Biology subjects

Yan, Z.

Publications and source records attributed to Yan, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Large-scale single-neuron recording using the uFINE array in human cortex

Monitoring neural population activity at single-cell resolution is essential for driving fundamental research and clinical innovations. However, translating advanced recording techniques from animal models to humans remains a significant challenge. Flexible neural electrodes have recently emerged as powerful tools for large-scale single-unit recordings due to their superior biocompatibility and high recording density. Here, we demonstrate reliable, high-density single-unit recordings during intraoperative procedures in human patients using ultra-Flexible Implantable Neural Electrode (uFINE) arrays. The uFINE array exhibited sufficient mechanical robustness to maintain structural integrity throughout surgical operations. We successfully recorded 616 single units from 10 patients, with up to 135 single units simultaneously recorded. The flexibility of uFINE array minimized signal disturbances from brain pulsations, enabling stable and continuous single-unit detection. Stimulus and response tuning were observed at the level of individual neurons in awake patients. This uFINE-based recording approach offers unique opportunities to investigate human-specific cognitive functions and develop next-generation brain-machine interfaces.

bioengineering↗

bioRxiv2025

Palmdelphin facilitates R-spondin2 secretion to activate Wnt signaling and promote colorectal cancer stemness and tumorigenesis

The Wnt signaling pathway is a key driver of stemness and progression which contributes to mortality in colorectal cancer (CRC). R-spondins bind to LGR receptors to inhibit ubiquitin E3 ligases, thus protecting Frizzled from degradation and activating downstream Wnt signaling. Herein, we identify Palmdelphin (PALMD) as a functional marker of CRC stem cells, interspersed between intestinal and colonic crypt base epithelial cells, and predictive of aggressive CMS4 CRC and poor survival. Gene knockdown and overexpression studies revealed that PALMD initiates paracrine activation of Wnt/{beta}-catenin signaling via interacting with and facilitating the secretion of R-spondin2 (RSPO2), resulting in enhanced stemness and tumor growth in vitro and in vivo. Physiologic or pharmacologic inhibition of the PALMD-RSPO2 axis using R-spondin2-specific antibody or 6-methyl-1,3,8-trihydroxyanthraquinone (emodin), respectively, attenuates PALMD- mediated Wnt reporter activation, self-renewal, and tumorigenesis in cell and patient-derived organoid models. Together, these findings identify PALMD as a previously unknown player in Wnt signaling in CRC, and underscore the pro-tumorigenic role of R-spondin2 in this context.

cancer biology↗

bioRxiv2025

The TONSL-MMS22L complex and FANCM form an interdependent complex on chromatin to counter replication stress

FANCM is branchpoint DNA translocase essential for cellular response to replication stress. Here, we show that replication stress stimulates FANCM and the TONSL-MMS22L heterodimer bound to histones H3-H4 to form an interdependent complex on chromatin. TONSL-MMS22L recruits FANCM and Fanconi anemia (FA) core complex to stalled and collapsed forks, maintains FANCM on replication-stressed chromatin, promotes FANCD2 monoubiquitination, facilitates both repair and replication traverse of DNA interstrand crosslinks (ICLs), and suppresses sister chromatid exchanges, through its interactions with FANCM and H3-H4. Reciprocally, both DNA translocase activity and phosphorylation of FANCM facilitate recruitment of TONSL-MMS22L and RAD51 to perturbed forks. Moreover, TONSL-MMS22L and FANCM function together to promote activation of the FA pathway, ICL repair, homologous recombination and replication traverse. Cancer patients with tumors with wildtype FANCM and low expression of TONSL-MMS22L have a more favorable prognosis than those with high expression. Thus, FANCM-TONSL-MMS22L acts coordinately as a complex on chromatin that resolves replication stress, and this complex may present a therapeutic target for wildtype FANCM-linked cancer.

cell biology↗

bioRxiv2024

DNA StairLoop: Achieving High Error-correcting and Parallel-processing Capabilities in DNA-based Data Storage

