Biology subjects

Feng, Y.

Publications and source records attributed to Feng, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Mapping Along-Tract White Matter Microstructural Differences in Autism

Previous diffusion magnetic resonance imaging (dMRI) research has indicated altered white matter microstructure in autism, but the implicated regions are highly inconsistent across studies. Such prior work has largely used conventional dMRI analysis methods, including the traditional microstructure model, based on diffusion tensor imaging (DTI). However, these methods are limited in their ability to precisely map microstructural differences and accurately resolve complex fiber configurations. In our study, we investigated white matter microstructure alterations in autism using the refined along-tract analytic approach, BUndle ANalytics (BUAN), and an advanced microstructure model, the tensor distribution function (TDF). We analyzed dMRI data from 365 autistic and neurotypical participants (5-24 years; 34% female) from 10 cohorts to examine commissural and association tracts. Autism was associated with lower fractional anisotropy and higher diffusivity in localized portions of nearly every commissural and association tract examined; these tracts inter-connected a wide range of brain regions, including frontal, temporal, parietal, and occipital. Taken together, BUAN and TDF allow robust and spatially precise mapping of microstructural properties in autism. Our findings rigorously demonstrate that white matter microstructure alterations in autism may be greater within specific regions of individual tracts, and that the implicated tracts are distributed across the brain.

neuroscience↗

bioRxiv2025

An Enhanced Mountain Climbing Search Algorithm to Enable Fast and Accurate Autofocusing in High Resolution Fluorescence Microscopy

Accurate and efficient autofocusing is essential for the automation of fluorescence microscopy, but background noise and shallow depth of field at high magnifications make autofocusing particularly challenging. Here, we present a fast and accurate autofocus algorithm to address these challenges. It is highly effective for high-magnification imaging, while performing equally well for low-magnification imaging tasks. The method is based on the mountain climbing search algorithm and yields improvements on autofocusing precision of up to 200-fold over current methods, whilst offering competitive speed and greatly extended search ranges. Our approach is broadly applicable: it demonstrated good stability and reproducibility across magnifications ranging from 20X to 100X, excels in both live cell imaging and high-resolution fixed sample imaging, and it is compatible with various microscopy techniques without the need for fiducial markers or hardware modifications on existing microscopes. To maximise its accessibility, we constructed a user-friendly interface compatible with the widely used Micromanager software. It generalises well across various imaging modalities and hardware platforms, making it particularly suitable for use in high-resolution screening of candidate drugs.

cell biology↗

bioRxiv2025

Design and Synthesis of Potent First-in-Class Histones Acetyltransferase Modulators.

Epigenetic regulation governs gene expression through histone modifications, particularly the acetylation of lysine residues. These modifications are orchestrated by enzymes such as histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among them, p300 plays a critical role in various disorders such as neurodegenerative conditions (i.e. Alzheimers disease, and Alzheimers Disease related dementia) and cancer (i.e. glioblastoma and B cell lymphoma). Our aim is to develop therapeutic interventions for these ailments. In this context, we designed and synthesized novel activators of the enzyme. Using an in vitro screening approach combined with structural activity relationship analysis, we successfully identified compounds that modulate histone acetylation.

biochemistry↗

bioRxiv2025

scKAN: Interpretable Single-cell Analysis for Cell-type-specific Gene Discovery and Drug Repurposing via Kolmogorov-Arnold Networks

Single-cell analysis has revolutionized our understanding of cellular heterogeneity, yet current approaches face challenges in efficiency and interpretability. In this study, we present scKAN, a framework that leverages Kolmogorov-Arnold Networks for interpretable single-cell analysis through three key innovations: efficient knowledge transfer from large language models through a lightweight distillation strategy; systematic identification of cell-type-specific functional gene sets through KANs learned activation curves; and precise marker gene discovery enabled by KANs importance scores with potential for drug repurposing applications. The model achieves superior performance on cell-type annotation with a 6.63% improvement in macro F1 score compared to state-of-the-art methods. Furthermore, scKANs learned activation curves and importance scores provide interpretable insights into cell-type-specific gene patterns, facilitating both gene set identification and marker gene discovery. We demonstrate the practical utility of scKAN through a case study on pancreatic ductal adenocarcinoma, where it successfully identified novel therapeutic targets and potential drug candidates, including Doconexent as a promising repurposing candidate. Molecular dynamics simulations further validated the stability of the predicted drug-target complexes. Our approach offers a comprehensive framework for bridging single-cell analysis with drug discovery, accelerating the translation of single-cell insights into therapeutic applications.

