Biology subjects

Zhao, Y.

Publications and source records attributed to Zhao, Y..

At least 307 records · Page 17Linked to original sources

bioRxiv2025

Powerful one-dimensional scan to detect heterotic QTL

To meet the growing global demand for food, increasing yields through heterosis in agriculture is crucial. A deep understanding of the genetic basis of heterosis has led to the development of a quantitative genetic framework that incorporates both dominance and epistatic effects. However, incorporating all pairwise epistatic interactions is computationally challenging due to the large sequencing depth and population sizes needed to uncover the genes behind complex traits. In this study, we developed hQTL-ODS, a one-dimensional scanning method that directly assesses the net contribution of each locus to heterosis. Simulations show that hQTL-ODS reduces computational time while offering higher power and lower false-positive rate. We applied this method to a population of 5,234 wheat hybrids with whole-genome sequenced profile, revealing key epistatic hubs that play a critical role in determining heterosis. Our findings offered valuable insights for improving breeding strategies to enhance crop yields.

genetics↗

bioRxiv2025

Distinct roles of neuronal phenotypes during neurofeedback adaptation

Learning adaptation allows the brain to refine motor patterns in response to changing environments rapidly. While population-level neural dynamics and single-neuron activity in motor learning have been widely studied, the contributions of individual neuron types remain poorly understood. Here, we employed a brain-machine interface (BMI) task with perturbations of varying difficulty to investigate single-neuron dynamics underlying neurofeedback adaptation in two rhesus macaques. Cortical neurons were classified based on waveform shape into narrow waveform (NW) and broad waveform (BW) categories, representing putative inhibitory interneurons and excitatory pyramidal neurons, respectively. Compared to BW neurons, NW neurons were more active and more strongly involved in the learning process. Moreover, task difficulty modulated neural responsiveness and coordination within both neuron groups, highlighting differential neuron engagement during motor learning. Our findings provide novel insights into single-neuron mechanisms underlying neurofeedback adaptation and emphasize the distinct functional roles of neuronal phenotypes in rapid learning processes. Author SummaryUnderstanding how the brain adapts to changes is crucial for improving treatments for neurological disorders and enhancing brain-machine interface (BMI) technology, which allows control of external devices using neural signals. In our study, we investigated how different types of brain cells contribute to the adaptation process when individuals encounter unexpected challenges during neurofeedback tasks. We discovered that one type of neuron was notably more active and played a more engaged role in rapidly adjusting neural activity compared to another type. These neurons demonstrated stronger coordination in their activity and showed greater responsiveness as the task difficulty increased. Our findings highlight the distinct roles of specific neurons in quickly adapting to neurofeedback tasks, offering insights that could enhance therapies for movement disorders and improve the precision and reliability of brain-controlled prosthetics.

neuroscience↗

bioRxiv2025

Digital Twin Brain Predicts rTMS Effects on Brain State Dynamics in Chronic Tinnitus

Predicting repetitive transcranial magnetic stimulation (rTMS) effects on whole-brain dynamics in clinical populations is crucial for developing personalized therapies and advancing precision medicine in brain disorders. This study provides the first proof-of-concept demonstrating that the Digital Twin Brain (DTB) can forecast rTMS effects on brain state dynamics in individuals with brain disorders (chronic tinnitus). First, we identified two aberrant brain states that predominantly overlapped with the somatomotor and default mode networks, respectively. Subsequently, we developed DTB for patients and derived regional responses for each brain region, revealing distinct roles of the parieto-occipital and frontal regions. Mechanistically, we examined the biological plausibility using tinnitus-specific risk genes and investigated the multi-scale neurobiological relevance. Clinically, we found that DTB can predict rTMS effects in an independent, longitudinal dataset (all r > 0.78). Particularly, the predictive capacity exhibits a state-specific nature. Overall, this work proposes a novel DTB-based framework for predicting rTMS effects in clinical populations and provides the first empirical evidence supporting its clinical utility. This approach may be generalizable to other brain disorders and neuromodulation techniques, promoting broader advancements in brain health.

neuroscience↗

bioRxiv2025

PepSeek: Universal Functional Peptide Discovery with Cooperation Between Specialized Deep Learning Models and Large Language Model

