Biology subjects

Yi, G.

Publications and source records attributed to Yi, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomic Characterization and Therapeutic Potential of the Lytic Bacteriophage Curly against Klebsiella pneumoniae in Human Innate Immune Cells and a Murine Pneumonia Model

Klebsiella pneumoniae is an important cause of severe respiratory and systemic infections, and the increasing prevalence of multidrug-resistant strains has created an urgent need for alternative antibacterial strategies. In this study, nine K. pneumoniae-infecting bacteriophages isolated from diverse environmental sources were characterized genomically and functionally. Genome analyses revealed substantial genomic and proteomic diversity among the isolates. Functional screening against the clinical K. pneumoniae isolate JJD85 identified Curly as the most active phage, producing the highest plaque-forming titer and rapid suppression of bacterial growth in liquid culture. Curly was predicted to have a virulent lifestyle and encoded structural, genome-packaging, and DNA replication-associated proteins. In primary human monocyte-derived macrophage cultures, Curly markedly reduced bacterial burden in both cell-associated and cell-free fractions, while treatment of primary human neutrophil cultures produced an approximately 10^6-fold reduction in total recoverable bacterial burden. Transmission electron microscopy demonstrated phage-like particles within bacterial profiles located in both extracellular and macrophage-associated intracellular compartments. In a C57BL/6J murine pneumonia model, intranasal Curly treatment reduced pulmonary bacterial burden in a dose-associated manner, with approximately 10-fold and 100-fold reductions at the low and high doses, respectively. Curly treatment also attenuated infection-associated lung inflammation and preserved pulmonary architecture. These findings identify Curly as a promising bacteriophage candidate against K. pneumoniae and support further evaluation of its host range, resistance profile, and therapeutic potential.

microbiology↗

bioRxiv2026

Population structure, genetic diversity and global migration of the banana Fusarium wilt pathogen, Fusarium oxysporum f. sp. cubense tropical race 4

O_LIThe current epidemic of banana Fusarium wilt is caused by Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4). Foc TR4 originates in Asia and was first reported in the early 1990s, whereafter it was restricted to five Asian countries and the Northern Territory of Australia for two decades. Since 2013, the fungus was detected in the Middle East, the Indian subcontinent, Africa and Latin America. Its recent spread may be caused by the expansion of Cavendish banana production and the movement of contaminated planting materials. C_LIO_LIWhole genome sequences of 119 Foc TR4 isolates were compared based on single nucleotide polymorphisms (SNPs) to assess the population structure, genetic diversity and relation among isolates from 20 countries to reveal the evolutionary origin and likely migration. C_LIO_LIFoc TR4 is a monophyletic lineage divided into four clusters. Two of the clusters included isolates mostly from eastern Indonesia and seem to be ancestral with many rare alleles and high genetic diversity supporting this region as centre of origin. The remaining clusters were less diverse and associated with pandemic expansion. C_LIO_LIKnowledge on Foc TR4 emergence and dispersal can be used to inform more effective biosecurity and management practice. C_LI

evolutionary biology↗

bioRxiv2026

Structural Dynamics of RNA Polymerase II During Nucleotide Addition Cycle

RNA polymerase II (RNAPII) drives gene expression through iterative nucleotide addition cycles (NACs) comprising translocation, substrate binding, and catalysis. The lack of pre-catalysis and post-catalysis intermediates has precluded a complete mechanistic understanding of the NAC. Here we present 43 cryo-EM structures capturing distinct stages of the S. cerevisiae RNAPII elongation complex (EC) NAC, including previously intractable transition intermediates. We establish a continuous spectrum of RNAPII EC structural dynamics during the NAC, which can be divided into two coordinated phases: a substrate-induced EC tightening phase and a post-catalysis EC relaxation phase. For the substrate-induced EC tightening phase, the substrate binding initiates allosteric conformational changes across the entire RNAPII EC, including TL folding, funnel closure, clamp closure, transcription bubble ordering, and precise alignment of the RNA 3'-end with substrate to form a catalysis-competent configuration. For the post-catalysis EC relaxation phase, we captured the long-sought, short-lived post-catalysis product state and identified a series of intermediates that reveal a reverse conformational transition that facilitates rapid translocation. Together, our findings define a comprehensive structural and dynamic framework for RNAPII NAC, yielding a "molecular movie" of RNAPII in action and revealing a fundamental principle by which the enzyme balances speed and fidelity through coordinated conformational dynamics.

molecular biology↗

bioRxiv2026

The Effects of Different Gait Patterns on Knee Joint Biomechanics and Dynamic Stability during Stair Walking in Healthy Adults