bioinformatics↗

bioRxiv2025

Construction of a low-temperature degrading synthetic bacterial community of corn straw

The stability of the cellulose structure in straw creates a challenge for short-term degradation in the natural environment, especially in the cold regions of north China. Therefore, to secure strains that can degrade straw at low temperatures, we selected soil samples from straw-returning land and used cellulose as the only carbon source. After conducting preliminary screening and further re-screening, we ultimately selected three strains that exhibited efficient degradation of corn straw at a temperature of 4 . Subsequently, the synthetic bacterial community C was constructed using these strains: Stenotrophomonas maltophilia, Flavobacterium johnsoniae and Pantoea rodasii. We conducted a 45-day solid-state and liquid-state fermentation experiment at low-temperature (12 ). The activity of lignocellulase was determined, and the enzyme production conditions were optimized. The results show that the liquid fermentation degradation rate of straw increased by 40 % compared with the control group in the natural state (without adding C). Similarly, the solid-state fermentation degradation rate of straw increased by 30 %, which was significantly faster than that of the control group. Finally, the enzyme production conditions of strain C were optimized as follows: culture time 96 h, inoculation amount 4 %, temperature 12 , pH 6.0, and Alkaline Carboxymethyl Cellulase (CMCase) activity 24.34 U/mL. The microbial system C efficiently degrades straw at low temperature, which is valuable for improving the comprehensive utilization rate of straw and has a broad application prospect in improving soil fertility.

microbiology↗

bioRxiv2025

Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimers Disease and Parkinsons Disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils and fibrils, represent other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for -synuclein aggregation is of great interest, however effective inhibitory peptides are often hydrophobic and hence difficult to handle; therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils, to produce proteins that bind along the surface of -synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation. Short statementConsensus-designed tetratricopeptide repeat (CTPR) proteins can be endowed with additional functionality including specific client recruitment. Here we created stable, soluble CTPR-based binders that recognise -synuclein fibrils with micromolar affinity. The CTPR scaffold provides a facile way to test potential fibril-binding or aggregation-modulating peptides and to probe their mechanisms of action.

biochemistry↗

bioRxiv2025

Single cell resolved spatial immune repertoire unveils spatial heterogeneity of lymphoid aggregates in human immune disorders

Adaptive immunity, mediated by T and B cell responses, is essential for defending against infections and cancers while also being implicated in autoimmune diseases. Tracking T and B cell repertoires in situ at single-cell resolution is essential for understanding adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we developed Stereo-XCR-seq, an efficient strategy for retrieving and sequencing TCR and BCR from Stereo-seq cDNA libraries at subcellular resolution. Stereo-XCR-seq provides unbiased full-length XCR reads alongside spatial transcriptomics, enabling the identification of heterogeneous lymphoid aggregates with distinct clonal activities in cancers and inflammatory bowel disease (IBD). We identified plasma cell aggregates that differ from tertiary lymphoid structures (TLSs) in both transcriptomic profiles and clonal activities, with spatial positioning potentially mediating unique immune responses. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities within tissue microenvironments, providing insights into lymphocyte adaption to environmental stimuli. This technology provides potential for advancing our understanding of tissue immunity and the development of therapeutic strategies for immune disorders.

immunology↗

bioRxiv2025

Axon Trafficking Counteracts Aberrant Protein Aggregation in Neurons

Directed axon trafficking of mRNA via ribonucleoprotein complexes (RNPs) is essential for the proper function and survival of neurons. However, the mechanisms governing RNP transport in axons remain poorly understood. Here, we identify Annexin A7 (ANXA7) as a critical adaptor facilitating the retrograde transport of T-cell intracellular antigen 1 (TIA1)-containing RNPs by linking them to the cytoplasmic dynein. Persistent axonal Ca{superscript 2} elevation disrupts ANXA7s linker role, causing the detachment of TIA1 granules from dynein, consequently impairing transport and triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, severely obstructing trafficking and causing pathological aggregation of TIA1 in axons, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression enhances trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. Our findings elucidate a novel mechanism underlying RNP axonal transport, highlighting its significance in the biology and pathology of central neurons.