Recent computational foundation models have revitalized the scientific discovery pipeline. However, developing foundational models for functional peptide discovery is costly due to the scarcity of wet-lab validated data. Meanwhile, conventional deep learning models are hard to generalize to unseen tasks or data distribution. Here, we introduce PepSeek, a universal approach for peptide discovery that synergistically integrates the most advanced large language model (LLM) with specialized small models. PepSeek harnesses the robust reasoning and generalization capabilities of LLM while leveraging the high predictive accuracy of specialized models trained for tasks such as antimicrobial activity regression and functional peptide generation. We have devised multiple collaborative strategies and task-specific modules demonstrating leading performance in peptide identification and generation. Notably, PepSeek achieves remarkable zero-shot prediction accuracy for peptides with diverse functionalities. We used PepSeek to identify a group of broad-spectrum antimicrobial peptide that exhibits low toxicity and high activity against drug-resistant bacteria, with the best surpassing all peptides currently undergoing clinical trials. Our framework establishes a new pipeline for scientific discovery with the help of LLM and specialized models.

bioinformatics↗

bioRxiv2025

Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

Aneuploidy, the gain or loss of chromosomes, is prevalent in both normal and disease conditions, however, experimental approaches to engineer and study aneuploidy remain limited, leaving its functional significance under-characterized. Here, we present CRISPR-Taiji (CRISPRt), an efficient method for inducing chromosome-specific mis-segregation and aneuploidy generation across all 24 human chromosomes via dead Cas9 (dCas9)-induced centromeric chromatin relaxation. Using CRISPRt with scRNA-seq, we generated the first comprehensive transcriptomic alteration landscape of nearly all autosomal aneuploidies at chromosome-arm resolution. This genotype-phenotype map provides causal evidence linking recurrent aneuploidies in clear cell renal cell carcinoma (ccRCC) to molecular and clinical phenotypes observed in patient tumors. Notably, chromosome 3(p) loss, the ccRCC initiating event, specifically drives strong interferon signaling activation, offering novel insights into ccRCC tumorigenesis and immune modulation. Overall, we establish CRISPRt as a simple, efficient and scalable approach for chromosome-specific aneuploidy engineering and characterization in preclinical models to advance aneuploidy research across diverse biological contexts.

genomics↗

bioRxiv2025

Entamoeba histolytica Gal/GalNAc lectin intermediate subunit promotes inflammation and epithelial damage in intestinal amebiasis through its C3 region.

Entamoeba histolytica is a common enteric protozoan that sometimes transitions from a symbiont to a pathogen, causing intestinal amebiasis and extraintestinal abscesses in the host. The early-to-intermediate stages of intestinal amebiasis are characterized by an intense inflammatory response, during which host innate immune defenses play an important role. Here, using the cecal infection model of C3H/HeNCrl mice, we performed single-cell RNA sequencing of cecal tissues and identified the prominent pro-inflammatory function of host macrophages in intestinal amebiasis. On the amoebic cell surface, Igl is an intermediate subunit of galactose- and N-acetyl-D-galactosamine-inhibitable lectins, which contributes to parasite adherence. We proposed that E. histolytica Igl diffuses along with amoebic extracellular vesicles and contacts host macrophages, binding to the TLR4 co-receptor MD2 through its C3 region and initiating the TLR4/MyD88/NF-{kappa}B inflammatory signaling pathway in host cells. Moreover, by inducing macrophage inflammation and cytokine production, E. histolytica indirectly impairs intestinal epithelium integrity through the Igl protein. To our knowledge, this is the first report showing a host single-cell atlas in the field of amebiasis research. In response to the parasite invasion during intestinal amebiasis, our study provides new insights elucidating the inflammatory formation and epithelial damage of gut mucosal immune system, and also conduces to the identification of potential drug targets for these amoebas.

microbiology↗

bioRxiv2025

Population-level constraints on single neuron tuning changes during behavioral adaptation