DNA-based data storage is a promising solution to the challenges of large-scale data storage. However, the low throughput of the mainstream inkjet-based DNA synthesis method has hindered its widespread adoption. In contrast, high-throughput electrochemical synthesis provides higher throughput but with more nucleotide insertion, deletion, and substitution errors. Here, we propose an innovative coding scheme with high error correction capabilities, called DNA StairLoop. This coding scheme features a staircase interleaver and allows for component codes such as the convolutional code and the ow-density Parity-check code, allowing for flexible adaptation of the coding scheme. Both the row and the column decoders are soft input and soft output, enabling further improvement in data recovery accuracy through iterative decoding. The staircase interleaver facilitates extensive parallel decoding capabilities while effectively preserving parallelism across a multitude of nodes. In the in vitro experiment, DNA StairLoop successfully recovered the raw information in a staircase block with a nucleotide error rate of more than 8%. The simulations revealed that the DNA StairLoop can correct 10% nucleotide errors. Moreover, in parallel computing processing, the decoding time of our code continues to decrease dramatically.

synthetic biology↗

bioRxiv2024

Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors

We conducted a genome-wide CRISPR/Cas9 screen in suspension 293-F cells transduced with rAAV5. The highly selected genes revealed after two rounds of screens included the previously reported KIAA039L, TM9SF2, and RNF121, along with a cluster of genes involved in glycan biogenesis, Golgi apparatus localization and endoplasmic reticulum penetration. In this report, we focused on solute carrier family 35 member A1 (SLC35A1), a Golgi apparatus-localized cytidine 5-monophosphate-sialic acid (CMP-SIA) transporter. We confirmed that SLC35A1 knockout (KO) significantly decreased rAAV5 transduction to a level lower than that observed in KIAA0319L or TM9SF2 KO cells. Although SLC35A1 KO drastically reduced the expression of 2,6-linked SIA on the cell surface, the expression of 2,3-linked SIA, as well as the cell binding and internalization of rAAV5, were only moderately affected. Moreover, SLC35A1 KO significantly diminished the transduction of AAV multi-serotypes, including rAAV2 and rAAV3 which do not utilize SIAs for primary attachment. Notably, the SLC35A1 KO markedly increased transduction of rAAV9 and rAAV11, which primarily attach to cells via binding to galactose. Further analyses revealed that SLC35A1 KO significantly decreased vector nuclear import. More importantly, although the C-terminal cytoplasmic tail deletion ({Delta}C Tail) mutant of SLC35A1 did not drastically decrease SIA expression, it significantly decreased rAAV transduction, as well as vector nuclear import, suggesting the C-tail is critical in these processes. Furthermore, the T128A mutant significantly decreased SIA expression, but still supported rAAV transduction and nuclear import. These findings highlight the involvement of the CMP-SIA transporter in the intracellular trafficking of rAAV vectors post-internalization. IMPORTANCErAAV is an essential tool for gene delivery in the treatment of genetic disorders, yet the mechanisms of rAAV transduction remain partially understood. GPR108 is vital for the transduction of most rAAV vectors, but not for rAAV5. We aimed to identify host factors that impact AAV5 transduction akin to GPR108. Using a genome-wide CRISPR/Cas9 screen in 293-F cells, we identified SLC35A1, a Golgi apparatus-localized CMP-sialic acid transporter that transports CMP-sialic acid from cytoplasm into the Golgi apparatus for sialylation, is essential to rAAV transduction. Further studies across various AAV serotypes showed SLC35A1 significantly affects vector nuclear import post-internalization. These results underscore the crucial role of SLC35A1 in intracellular trafficking beyond the initial cell attachment of rAAV.

microbiology↗

bioRxiv2024

Stromal KITL/SCF promotes pancreas tissue homeostasis and restrains tumor progression