neuroscience↗

bioRxiv2025

Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology

Alzheimers disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. We used silicon probes to simultaneously record neural activity in MEC and hippocampus before or after the onset of spatial memory impairment in the 3xTg mouse model of AD pathology. We found that reduced hippocampal theta power, reduced MEC-CA1 theta coherence, and altered phase locking of MEC and hippocampal neurons all coincided with the emergence of spatial memory impairment in 3xTg mice. Together, these findings indicate that disrupted temporal coordination of neural activity in the MEC-hippocampal system parallels the emergence of memory impairment in a model of AD pathology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/633171v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@11606a5org.highwire.dtl.DTLVardef@10e5d0borg.highwire.dtl.DTLVardef@1feabe1org.highwire.dtl.DTLVardef@c646ed_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG HighlightsO_LISpatial memory impairments in 3xTg mice emerge between 6 and 8 months of age C_LIO_LIMemory deficits emerge alongside reduced HPC theta power and reduced CA1-MEC theta coherence C_LIO_LIMemory deficits emerge alongside disrupted timing of MEC and HPC neural activity C_LIO_LIInterneuron loss in MEC and interneuron desynchronization in HPC occur prior to memory impairment C_LI

neuroscience↗

bioRxiv2025

Infectome analysis of bat kidneys from Yunnan province, China, reveals close relatives of Hendra-Nipah viruses and prevalent bacterial and eukaryotic pathogens

Bats are natural reservoirs for a wide range of microorganisms, including many notable zoonotic pathogens. However, the infectome of bat kidneys remains poorly understood. To address this gap, we performed meta-transcriptomic sequencing on kidney tissues from 142 bats, spanning ten species sampled at five locations in Yunnan province, China. This analysis identified 22 viral species, including 20 novel viruses, two of which represented newly discovered henipaviruses closely related to the highly pathogenic Hendra and Nipah viruses. These henipaviruses were found in the kidneys of bats inhabiting an orchard near villages, raising concerns about potential fruit contamination via bat urine and transmission risks to livestock or humans. Additionally, we identified a novel protozoan parasite, tentatively named Klossiella yunnanensis, along with two highly abundant bacterial species, one of which is a newly discovered species--Flavobacterium yunnanensis. These findings broaden our understanding of the bat kidney infectome, underscore critical zoonotic threats, and highlight the need for comprehensive, full-spectrum microbial analyses of previously understudied organs to better assess spillover risks from bat populations.

microbiology↗

bioRxiv2025

Comprehensive Infectome Analysis Reveals Diverse Infectious Agents with Zoonotic Potential in Wildlife

Understanding wildlife-pathogen interactions is crucial for mitigating zoonotic risk. Through meta-transcriptomic sequencing we profiled the infectomes of 1,922 samples from 67 mammalian species across China, uncovering a remarkable diversity of viral, bacterial, fungal, and parasitic pathogens. Of the 195 pathogens identified, 62 were novel, including a bi- segmented coronavirus in diseased lesser pandas, which we propose represents a new genus - Zetacoronavirus. The orders Carnivora and Rodentia exhibited the highest pathogen diversity and were implicated in numerous host-jumping events. Comparative analysis of diseased versus healthy animals revealed a trend of higher pathogen loads in the former, with possible differences in tissue tropisms. In total, 48 zoonotic and 17 epizootic pathogens were identified, with frequent cross-species transmission, emphasizing the potential for emerging public health threats. This study highlights the urgent need for wildlife pathogen surveillance to inform proactive disease management strategies.

microbiology↗

bioRxiv2025

LCORL and STC2 variants increase body size and growth rate in cattle and other animals

Using ancestral recombination graphs, we investigated recent selection signatures in European beef cattle breeds, pinpointing sweep-driving variants in the LCORL and STC2 loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation in LCORL occurs mainly in central-European cattle, and stimulates growth. Remarkably, convergent truncating mutations were also found in commercial breeds of sheep, goats, pigs, horses, dogs, rabbits, and chickens. In the STC2 gene, we identified a missense mutation (A60P) located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.

