-seq) based on a microfluidic system. The SmC-seq can provide a non-biased genome-wide methylome at about single-cell scale (10 m in width per channel). We further applied this SmC-seq to explore the spatiotemporal dynamics of DNA methylation during post-implantation development in mouse. A clear spatial heterogeneous pattern of DNA methylation among inner cell mass-derived tissues can be observed. Additionally, we identified a two-layer organization in the ectoplacental cone at the E8.5 stage, characterized by distinct DNA methylation patterning and proliferation states. Unexpectedly, a portion of maternal tissue with low DNA methylation level, enriched for nutrient-supplier progenitor cell, is observed in the middle region of maternal decidua after implantation. The hypomethylated regions in the nutrient-supplier progenitor cell cluster are associated with cell proliferation. Interestingly, the genes associated with hypomethylated regions in the mature nutrient-supplier cell cluster are enriched in exocytosis and nutrient synthesis, which is associated with nutrient provision before functional placenta is formed to support mammalian embryogenesis. In summary, SmC-seq enables spatial mapping of DNA methylation and facilitates our understanding of various biological events.

genomics↗

bioRxiv2025

A high-throughput methods SNIPR-Nm reveals small RNA methylation ratio

Small RNAs regulate gene expression and genome stability, and their functions are shaped by 3'-terminal 2'-O-methylation (Nm). Although Nm is universal in plants and mainly marks animal piRNAs, recent evidence reveals Nm on mammalian miRNAs, highlighting broader regulatory roles. However, current sequencing underestimates Nm-modified RNAs due to ligation bias, and existing qPCR-based methods cannot simultaneously quantify abundance and modification, leaving Nm dynamics largely unexplored. We developed a unified enzymatic strategy that integrates poly(A) polymerase and a thermostable ligase to measure both small RNA abundance and 3'-end Nm status. Applied to mouse testis, it enables robust quantification of Nm ratios for piRNAs and miRNAs. Our method offers a versatile tool for dissecting small RNA methylation in development and disease.

genetics↗