Biology subjects

Zhu, T.

Publications and source records attributed to Zhu, T..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Miniaturized and accessible functional ultrasound imaging system for freely moving mice

Functional ultrasound (fUS) imaging provides brain-wide activity maps with high spatiotemporal resolution and deep penetration, positioning it as a key technology for future non-invasive brain-computer interfaces (BCIs). Realizing this potential, particularly for chronic BCI applications requiring long-term monitoring in naturalistic settings, critically depends on significant system miniaturization to overcome the cost and complexity limitations of current platforms. Addressing this challenge, we present mini-fUS, a miniaturized, cost-effective fUS platform engineered for accessibility without compromising core performance for demanding neuroscience research. The system features a compact transmit-receiver, low-noise power supply, and high-speed data transfer, achieving pulse repetition frequencies up to 5 kHz with negligible jitter. Real-time GPU-accelerated beamforming and singular value decomposition (SVD) enable whole-brain activity mapping, demonstrated here in freely moving mice at up to 3.57 Hz with [~]100 {micro}m spatial resolution and 15 mm penetration depth. Validated through recordings of brain activity during sensory stimulation, anesthesia, and behavior, this design defines a practical hardware-software framework for fUS. By significantly improving accessibility and enabling robust monitoring in mobile subjects, this work advances the development of fUS for both fundamental research and future BCI technologies, while clarifying essential fUS operational principles.

neuroscience↗

bioRxiv2025

Inulin reduces Ralstonia invasion by promoting cooperation between Lysinibacillus sphaericus and Pseudoarthrobacter spp.

In field production, beneficial microbial agents are typically applied along with key resources that beneficial microbes prefer to utilize. This practice aims to help the beneficial microbes colonize the field and exert their disease resistance functions. However, the mechanisms by which these key resources influence the colonization and disease resistance effects of beneficial microbes remain unknown. In this study, we found that inulin can enhance the growth capacity of Lysinibacillus sphaericus HR92 and its ability to inhibit Ralstonia solanacearum. Further investigation revealed that inulin can enhance strain HR92s flagellar assembly, bacterial chemotaxis, fatty acid metabolism, and siderophore synthesis capabilities, ultimately improving strain HR92s effectiveness in controlling bacterial wilt. Moreover, adding inulin to the soil can enrich Pseudarthrobacter strains. This genus enhances the expression of genes involved in the synthesis of the antibacterial substance HR92, and competes for nutrients with Ralstonia solanacearum, thereby further inhibiting the occurrence of bacterial wilt disease. Additionally, the combination of inulin and Pseudarthrobacter strains upregulates the valine and leucine pathway genes in strain HR92. These genes play a crucial role in the synthesis of surfactin and the antimicrobial VOC 3-methyl-1-butanol. We have demonstrated that the addition of key resources not only enhances the control efficacy of beneficial bacteria against soil-borne diseases but also enriches the "helpers" of beneficial bacteria in soil. ImportanceRalstonia solanacearum is a plant pathogen that can cause bacterial wilt in several important crops. Given the limitations of beneficial bacterial inoculation, we propose a strategy to enhance the biocontrol efficacy of beneficial microorganisms by utilizing key resources. In this study, we demonstrate that key resources inulin can improve the biological control effects of beneficial bacteria, thereby maintaining plant health. Furthermore, we found that increasing the concentration of inulin altered the diversity of the rhizosphere microbiota and specifically enriched the abundance of Pseudarthrobacter, which compete with pathogens for nutrients on one hand and, on the other hand, synergize with inulin to enhance the biocontrol efficacy of the beneficial bacterium HR92. Together, our study reveals that key resources can enhance the biocontrol efficacy of beneficial bacteria and enrich potential beneficial bacteria in resident microbial communities, further reducing tomato diseases.

microbiology↗

bioRxiv2025

DeepSAP: Improved RNA-Seq Alignment by Integrating Transcriptome Guidance with Transformer-Based Splice Junction Scoring