Components of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and non-immune stromal elements enable loss of homeostasis during tumor evolution. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. Here we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify loss of stromal KITL during tumorigenesis as tumor-promoting. Genetic inhibition of mesenchymal KITL in the contexts of homeostasis, injury, and cancer together indicate a role for KITL signaling in maintenance of pancreas tissue architecture, such that loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment. Statement of significanceBy analyzing transcriptional programs in healthy and tumor-associated pancreatic mesenchyme, we find that a sub-population of mesenchymal cells in healthy pancreas tissue express the paracrine signaling factor KITL. Loss of mesenchymal KITL is an accompanying and permissive feature of pancreas tumor evolution, with potential implications for cancer interception.

cancer biology↗

bioRxiv2024

Rapid protein evolution by few-shot learning with a protein language model

Directed evolution of proteins is critical for applications in basic biological research, therapeutics, diagnostics, and sustainability. However, directed evolution methods are labor intensive, cannot efficiently optimize over multiple protein properties, and are often trapped by local maxima. In silico-directed evolution methods incorporating protein language models (PLMs) have the potential to accelerate this engineering process, but current approaches fail to generalize across diverse protein families. We introduce EVOLVEpro, a few-shot active learning framework to rapidly improve protein activity using a combination of PLMs and protein activity predictors, achieving improved activity with as few as four rounds of evolution. EVOLVEpro substantially enhances the efficiency and effectiveness of in silico protein evolution, surpassing current state-of-the-art methods and yielding proteins with up to 100-fold improvement of desired properties. We showcase EVOLVEpro for five proteins across three applications: T7 RNA polymerase for RNA production, a miniature CRISPR nuclease, a prime editor, and an integrase for genome editing, and a monoclonal antibody for epitope binding. These results demonstrate the advantages of few-shot active learning with small amounts of experimental data over zero-shot predictions. EVOLVEpro paves the way for broader applications of AI-guided protein engineering in biology and medicine.

bioengineering↗

bioRxiv2024

Large-scale genome analyses provide insights into Hymenoptera evolution

The order Hymenoptera includes a large number of species with diverse lifestyles and is known for its significant contributions to natural ecosystems. To better understand the evolution of this diverse order, we performed large-scale comparative genomics on 131 species from 13 superfamilies, covering most representative groups. We used these genomes to reveal an overall pattern of genomic change in terms of gene content and evolutionary rate throughout hymenopteran history. We identified genes that possibly contributed to the evolution of several key innovations, such as parasitoidism, wasp-waist, sting, and secondary phytophagy. We also discovered the distinct genomic trajectories between the clade containing major parasitoid wasps (Parasitoida) and stinging species (Aculeata) since their divergence, which are involved in many aspects of genomic change, such as rapidly evolving gene families, gene gain and loss, and metabolic pathway evolution. In addition, we explored the genomic features accompanying the three independent evolution of secondary phytophagy. Our work provides insights for understanding genome evolution and the genomic basis of diversification in Hymenoptera.

genomics↗

bioRxiv2024

PlantRNA-FM: An Interpretable RNA Foundation Model for Exploration 1 Functional RNA Motifs in Plants

The complex language of plant RNA encodes a vast array of biological regulatory elements that orchestrate crucial aspects of plant growth, development, and adaptation to environmental stresses. Recent advancements in foundation models (FMs) have demonstrated their unprecedented potential to decipher complex language in biology. In this study, we introduced PlantRNA-FM, a novel high-performance and interpretable RNA FM specifically designed based on RNA features including both sequence and structure. PlantRNA-FM was pre-trained on an extensive dataset, integrating RNA sequences and RNA structure information from 1,124 distinct plant species. PlantRNA-FM exhibits superior performance in plant-specific downstream tasks, such as plant RNA annotation prediction and RNA translation efficiency (TE) prediction. Compared to the second-best FMs, PlantRNA-FM achieved an F1 score improvement of up to 52.45% in RNA genic region annotation prediction and up to 15.30% in translation efficiency prediction, respectively. Our PlantRNA-FM is empowered by our interpretable framework that facilitates the identification of biologically functional RNA sequence and structure motifs, including both RNA secondary and tertiary structure motifs across transcriptomes. Through experimental validations, we revealed novel translation-associated RNA motifs in plants. Our PlantRNA-FM also highlighted the importance of the position information of these functional RNA motifs in genic regions. Taken together, our PlantRNA-FM facilitates the exploration of functional RNA motifs across the complexity of transcriptomes, empowering plant scientists with novel capabilities for programming RNA codes in plants.