In neurofeedback training, select neurons - of the billions that comprise the brain - are able to adapt their activity to produce a desired behavior, even though the feedback signal is low-dimensional. However, the extent that individual neurons are able to alter their activity within the context of the neurofeedback population is unclear. Using a brain-computer interface in monkeys (n=2; Macaca mulatta), we tested how the tuning of individual neurons changed in response to various feedback perturbations. Overall, we found that neurons that co-varied their activity the most with the population and those that contributed most to the behavior prior to the perturbation were most resistant to change- regardless of perturbation type. The degree to which individual neurons counteracted the applied perturbation explained daily differences in how well neurons collectively produced adapted behavior. Our work provides important insight into how population-level constraints impact the ability of individual neurons to adapt and support behavioral flexibility.

bioengineering↗

bioRxiv2025

Discovery of D2469079A, A novel selective Toll-Like Receptor 7/8 Antagonist with Brain Penetrance

Aberrant activation of endosomal Toll-like receptors (TLRs) 7 and 8, which recognize single-stranded RNA, is strongly implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). And the frequent neuropsychiatric involvement in SLE highlights the need for brain-penetrant therapies. Here, we report the identification and characterization of D2469079A, a novel, potent dual TLR7/TLR8 antagonist (low nM IC50 in humanized HEK-Blue assays) selective against hTLR9. D2469079A demonstrates favorable in vitro properties, including adequate solubility and high microsomal stability. It exhibited desirable pharmacokinetic profiles across multiple preclinical species (mice, rats, dogs) and achieved significant cerebrospinal fluid (CSF) exposure, confirming its high permeability and brain penetration. Consistent in vivo efficacy was observed in both acute and chronic stimulation models. Importantly, D2469079A displayed a favorable safety profile, lacking significant liabilities related to CYP450 inhibition/induction, hERG interaction, or toxicity in a 14-day rat study. These findings position D2469079A as a promising drug candidate with excellent drug-like characteristics for the treatment of TLR7/8-driven autoimmune diseases, potentially including neuropsychiatric manifestations. We are actively seeking partners for collaborative clinical development.

immunology↗

bioRxiv2025

Domain-general neural effects of associative learning and expectations on pain and hedonic taste perception

Predictive cues significantly influence perception through associative learning. However, it is unknown whether circuits are conserved across domains. We investigated how associative learning influences perceived intensity and valence of pain and hedonic taste and whether the mechanisms that support expectancy-based modulation vary as a function of aversiveness and modality. Sixty participants were randomly assigned to receive either painful heat, unpleasant liquid saline, or pleasant liquid sucrose during fMRI scanning. Following conditioning, cues that were initially associated with low or high intensity outcomes were intermittently followed by stimuli calibrated to elicit medium intensity ratings. Learned cues modulated expectations and subjective outcomes similarly across domains. Consistent with this, the orbitofrontal cortex exhibited domain-general anticipatory activation. The left anterior insula mediated domain-general cue effects on subjective intensity, whereas the thalamus mediated cue effects on subjective valence. Notably, these two regions were nearly identical to those previously implicated in mediating cue effects on pain (nearly identical to those previously implicated in cue effects on mediating pain (Atlas et al., 2010). Pain specificity was evident when we measured variations in stimulus intensity, whether we used univariate or multivariate approaches, but there was minimal evidence of specificity by modality or aversiveness when we examined cue effects on medium trials. These findings suggest that shared neural circuits mediate the effects of learned expectations on perception, linking pain with other areas of affective processing and perception across domains.

neuroscience↗

bioRxiv2025

Unpacking similarity effects in visual memory search: categorical, semantic, and visual contributions

Visual memory search involves comparing a probe item against multiple memorized items. Previous work has shown that distractor probes from a different object category than the objects in the memory set are rejected more quickly than distractor probes from the same category. Because objects belonging to the same superordinate category usually share both visual and semantic features compared with objects of different categories, it is unclear whether the category effects reported in previous studies reflected visual and/or semantic target-distractor similarity. Here, we employed old/new recognition tasks to examine the role of categorical, semantic, and visual similarity in short- and long-term memory search. Participants (N=64) performed visual long-term memory (LTM) or short-term memory (STM) search tasks involving animate and inanimate objects. Trial-wise RT variability to distractor probes in LTM and STM search was modelled using regression analyses that included predictors capturing categorical target-distractor similarity (same or different category), semantic target-distractor similarity (from a distributional semantic model), and visual target-distractor similarity (from a deep neural network). We found that categorical, semantic, and visual similarity all explained unique variance in trial-wise memory search performance. However, their respective contributions varied with memory set size and task, with STM performance being relatively more strongly influenced by visual and categorical similarity and LTM performance being relatively more strongly influenced by semantic similarity. These results clarify the nature of the representations used in memory search and reveal both similarities and differences between search in STM and LTM.