genetics↗

bioRxiv2024

CRISPR-Cas supervises diverse anti-phage defense systems

A variety of bacterial anti-phage systems have recently been discovered1-3, but how these systems synergize to defend against diverse phages remains poorly understood. Here, we report that the adaptive immune system CRISPR-Cas supervises the expression of diverse immune systems by exploiting the regulatory CRISPR RNA-like RNAs (crlRNAs). The crlRNAs target and inhibit the promoters of various immune systems, including the newly characterized Nezha and Gabija, as well as eight previously unrecognized systems that feature distinct defensive domains. Notably, CRISPR regulation balances the expression level of these systems to ensure effective anti-phage activity while avoiding their autoimmunity risks. In return, the supervised immune systems trigger abortive infections when CRISPR-Cas is inhibited by viral anti-CRISPR proteins, thereby offering an anti-anti-CRISPR protection at the population level. Moreover, these systems complement CRISPR immunity with a differing anti-phage profile. These findings highlight the pivotal role of CRISPR-Cas in orchestrating a diverse range of immune systems and showcase the delicate synergy among the multilayered defense strategies in prokaryotes.

microbiology↗

bioRxiv2024

Lipid Nanoparticle Barcoding for Multiplexed Single-Cell RNA Sequencing

Sample multiplexing is an emerging method in single-cell RNA sequencing (scRNA-seq) that addresses high costs and batch effects. Current multiplexing schemes use DNA labels to barcode cell samples but are limited in their stability and extent of labeling across heterogeneous cell populations. Here, we introduce Nanocoding using lipid nanoparticles (LNPs) for high barcode labeling density in multiplexed scRNA-seq. LNPs reduce dependencies on cell surface labeling mechanisms due to multiple controllable means of cell uptake, amplifying barcode loading 10-100-fold and allowing both protection and efficient release by dissolution. In cultured cell lines and heterogeneous cells from tissue digests, Nanocoding occurs in 40 minutes with stability after sample mixing and requires only commercially available reagents without novel chemical modifications. In spleen digests, 6-plex barcoded samples show minimal unlabeled cells, with all barcodes giving bimodal count distributions. Challenging samples containing lipid-rich debris and heterogeneous cells from adipose tissue of obese rodents show more than 95% labeling with all known subtypes identified. Using Nanocoding, we investigate gene expression changes related to aging in adipose tissue, profiling cells that could not be readily identified with current direct conjugate methods using lipid or antibody conjugates. This ease of generating and tuning these constructs may afford efficient and robust whole-sample multiplexing with minimal sample crosstalk.

bioengineering↗

bioRxiv2024

GlioME: A Novel Organoid Model Retaining the Glioma Mi-croenvironment for Personalized Drug Screening and Thera-peutic Evaluation

Glioma is an aggressive brain tumor with a poor prognosis. Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging, limiting its clinical applications. Here, we present a novel approach to generate glioma organoids with a microenvironment (GlioME) from patient-derived glioma tissue. These organoids maintain the genetic and epigenetic characteristics of the primary tumor and preserve cell-to-cell interactions within the tumor microenvironment, including resident immune cells. Bulk RNA sequencing, whole exome sequencing, and DNA methylation analysis were used to confirm the molecular similarities between the organoids and primary glioma tissues. Immunofluorescence and flow cytometry were used to assess immune cell viability, comparing GlioME with floating glioma organoids. GlioME exhibited high responsiveness to chemotherapy and targeted therapy, demonstrating its potential for therapeutic screening applications. Notably, GlioME accurately predicted patient response to the recently approved MET inhibitor, vebreltinib. Thus, this organoid model provides a reliable in vitro platform for glioma microenvironment-related research and clinical drug screening.