Advancements in high-throughput sequencing have revolutionized the field of transcriptomics, pro-viding unprecedented insights into gene expression, splicing events, and fusions. Despite these advancements, the analysis of RNA-seq data remains challenging due to the presence of complex splice junctions, multi-mapped reads, and chimeric events. In this study, we present DeepSAP, an innovative approach that improves the accuracy of RNA-seq alignment by integrating Transcriptome-Guided Genomic Alignment, as implemented in GSNAP, with improved splice junction scoring, predicted by a transformer-based deep learning model. Our work demonstrates synergy between these methods, resulting in enhanced detection of splice junctions, identification of indels, and resolution of complex splicing patterns. On a standard benchmark of human simulated datasets, DeepSAP achieves the highest mean F1 score (0.971) for splice junction detection, outperforming DRAGEN (0.933), novoSplice (0.914), STAR (0.821), HISAT2 (0.662), and Subjunc (0.770). By integrating the unique capabilities of transcriptome-guided alignment and large language models, our splice junction scoring approach captures intricate sequence patterns surrounding splice donor and acceptor sites, providing significant advancement in RNA-seq data analysis.

bioinformatics↗

bioRxiv2025

The response of ETV6-NTRK3 condensates to TRK inhibitors elucidates their precise phase separationmechanism

NTRK fusion oncoproteins are considered to mediate oncogenesis in multiple rare cancers. These fusion oncoproteins form cytoplasmic kinase condensates to hyper-activate downstream signaling pathways. However, their responses to TRK inhibitors have not been investigated. Here we show that TRK inhibitors induce a quantity increasement and liquid-to-solid transition of ETV6-NTRK3 condensates. During this process, the ETV6-NTRK3 condensates undergo rapid dissolution and subsequent reemergence, with entirely altered components. We proposed a novel phase separation model for ETV6-NTRK3 that both ETV6 and NTRK3 fragments contribute to the condensates formation. These findings refresh the understanding of the phase separation mechanism of NTRK fusion proteins and provide basis for phenotype-based TRK inhibitor screening strategy.

cell biology↗

bioRxiv2024

Time-resolved fluorescent proteins towards fluorescence microscopy in the temporal and spectral domains

Fluorescence microscopy has been widely applied in life sciences. While steady-state fluorescence intensity is mostly used, the time-resolved detection mode relying on fluorescence lifetime remains underexplored. Herein, we present a family of time-resolved fluorescent proteins (TRFP). Using a strategy that regulates lifetime without affecting spectra of FPs, we have developed different TRFPs that cover the visible spectrum and a wide range of lifetime. TRFPs are employed in the temporal-spectral resolved microscopy, allowing the simultaneous imaging of 9 different proteins in live cells and correlation of multiple activities to cell cycles. Finally, TRFPs are integrated into multiplexing super-resolution microscopy to concurrently visualize 4 proteins in live cells, acquiring a remarkable 50 nm spatial resolution using lifetime as signal. TRFPs represent a transformative toolset towards fluorescence microscopy in both the temporal and spectral domains. Beyond the multiplexing imaging, TRFPs could introduce unprecedented opportunities of system complexity and quantitative accuracy into biological research.

biochemistry↗

bioRxiv2024

Structural, genetic, and adaptive basis of superhydrophobicity in rice leaves

In most plants, leaf surfaces exhibit water-repellent properties, which protect against pathogens and weather. Plants such as lotus and rice have evolved outstanding water-repellent properties, so-called superhydrophobicity. However, the structural and genetic basis of these properties in crop plants remains unclear. In this study, we identified the genes and microstructures responsible for superhydrophobicity by analyzing water repellence in rice mutants and cultivars, as well as wild Oryza species. Analysis of the surface structure of mutant leaves revealed that the degree of water repellency in rice largely depends on the accumulation of cuticular wax. Meanwhile, although papillae differentiation contributes minorly to water repellency, it is suggested to play a crucial role in achieving superhydrophobicity. These morphological characteristics are regulated by at least five previously characterized genes. We also found that superhydrophobicity is present in ancestral species, is retained by most cultivated rice, and appears to have evolved independently of rice domestication. Understanding the mechanisms of water repellence and their applications should provide important insight into the natural design of water repellence, as well as a basis for future innovation.

plant biology↗

bioRxiv2024

Accurate structure prediction of immune proteins using parameter-efficient transfer learning