bioinformatics↗

bioRxiv2024

MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi

Borrelia (or Borreliella) burgdorferi, the causative agent of Lyme disease, is a motile and invasive zoonotic pathogen, adept at navigating between its arthropod vector and mammalian host. While motility and chemotaxis are well established as essential for its enzootic cycle, the function of methyl-accepting chemotaxis proteins (MCPs) in the infectious cycle of B. burgdorferi remains unclear. In this study, we demonstrate that MCP5, one of the most abundant MCPs in B. burgdorferi, is differentially expressed in response to environmental signals as well as at different stages of the pathogens enzootic cycle. Specifically, the expression of mcp5 is regulated by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, which are critical for the spirochetes colonization of the tick vector and mammalian host, respectively. Infection experiments with an mcp5 mutant revealed that spirochetes lacking MCP5 could not establish infections in either C3H/HeN mice or Severe Combined Immunodeficiency (SCID) mice, which are defective in adaptive immunity, indicating the essential role of MCP5 in mammalian infection. However, the mcp5 mutant could establish infection and disseminate in NOD SCID Gamma (NSG) mice, which are deficient in both adaptive and most innate immune responses, suggesting a crucial role of MCP5 in evading host innate immunity. In the tick vector, the mcp5 mutants survived feeding but failed to transmit to mice, highlighting the importance of MCP5 in transmission. Our findings reveal that MCP5, regulated by the Rrp1 and Rrp2 pathways, is critical for the establishment of infection in mammalian hosts by evading host innate immunity and is important for the transmission of spirochetes from ticks to mammalian hosts, underscoring its potential as a target for intervention strategies. SUMMARYLyme disease is the most commonly reported arthropod-borne illness in the US, Europe, and Asia. The causative agent of Lyme disease, Borrelia burgdorferi, is maintained in an enzootic cycle involving arthropod vectors (Ixodes ticks) and rodent mammalian hosts. Understanding how B. burgdorferi moves within this natural cycle is crucial for developing new strategies to combat Lyme disease. The complex nature of the enzootic cycle necessitates sensory-guided movement in response to environmental stimuli. B. burgdorferi possesses a unique and intricate chemotaxis signaling system, with methyl-accepting chemotaxis proteins (MCPs) at its core. These proteins are responsible for sensing environmental signals and guiding bacterial movement toward or away from stimuli. This study found that one of the MCPs, MCP5, is highly expressed and differentially regulated during the enzootic cycle by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways. MCP5 is crucial for mammalian infection, aiding in immune evasion and transmission from ticks to mammals, providing a foundation for further research into B. burgdorferis navigation within its hosts.

microbiology↗

bioRxiv2024

Genome sequencing of 'Fuji' apple clonal varieties reveals evolutionary history and genetic mechanism of the spur-type morphology

Somatic variations arising during asexual reproduction can lead to the emergence of bud sports exhibiting advantageous traits, forming the basis for bud sport breeding in perennial plants. Here, we report a near-complete, fully phased genome assembly of Fuji apple, enabling comprehensive identification of somatic variants across 74 clonally propagated Fuji varieties. Phylogenetic analysis of Fuji sport varieties indicates that the emergence of spur-type and early maturation traits results from multiple independent formation events. A number of putative functional somatic variants are identified, including one spur-type specific deletion located in the promoter of the TCP transcription factor gene MdTCP11. DNA methylation level of the deletion-associated miniature inverted-repeat transposable element is lower in the spur-type varieties compared to the standard-type varieties, while the expression of MdTCP11 is significantly higher. Overexpression of MdTCP11 in apple decreases the plant height, highlighting its important role in the development of spur-type apple varieties. This study sheds light on the 80-year cloning history of Fuji and provides valuable candidate causative mutations for apple breeding.