neuroscience↗

bioRxiv2025

SCARF: Single Cell ATAC-seq and RNA-seq Foundation model

Recent advances in single-cell multi-omics have provided unprecedented insights into gene regulation by jointly profiling transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) landscapes. However, the inherent heterogeneity and high dimensionality of these multimodal data present significant challenges for effective integration and downstream analysis. Foundation models have demonstrated strong representation learning capabilities for scRNA-seq or scATAC-seq data. So far, however, no model has been specifically developed for the integrative analysis of these two modalities. Here, we introduce SCARF, a single cell ATAC-seq and RNA-seq foundation model. SCARF is pre-trained on X-Omics, the largest curated collection of single-cell multi-omics data to date, comprising over 2.7 million cells across multiple tissues and species. The model utilizes a Mamba architecture for efficiently capturing long-context relationships between genes and between accessible regions. Modality-specific and shared features are learned by the model through self-supervised learning and contrastive learning, respectively. SCARF achieves state-of-the-art performance on multiple downstream tasks, including cell representation, cell matching, and cross-omics translation. Furthermore, SCARF enables few-shot cell type annotation, demonstrating strong generalizability across previously unseen datasets. These results highlight the power of foundation models for advancing integrative analysis of single cell multi-omics data, with broad applications in important tasks including cellular characterization, gene or genomic perturbation analysis, and regulation network analysis.

bioinformatics↗

bioRxiv2025

The Role of N-acetylcysteine Amide in Acute Graft-versus-host Disease Mouse Model

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic hematopoietic cell transplantation (allo-HCT), resulting in reduced quality of life, morbidity, and mortality in transplanted patients. Clinical strategies to prevent GvHD are frequently associated with off-target effects and dose-related toxicity. Given that oxidative stress is elevated in allo-HCT recipients and contributes to the pathogenesis of GvHD, the current study aims to characterize the role of N-acetylcysteine amide (NACA), a novel antioxidant, as the prophylactic treatment for acute GvHD. Using a murine GvHD model, we found that oral administration of NACA significantly reduced GvHD severity, prolonged survival, and improved the clinical manifestations and integrity of target organs compared to saline or N-acetylcysteine (NAC) treatment. NACA modulated splenic T cells differentiation with an increase in the regulatory (Treg) subset and a decrease in the cytotoxic (CD8+) subset. Moreover, inflammatory mediators, such as ROS and pro-inflammatory cytokines were downregulated by NACA treatment. In addition, NACA hindered donor T-cell proliferation in the recipients, and restrained Th1 and Th17, but not Th2 polarization. Importantly, NACA did not influence full donor engraftment in bone marrow and spleen. Taken together, our findings provide a new candidate for GvHD prophylactic treatment by targeting oxidative stress that can be easily translated to clinical use. Key PointsO_LINACA provides superior prophylactic effect against aGvHD compared to NAC in an allogeneic transplantation mouse model. C_LIO_LINACA treatment neither showed systemic toxicity nor altered the engraftment of the donor cells. C_LI

pharmacology and toxicology↗

bioRxiv2025

A novel antioxidant N-acetylcysteine Amide Alleviates Cyclophosphamide-induced Endothelial Damage

The alkylating agent cyclophosphamide (Cy) is one of the important corner stones in cancer treatment. Cy is used also as a part of conditioning regimens prior to hematopoietic cell transplantation and as a prophylactic treatment post transplantation in graft-versus-host disease. Existing evidence showed that high doses of Cy are associated with a number of side effects, including damage on arterial endothelium, which might contribute to late cardiovascular disorders. Oxidative stress has been characterized in such pathogenesis and is an exploitable target for treatment. Herein, the study aimed to investigate the protective role of the novel antioxidant N-acetylcysteine amide (NACA) in Cy-induced endothelial injury and explore the underlying mechanism. Our in vivo results showed that NACA partially reduced the endothelial injury and recovered the integrity of arterial endothelium in the mice treated with Cy. In addition, we found that NACA decreased the cytotoxicity of Cy on endothelial cells through alleviating caspase-dependent apoptosis, DNA damage and oxidative stress. Meanwhile, NACA pre-treatment rebalanced endothelial nitric oxide synthase (eNOS) and arginase I and preserved the angiogenic capability of endothelial cells which was compromised by Cy through blockage of Notch signaling pathway. Interestingly, in comparison to N-acetylcysteine (NAC), its amide derivative NACA showed superior ability to alleviate Cy-induced endothelial damage. In conclusion, the current study proved the robust endothelial protective potential of NACA, facilitating clinical use of the novel antioxidant.