Accurate prediction of immune protein structures is crucial for understanding the immune system and advancing immunotherapy development. While deep learning methods have significantly advanced protein structure prediction by extracting evolutionary constraints from homologous sequences of a target protein, they struggle with immune proteins due to the limited number of known structures and the lack of homologous sequences in hypervariable regions. To address this challenge, we propose ImmuneFold, a transfer learning approach that fine-tunes ESMFold specifically for immune proteins. We leverage low-rank adaption (LoRA), a parameter-efficient fine-tuning technique that requires considerably less memory and substantially fewer parameters. Evaluations on various immune proteins, including T-cell receptors, antibodies, and nanobodies, demonstrate that ImmuneFold outperforms existing methods in prediction accuracy. Furthermore, we apply ImmuneFold to develop a zero-shot protocol for TCR-epitope binding prediction. Unlike previous supervised methods suffering from severe overfitting due to limited experimental binding data, our approach first predicts TCR-epitope structure using ImmuneFold and then directly estimates the binding affinity by calculating Rosseta energy. Evaluations on experimental binding datasets suggest that our method is robust and accurate in predicting TCR-epitope binding. In summary, ImmuneFold demonstrates accurate predictions of immune protein structures and TCR-epitope binding, highlighting its potential to advance the development of immunotherapies.

bioinformatics↗

bioRxiv2024

Interspecies Organoids Reveal Human-Specific Molecular Features of Dopaminergic Neuron Development and Vulnerability

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.

evolutionary biology↗

bioRxiv2024

Molecular Specification of Claustro-Amygdalar and Paleocortical Neurons and Connectivity

The ventropallial excitatory neurons (ExNs) in the claustro-amygdalar complex and piriform cortex (PIR; part of paleocortex) form crucial reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that result in adaptive behaviors. Early-life disruptions in these circuits are linked to neuropsychiatric disorders, highlighting the importance of understanding their development. Our study uncovers that transcription factors SOX4, SOX11, and TFAP2D play a pivotal role in the development, identity, and PFC connectivity of these neurons. Using mouse models, we demonstrate that the absence of transcription factors SOX4 and SOX11 in post-mitotic ExNs dramatically reduces the size of the basolateral amygdala complex (BLC), claustrum, and PIR. SOX4 and SOX11 control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including humans, identified conserved Tfap2d expression in developing ExNs of BLC, claustrum, paleocortex including PIR, and the associated transitional areas of the frontal, insular and temporal cortex. While the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat behaviors, differences emerge in the manifestation of Tfap2d dosage, particularly in terms of changes observed in BLC size and the connectivity pattern between the BLC and PFC. This underscores the significance of Tfap2d dosage in orchestrating developmental shifts in BLC-PFC connectivity and behavioral modifications reminiscent of symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial ventropallial ExNs and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability

The integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.

plant biology↗

bioRxiv2024

Pan-cistrome analysis of the leaf accessible chromatin regions of 214 maize inbred lines

Characterizing the noncoding regions of the genome, particularly the cis-regulatory elements (CREs) located in accessible chromatin regions (ACRs) in gene promoters, is crucial for understanding how gene expression is regulated and how genotype contributes to phenotypic diversity in plants.In this study, we used ATAC-seq to resequence and map the ACRs of 214 maize inbred lines. We identified 82,174 ACRs and reported that 39.55% of them exhibited significant variation across the population. Next, we used the accessibility of ACRs as a quantitative feature and performed a chromatin associability GWAS (caGWAS), resulting in 27,004 caQTLs. Among them, 2,463 were predicted to disrupt the cis-regulatory elements that TF binds in these ACRs, suggesting that TF binding affects chromatin accessibility. Specifically, we identified two caACRs that regulate the expression of fad7, which encodes a fatty acid desaturase and affects the linolenic acid content.Our findings highlight the dynamic nature of maize ACRs and demonstrate that chromatin accessibility information could be used for GWASs, offering key insights into the genetic and regulatory mechanisms of chromatin accessibility and its impact on complex traits in plants.

genomics↗

bioRxiv2024

Efficacy and Safety of a novel virulent phage against acute pulmonary infection of Acinetobacter baumanniii in mice