cancer biology↗

bioRxiv2024

Lifespan Normative Modeling of Brain Microstructure

Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brains white matter (WM) microstructure. Here we present a large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N=54,583 individuals; age: 4-91 years). We extracted regional diffusion tensor imaging (DTI) metrics using a standardized analysis and quality control protocol and used hierarchical Bayesian regression (HBR) to model the statistical distribution of derived WM metrics as a function of age and sex. We extracted the average lifespan trajectories and corresponding centile curves for each WM region. We illustrate the utility of the method by applying it to detect and visualize profiles of WM microstructural deviations in a variety of contexts: in mild cognitive impairment, Alzheimers disease, and 22q11.2 deletion syndrome - a neurogenetic condition that markedly increases risk for schizophrenia. The resulting large-scale model provides a common reference to identify disease effects on the brains microstructure in individuals or groups, and to compare disorders, and discover factors affecting WM abnormalities. The derived normative models are a valuable resource publicly available to the community, adaptable and extendable to future datasets as the available data expands.

neuroscience↗

bioRxiv2024

RetS senses neurotransmitter norepinephrine and adrenergic agents to regulate Pseudomonas aeruginosa virulence

Bacterial cells employ diverse mechanisms to perceive and respond to host-associated molecules, coordinate intracellular signal transduction, and engage in interkingdom communications. In this study, we firstly discovered that the adrenergic antagonist dronedarone (DDR) effectively suppresses quorum sensing (QS) and pathogenesis of the opportunistic pathogen P. aeruginosa. Further analysis revealed that DDR targets RetS, an bacterial surface receptor critical for suppressing the GacS/GacA two-component regulatory system (TCS). Interestingly, the adrenergic agonist norepinephrine (NE) was found to exert opposite effects against RetS, thereby reversing DDR-induced phenotypes in P. aeruginosa. Moreover, we identified the hinge region of RetSDISMED2 serves as a binding pocket of NE and DDR, which provides potential mechanisms of the antagonistic effect of NE and DDR. Our study demonstrated that NE promotes P. aeruginosa infections while DDR can serve as an anti-virulence compound against P. aeruginosa infections. Thus, RetS might serve as a bacterial adrenergic receptor which keeps the NE under constant surveillance. SignificanceSensing and recognition of host-derived molecules, as well as therapeutic drugs, are crucial for the survival of pathogens during infection process. The adrenergic drugs are well known to affect virulence and pathogenesis of the opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). In this work, we have provided in-depth characterization of a Norepinephrine (NE) receptor in P. aeruginosa, the RetS membrane protein. NE is the-adrenergic agonist known as a stress hormone, exerts its activity through interaction with mammalian adrenergic receptors (AR). It has been shown that increased NE concentration during early sepsis can stimulate the growth of various Gram-negative and Gram-positive bacteria, including P. aeruginosa. We revealed that both adrenergic agonist NE and another adrenergic antagonist dronedarone (DDR) are able to interfering the RetS-GacS/GacA signaling cascade of P. aeruginosa and execute opposite impact on the pathogenesis of P. aeruginosa during infections.

microbiology↗

bioRxiv2024

Chaperonin TRiC bridges radial spokes for folding proteins locally translated in mammalian sperm flagella

As animals evolved from external to internal fertilization, sperm flagella, which once transiently propelled sperm in water to reach nearby eggs, developed to beat for days or even longer within the female reproductive tract. How flagella were remodeled accordingly remains unclear. Unlike externally fertilizing zebrafish and sea urchin, mammalian sperm flagella feature a unique barrel-shaped bridge between axonemal radial spokes RS1 and RS2, though its components and function remain unknown. Here, using cryo-EM and cryo-ET combined with mass spectrometry and immunofluorescence staining, we reveal that this RS1-RS2 barrel (RRB) in mammalian sperm flagella is a group II chaperonin TRiC/CCT. We purified and resolved the unforeseen cryo-EM structure of TRiC from bovine sperm flagella, discovering that flagella TRiC contains the testis-specific CCT6B subunit. Additionally, we resolved the cryo-ET map of mouse sperm flagella RSs, containing the RRB, achieving unprecedented local resolution of 10-14 [A]. The in-situ RRB map displays two extra densities within its chambers in a polarized manner, suggesting the presence of folding substrates and a co-chaperone (likely phosducin-like 2). Notably, mammalian flagella also contain components of translation machineries and actively synthesize proteins. Our results suggest that the RRB TRiC folds locally translated proteins to sustain mammalian flagella, providing new insights into flagellar remodeling in internally fertilizing species. Our findings also shed lights on male fertility and potential treatments for infertility.

biophysics↗