pharmacology and toxicology↗

bioRxiv2025

Influence of Macrocyclization Strategies on DNA-Encoded Cyclic Peptide Libraries

Discovery of cyclic peptide hits using DNA-encoded libraries (DELs) has recently been extensively researched, with significant efforts directed toward developing DEL-compatible macrocyclization methods. To investigate how different cyclic linkers influence DEL selection outcomes, we constructed eight distinct sub-libraries and screened them against two protein targets, MDM2 and GIT1, resulting in two representative yet contrasting scenarios. Validation studies for MDM2 revealed that structural similarity patterns observed across multiple sub-libraries could enhance confidence in the authenticity of identified hits. Notably, cmp-10 demonstrated potent inhibitory activity, exhibiting an inhibition constant of 11 nM. In contrast, selections against GIT1 produced discrete enrichment patterns. From these outcomes, two exemplary compounds were selected and validated through both on-DNA and off-DNA modes. cmp-17 was confirmed to bind specifically to the desired binding pocket, displaying a dissociation constant of 1.22 M. Furthermore, ITC experiments using mutant GIT1 proteins (GIT1L271A/L279A and GIT1L271L/L279L) provided additional insights into the mechanism by which cmp-17 disrupts the interaction between GIT1 and {beta}-Pix.

biochemistry↗

bioRxiv2025

Lysosomal cathepsin D regulates bone turnover through distinct mode of actions of the autophagy pathways in osteoblasts and osteoclasts

Insufficiency in nutrient availability, oxidative stress and autophagy failure are fundamental factors for the decline of bone mass and strength with aging. Accumulating evidence indicates that these factors affect normal autophagosomal or lysosomal activities which are the major force in clearance of aggregated or damaged proteins. Cathepsin D (CtsD), the principal lysosomal aspartate protease and a main endopeptidase, exists in the skeleton during development or homeostasis. However, the molecular and cellular mechanisms of CtsD mediated autophagosome or lysosome function in the skeletal homeostasis remain unclear. In the present study, we showed that deletion of CtsD dramatically decreased bone mass in the 3-week old mutant mice compared with their control littermates as indicated by decreased bone volume (BV), bone volume / total volume (BV/TV), bone surface (BS), trabecular number, trabecular thickness and increase trabecular separation in the microCT analysis. Histomorphometry analysis revealed that the phenotype was characterized by decreased osteoblast numbers, osteoblast surface/bone surface and mineral apposition rate, increased osteoclast numbers, osteoclast surface/bone surface and erosion surface/bone surface. At molecular level, siRNA medicated inactivation of CtsD in MC3T3E1 cells attenuated osteoblastic differentiation and downregulated LC3B expression, which was accompanied by decreased levels of P62, p-Akt and p-GSK3beta in osteoblasts. Intriguingly, inactivation of CtsD in RAW264.7 cells increased osteoclast differentiation with decreased LC3B expression but upregulated P62 level. This was accompanied by alterations in the formation of autophagosome and differential transcription profiles associated with the autophagy pathway during the differentiation of osteoblasts and osteoclasts. The results suggest that CtsD mediated autophagy pathway plays important roles in regulation of bone mass and homeostasis through distinct mode of actions in osteoblasts and osteoclasts, and CtsD may serve as a potential therapeutic target for the maintenance of bone mass.