Acinetobacter baumannii (A.baumannii) is a notable opportunistic pathogen responsible for severe hospital-acquired infections, with multidrug-resistant strains posing significant treatment challenges. Phage therapy, which employs bacteriophages as natural bacterial antagonists, has gained renewed attention as a promising solution to combat antibiotic-resistant infections. In this study, we isolated and characterized a novel virulent phage, vB_AbaS_qsb1, which specifically lyses A.baumannii. Phylogenetic and genomic analyses indicate that vB_AbaS_qsb1 is the founding member of a previously unreported genus, which we have named as Acinibactriovirus, with Acinibactriovirus lysinus as the type species. vB_AbaS_qsb1 demonstrated robust stability across diverse temperature and pH ranges, a short latent period, and no known virulence or antibiotic resistance genes within its 54,713 bp dsDNA genome. Safety assessments showed that high-dose vB_AbaS_qsb1 induced no adverse effects in mice, with histopathology confirming its safety profile. Therapeutic experiments further indicated that vB_AbaS_qsb1 provided at least 50% protection against A.baumannii-induced pneumonia, significantly reducing bacterial loads and inflammation markers, while maintaining high phage titers in lung tissue.This study introduces vB_AbaS_qsb1 as a promising candidate for phage therapy against A.baumannii, offering both innovative insights and a valuable framework for future isolation, genomic characterization, and efficacy evaluation of phages targeting antibiotic-resistant bacteria. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/617119v3_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@17bf4cdorg.highwire.dtl.DTLVardef@104c49eorg.highwire.dtl.DTLVardef@89e1dorg.highwire.dtl.DTLVardef@1c4b018_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Weakened airway epithelial junctions and enhanced neutrophil elastase release contribute to age-dependent bacteremia risk following pneumococcal pneumonia

Streptococcus pneumoniae (Sp; pneumococcus), the most common agent of community-acquired pneumonia, can spread systemically, particularly in the elderly, highlighting the need for adjunctive therapies. The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E-cadherin. After mouse lung challenge, pneumolysin (PLY), a key Sp virulence factor, stimulates epithelial secretion of an inflammatory eicosanoid, triggering the infiltration of polymorphonuclear leukocytes (PMNs) that secrete high levels of neutrophil elastase (NE), thus promoting epithelial damage and systemic infection. Here, pulmonary E-cadherin staining of intratracheally inoculated mice revealed PLY-mediated disruption of AJC independently of PMNs. Apical infection of air-liquid interface (ALI) respiratory epithelial monolayers similarly showed that PLY disrupts AJCs. This epithelial damage promoted PMN transmigration and bacterial apical-to-basolateral translocation, and pharmacologically fortifying epithelial barrier function diminished both barrier breach in vitro and bacteremia in vivo. E-cadherin staining after Sp intratracheal inoculation of >20-month-old mice, or apical infection of ALI monolayers derived from these mice, revealed an age-associated vulnerability to PLY-mediated AJC disruption, which in turn enhanced PMN migration and bacteremia. In addition, we found that PMNs from aged mice secrete increased levels of tissue-damaging NE. Simultaneous pharmacological inhibition of tissue-destructive NE and fortification of pulmonary epithelial barrier function was required to reduce the level of Sp bacteremia in aged mice to that of young mice. This work underscores the importance of fully characterizing the multifactorial sources of age-associated susceptibility in devising adjunctive therapies to mitigate invasive pneumococcal disease in the elderly.

microbiology↗

bioRxiv2024

Using TMS-EEG to study the intricate interplay between GABAergic inhibition and glutamatergic excitation during reactive and proactive motor inhibition

Transcranial magnetic stimulation (TMS) studies have provided insight into the neurotransmission underlying motor inhibition but are limited to the primary motor cortex (M1). To investigate {gamma}-aminobutyric acid (GABA) and glutamatergic neurotransmission across the broader motor inhibition network, we combined TMS with electroencephalography (EEG). The N45 and N100 components of the TMS-evoked potentials (TEPs) have been liked to GABAa and GABAb signaling, respectively, whereas the N15, P30 and P60 TEPs are believed to reflect glutamatergic neurotransmission. This study investigates how these components are modulated during reactive and proactive motor inhibition. Twenty-four healthy participants completed two TMS-EEG sessions targeting either the left M1 or the pre-supplementary motor area (preSMA) at rest and during a stop-signal task. We compared TEP amplitudes across TMS conditions (active/sham) and trial types and assessed their relationship with task performance. Participants with a higher N45 amplitude over M1 at rest demonstrated a faster stop-signal reaction time. Active TMS during successful motor inhibition evoked higher N15 amplitudes over preSMA than during uncertain go trials, suggesting that an early excitatory signal from preSMA is crucial for reactive inhibition. In contrast, proactive inhibition was linked to lower P30 amplitudes in M1, possibly reflecting reduced motor facilitation. These findings provide novel empirical insights into the neurophysiological mechanisms underpinning motor inhibition, emphasizing the importance of a coordinated balance between inhibitory processes in M1 and early glutamatergic excitatory signals from preSMA for effective inhibition.