plant biology↗

bioRxiv2024

CellAgent: An LLM-driven Multi-Agent Framework for Automated Single-cell Data Analysis

Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data analysis are pivotal for advancing biological research, enabling precise characterization of cellular heterogeneity. However, existing analysis approaches require extensive manual programming and tool manipulation, posing significant challenges for researchers. To address this, we introduce CellAgent, an autonomous, LLM-driven approach that performs end-to-end scRNA-seq and spatial transcriptomics data analysis through natural language interactions. CellAgent employs a multi-agent hierarchical decision-making framework, simulating a "deep-thinking" workflow to ensure that each analytical step remains consistent with the overall task objective. To further enhance its capabilities, we developed sc-Omni, a high-performance, expert-curated toolkit that consolidates essential tools for scRNA-seq and spatial transcriptomics analysis. Additionally, we introduce a self-reflective optimization mechanism, enabling automated, iterative refinement of results through specialized evaluation methods, effectively replacing traditional manual assessments. Benchmarking against human experts demonstrates that CellAgent achieves approximately 60% improvement in efficiency across multiple downstream applications. In terms of accuracy, it maintains performance comparable to existing approaches while preserving natural language interactions. By translating natural language interactions into optimized analytical workflows, CellAgent establishes a scalable paradigm for LLM-driven scientific discovery, bridging the gap between experimental biologists and complex data analytics. This framework minimizes reliance on manual coding and exhaustive deliberation, ushering in the era of the "AI Agent for Science."

bioinformatics↗

bioRxiv2024

Evolutionary analysis of paired box gene family and biological function exploration of Lr.Pax7 in lamprey (Lethenteron reissneri)

The Pax(paired box)gene family comprises highly conserved transcription factors that play a crucial regulatory role in embryonic development, tissue morphogenesis, and cell differentiation. The gene family comprises of nine members, namely Pax1 to Pax9, each exhibiting distinct functionalities and expression patterns. Among the members of the Pax family, Pax7 is particularly involved in key regulatory functions related to skeletal muscle development and satellite cell biology in vertebrates. However, the precise role of Pax7 and its downstream targets in jawless vertebrates such as lamprey remains relatively understudied. Therefore, investigating the expression and function of lampreys Pax genes holds significant value as a model organism for understanding developmental processes, evolution, and interactions with other vertebrates. In this study, we identified Pax7 in Lethentero reissneri and multiple bioinformatics analyses suggested that it may represent the ancestral gene of the Pax7 shared among higher vertebrates. To further elucidate the function and regulatory mechanism of Pax7, we performed transcriptome sequencing analysis after silencing Lr.Pax7 expression which revealed alterations in metabolic processes along with associated genes(Plcy,Jagged2,Hes,Myod,Frizzled2,etc) involved in various immune pathways(Notch, Wnt, IL-17, TNF, etc), myogenesis process, adipocyte formation process consistent with those observed in higher vertebrates. Comparative studies between lamprey and high vertebrates could provide valuable insight into understanding the functional role of Pax7 and its downstream targets across diverse biological process as well as disease states.

evolutionary biology↗

bioRxiv2024

PLK1-Mediated Phosphorylation Cascade Activates the Mis18 Complex to Ensure Centromere Inheritance