cell biology↗

bioRxiv2025

TIR immune signaling is blocked by phosphorylation to maintain plant growth

Toll/interleukin-1 receptor (TIR) domain proteins are immune signaling components and function as NAD+-cleaving enzymes to activate defense responses. Activation of TIRs represses growth and drives cell death in plants and promotes axon degeneration in animals, but how plant TIRs are repressed remains unclear. Here, we show that TIR NADase activity requires a conserved serine residue spatially close to the catalytic glutamate. The plant Ca2+-dependent protein kinases (CPKs), the mammalian Ca2+/calmodulin-dependent protein kinase II delta (CAMK2D) and TANK binding kinase 1 (TBK1) phosphorylate TIR domains at this conserved serine, which blocks TIR NADase activities and functions and thus maintains growth in plants and suppresses SARM1 TIR signaling in animals, respectively. Our findings define a fundamental molecular mechanism by which phosphorylation at a conserved serine residue blocks TIR signaling to balance growth and defense trade-offs.

plant biology↗

bioRxiv2025

The piRNA PETPIR Regulates Trophoblast Function by Modulating YTHDF2-Mediated m6A Methylation of NDRG1 in Preeclampsia

Preeclampsia is marked by abnormal placental development and impaired trophoblast function. We identified Preeclampsia-associated trophoblast piRNA (PETPIR) as an important regulator of trophoblast function and m6A modifications. Placental samples from preeclamptic and healthy pregnancies were analyzed using piRNA microarrays and m6A epitranscriptomic profiling. Functional assays in trophoblast cells, transcriptomic analysis, and an in vivo PETPIR-overexpressing mouse model were employed to investigate PETPIRs mechanistic roles. We found that PETPIR was significantly upregulated in preeclamptic placentas. PETPIR inhibited trophoblast cell proliferation, migration, and invasion by inducing cell cycle arrest and apoptosis. Transcriptome analysis demonstrated that PETPIR activated hypoxia-responsive pathways. Additionally, PETPIR enhanced global m6A methylation and stabilized NDRG1 transcripts by interacting with the m6A reader YTHDF2. In vivo, PETPIR overexpression in pregnant mice recapitulated key features of preeclampsia, including maternal hypertension and fetal growth restriction. These results suggest PETPIR is a key player in the pathogenesis of preeclampsia, functioning through the PETPIR/YTHDF2/NDRG1 axis to drive hypoxia and m6A epitranscriptomic dysregulation. We provide novel insights into preeclampsias molecular mechanisms, highlighting piRNA as a promising biomarker and therapeutic target.

molecular biology↗

bioRxiv2025

Restoration of Susceptibility of blaNDM-bearing Escherichia. coli to Carbapenem Antibiotics by Exogenous N-acetylcysteine

The global spread of the New Delhi metallo-{beta}-lactamase (NDM) -producing carbapenem-resistant Enterobacteriaceae pose a serious threat to public health, as NDM and its variants enzymes efficiently hydrolyze almost {beta}-lactam antibiotics. The development of novel antibiotics or antibiotic adjuvants capable of eradicating antibiotic-resistance bacteria through multiple mechanisms represents a promising strategy for reversing antibiotic resistance and preventing the emergence of new resistance. In this study, we utilized high-performance liquid chromatography (HPLC) to demonstrate that N-acetylcysteine (NAC) is a prominent reducing metabolite in bacteria harboring NDM-5. Notably, NAC was able to restore carbapenem susceptibility in NDM-producing bacteria in vitro. Subsequently, we further investigated the underlying mechanisms involved. Our findings revealed that NAC exerts its effect through multiple mechanisms that collectively contribute to reversing meropenem resistance. Firstly, NAC may inhibit biofilm formation and reduces polysaccharide production in NDM-positive Escherichia coli. and this potential mechanism was verified by transcriptomic analysis, reverse transcription PCR (RT-PCR) and a biofilm restoration experiment involving the addition of citrate cycle intermediate metabolites. Secondly, RT-PCR analysis demonstrated that NAC significantly downregulates the expression of blaNDM-5. Additionally, NAC exhibited competitive inhibition of NDM activity in vitro. Thirdly, NAC was found to enhance the intracellular accumulation of meropenem, therapy increasing its bactericidal efficacy. These three independent mechanisms offer valuable insights for developing adjuvants. The discovery offers a promising prospect for combating the antibiotic resistance concern. This study paves the way for further exploration and potential clinical applications in the fight against antibiotic-resistant bacterial infections.

pharmacology and toxicology↗