neuroscience↗

bioRxiv2024

Fluctuating chromatin facilitates enhancer-promoter communication by regulating transcriptional clustering dynamics

AbstractEnhancers regulate gene expression by forming contacts with distant promoters. Phase-separated condensates or clusters formed by transcription factors (TFs) and co-factors are thought to facilitate these enhancer-promoter (E-P) interactions. Using polymer physics, we developed distinct coarse-grained chromatin models that produce similar ensemble-averaged Hi-C maps but with "stable" and "dynamic" characteristics. Our findings, consistent with recent experiments, reveal a multi-step E-P communication process. The dynamic model facilitates E-P proximity by enhancing TF clustering and subsequently promotes direct E-P interactions by destabilizing the TF clusters through chain flexibility. Our study promotes physical understanding of the molecular mechanisms governing E-P communication in transcriptional regulation. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/610578v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@114b51borg.highwire.dtl.DTLVardef@7e261forg.highwire.dtl.DTLVardef@1f8dc3forg.highwire.dtl.DTLVardef@143ecb5_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Large scale comparative wheat phosphoproteome profiling pinpoints temperature-associated molecular signatures

Elevated temperatures resulting from climate change adversely affect natural and crop ecosystems, necessitating the development of heat-tolerant crops. We established a framework to precisely identify wheat protein-phosphorylated sites associated with varying temperature sensitivities. We identified specific kinases primarily associated with a specific temperature, but our results also suggest a striking overlap between cold and heat signaling. We furthermore demonstrated that the phosphorylation state of a specific set of proteins creates a unique signature for heat stress tolerance. These findings can potentially aid in the identification of targets for breeding or genome editing to enhance sub/supra optimal temperature tolerance.

plant biology↗

bioRxiv2024

Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits

Unraveling the regulatory mechanisms that govern complex traits is pivotal for advancing crop improvement. Here we present a comprehensive regulome atlas for rice (Oryza sativa), charting the chromatin accessibility across 23 distinct tissues from three representative varieties. Our study uncovers 117,176 unique open chromatin regions (OCRs), accounting for [~]15% of the rice genome, a notably higher proportion compared to previous reports in plants. Integrating RNA-seq data from matched tissues, we confidently predict 59,075 OCR-to-gene links, with enhancers constituting 69.54% of these associations, including many known enhancer-to-gene links. Leveraging this resource, we re-evaluate genome-wide association study results and discover a previously unknown function of OsbZIP06 in seed germination, which we subsequently confirm through experimental validation. We optimize deep learning models to decode regulatory grammar, achieving robust modeling of tissue-specific chromatin accessibility. This approach allows to predict cross-variety regulatory dynamics from genomic sequences, shedding light on the genetic underpinnings of cis-regulatory divergence and morphological disparities between varieties. Overall, our study establishes a foundational resource for rice functional genomics and precision molecular breeding, providing valuable insights into regulatory mechanisms governing complex traits.

genomics↗

bioRxiv2024

AFC kinases function as thermosensors that regulate warm temperature-responsive growth in Arabidopsis

Plants respond to elevated temperatures with enhanced elongation growth that depends on rapid transcriptional, post-transcriptional, and post-translational reprogramming. However, it is unclear how temperature information integrates with the splicing machinery to establish warm temperature-dependent splicing patterns. In animals, CDC2-LIKE KINASES (CLKs) function as body temperature sensors that control temperature-dependent splicing via phosphorylation of serine/arginine-rich (SR) proteins. Here we demonstrate that the CLK-homologous ARABIDOPSIS FUS3-COMPLEMENTING (AFC) kinases likewise regulate post-transcriptional RNA processing to control warm temperature-dependent growth in Arabidopsis. The contrasting temperature-activity profiles of the three AFCs depend on specific structural elements, including a conserved activation segment within the kinase domain. Combining protein structure prediction with site-directed mutagenesis, we provide insights into structural features that determine the different temperature-activity profiles of the three AFC paralogs. Analyses of afc mutant plants demonstrate their role in establishing temperature-dependent splicing patterns and thermomorphogenic hypocotyl elongation. Finally, our data indicate SR34 and SR34a as phosphorylation targets mediating temperature-dependent hypocotyl elongation downstream of AFCs. In conclusion, our study provides evidence that temperature-controlled AFC activity is evolutionarily conserved between plants and animals and implicates AFCs in the control of thermomorphogenesis.

plant biology↗