Accurate chromosome segregation requires the attachment of spindle microtubules to centromeres, which are epigenetically defined by the enrichment of CENP-A nucleosomes. During DNA replication, existing CENP-A nucleosomes undergo dilution as they get redistributed among the two DNA strands. To preserve centromere identity, CENP-A levels must be restored in a cell-cycle controlled manner orchestrated by the Mis18 complex. Here we provide a comprehensive mechanistic basis for PLK1-mediated licensing of CENP-A loading. We demonstrate that PLK1 interacts with Mis18 and Mis18BP1 subunits of the Mis18 complex by recognising self-primed phosphorylations of Mis18 (S54) and Mis18BP1 (T78 and S93) through its Polo-box binding domain. Disrupting these PLK1 phosphorylations perturbed the centromere recruitment of HJURP and new CENP-A loading. Biochemical and functional analyses show that phosphorylation of Mis18 and subsequent PLK1 binding is required to activate the Mis18/{beta} complex for robust Mis18/{beta}-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance. One-Sentence SummaryPLK1 phosphorylation cascade licenses CENP-A loading by facilitating HJURP centromere recruitment via Mis18/{beta} activation.

cell biology↗

bioRxiv2024

Nodulation Trio in Medicago truncatula: Unveiling the Overlapping Roles of MtLYK2, MtLYK3, and MtLYK2bis

The perception of rhizobial nodulation factors (NF) by plant NF receptors is crucial for mediating legume nodulation. In Medicago truncatula nodulation, a proposed two-receptor model designates MtLYK3 as an entry receptor, while other LYK proteins, with unidentified functions, may serve as signaling receptors. Here, we generated the single, double, and triple mutants for M. truncatula MtLYK2, MtLYK3, and MtLYK2bis using CRISPR/Cas technology and examined their roles in nodulation. Our findings suggest that all three LYKs possess redundant functions in Medicago nodulation, with their distinct contributions attributed to varying transcription patterns.Our findings also suggest that a one-receptor model with multiple specificities that mediates both signaling and entry responses is more suitable in M. truncatula.

plant biology↗

bioRxiv2024

TMEM63B functions as a mammalian thirst receptor

Thirst drives animals to reinstate water homeostasis by fluid intake. An increase of blood osmolality is thought to induce thirst by activating a thirst receptor expressed in the subfornical organ (SFO), but the molecular identity of this receptor remains elusive. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian thirst receptor in the SFO and mediates osmotic and dehydrated thirst. First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation. Heterologously expressed TMEM63B is activated by hypertonic stimuli and point mutations can alter the reversal potential of the channel. More importantly, purified TMEM63B in liposomes establishes osmolarity-gated currents. Finally, Tmem63b knockout mice have profound deficits in thirst, and deleting TMEM63B within the SFO neurons recapitulated this phenotype. Taken together, these results provide a molecular basis for thirst 82and demonstrate TMEM63B is the long-sought mammalian thirst receptor.

neuroscience↗

bioRxiv2024

Adaptive, sample-specific parameter selection for more accurate transcript assembly

We introduce AutoTuneX, a data-driven, AI system designed to automatically predict optimal parameters for transcript assemblers -- tools for reconstructing expressed transcripts from the reads in a given RNA-seq sample. AutoTuneX is built by learning parameter knowledge from existing RNA-seq samples and transferring this knowledge to unseen samples. On 1588 human RNA-seq samples tested with two transcript assemblers, AutoTuneX predicts parameters that resulted in 98% of samples achieving more accurate transcript assembly compared to using default parameter settings, with some samples experiencing up to a 600% improvement in AUC. AutoTuneX offers a new strategy for automatically optimizing use of sequence analysis tools.

bioinformatics↗

bioRxiv2023

Armillaria korhonenii, the sixteenth biological species of Armillaria from China

Armillaria korhonenii, designated as Chinese biological species Q (CBSQ) here, is described as a new species based on phylogenetic and morphological evidence as well as the results of mating tests. This species is the sixteenth biological species of Armillaria reported from China following the discovery of 15 previously known biological species. Phylogenetically, A. korhonenii is the earliest divergent lineage of the genus Armillaria as inferred from the nucleotide sequences of the Elongation Factor 1-Alpha (EF1a). Morphologically, it is characterized by its ellipsoid to elongate basidiospores, yellowish orange to honey yellow pileus with fibrillose squamules. Mating tests indicated that A. korhonenii is a tetrapolar heterogeneous species and is inter-sterile with all the tested species except partial compatibility with CBSH.

microbiology↗