ObjectiveTo investigate the effects of different gait patterns on knee joint biomechanics and dynamic stability during stair ascent. MethodsFourteen healthy males were recruited to ascend stairs using two distinct gait patterns: the "single-step" (leading with the same leg) and "cross-step" (alternating legs) strategies. Kinematic and kinetic data were collected synchronously using a Qualisys infrared motion capture system and a Kistler 3D force plate. Dynamic stability was quantified using the Margin of Stability (MOS), and knee joint biomechanics were evaluated using Patellofemoral Joint Stress (PFJS) and other relevant metrics. ResultsThroughout the gait cycle, there was no significant difference in the Medio-Lateral (ML) MOS between the single-step and cross-step patterns (P=0.318). However, in the Anterior-Posterior (AP) direction, the MOS for both patterns remained negative and decreased over time, with the cross-step pattern exhibiting significantly lower AP MOS values than the single-step pattern (P=0.002). At the moment of left foot-off, significant differences were observed in the right knee joint angle, right knee joint moment, net joint moment, effective quadriceps muscle lever arm, Quadriceps Force (QF), the angle between the quadriceps tendon and patellar ligament, Patellofemoral Joint Force (PFJF), patellofemoral joint stress, and patellofemoral contact area (all P<0.001). ConclusionsDuring stair ascent, the cross-step pattern reduces body stability, thereby increasing the risk of backward falls. Furthermore, this pattern increases patellofemoral joint stress, subjecting the knee to greater loading. Therefore, it is recommended to enhance lower limb muscle strength through targeted training to reduce fall risk. Additionally, adopting a more cautious gait strategy (such as the single-step pattern) can help minimize patellofemoral joint loading and mitigate the risk of patellofemoral pain.

biophysics↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2025

MindSight: A Bio-Inspired Neural Architecture for Visual Restoration via Cortical Electrical Stimulation

Visual impairment is a common condition worldwide, and cortical electrical stimulation is one of the approaches to aid in visual restoration. However, existing methods suffer from limited precision, flexibility, and generalization in generating the desired visual perception. In this paper, we propose a novel deep learning-based algorithm for cortical electrical stimulation, named "MindSight," aimed at enhancing the clarity and accuracy of induced visual perceptions. Our framework introduces three key innovations: (1) A differentiable biophysical model simulating cortical state transitions under electrical stimulation, enabling end-to-end training; (2) A dual-path training architecture combining neural decoding fidelity with phosphene simulation constraints; (3) An attention-guided background gated network for input filtration and, a multi-channel activation constraint to ensure the effectiveness of electrical stimulation. We validated our approach through novel experiments with macaque monkeys, demonstrating superior performance in visual perception tasks. These results highlight the potential of our approach in assisting individuals with visual impairments. Codehttps://github.com/zyj9902/MindSight

bioengineering↗

bioRxiv2025

Differences between Scaly-sided Merganser (Mergus squamatus) and Common Merganser (M. merganser) feather microstructure

The microstructures of breast feathers, flank feathers, rectrices, and down feathers of both Scaly-sided Merganser (Mergus squamatus) and Common Merganser (M. merganser) were meticulously examined using scanning electron microscope. The observed data were subjected to the Mann-Whitney U test, followed by hierarchical clustering and Fishers discriminant analysis of indicators with significant differences in morphological structure. The findings revealed statistically significant differences between Scaly-sided Merganser and Common Merganser in terms of the length of the base handle from distal barbules in the breast feathers, the length of the base handle, the number of hooked barbules, the number of cilia from distal barbules, and the number of ventral teeth from proximal barbules in rectrices. Additionally, variations in the distance between nodules, the nodular diameter, and the length of the base nodular of the down feathers were noted. Hierarchical clustering successfully categorized Scaly-sided Merganser and Common Merganser into distinct groups, achieving a 100% accuracy rate. Moreover, Fishers discriminant analysis demonstrated a 100% correctness rate when the back-substitution method was used to test the discriminant equation. Consequently, the length of the base handle of distal barbules in breast feathers, along with all selected indicators from rectrices and down feathers, may provide references to identify Scaly-sided Merganser and Common Merganser.

zoology↗

bioRxiv2025

Spatial transcriptomic analysis of HIV and tuberculosis coinfection in a humanized mouse model reveals specific transcription patterns, immune responses and early morphological alteration signaling

Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) coinfection is one of the biggest public health concerns worldwide. Both pathogens are adept at modulating immune response and, in the case of Mtb, even inducing structural modification of the affected tissue. The present study aimed at understanding the early phenotypical and functional changes in immune cell infiltration in the affected organ, using a humanized mouse model. The humanized mice were infected with either HIV or Mtb in single infection, or with both pathogens in coinfection. Three weeks after the infection, lung samples were collected, and spatial transcriptomics analysis was performed. This analysis revealed high infiltration of CD4+ T cells in Mtb infection, but not in HIV or coinfection. Coinfected mice also showed a minimal number of NK cells compared to the other groups. In addition to infection status, histological features also influenced the immune cell infiltration pattern in the lungs. Two distinct airway regions with distinct immune cell abundance patterns were detected by spatial transcriptome profiling. A lymphoid cell aggregate detected in coinfection lung exhibited distinct transcript profile. The cellular architecture in the lymphoid cell aggregate did not follow the spatial patterns seen in mature granulomas. However, lymphoid cell aggregates exhibited granuloma gene expression signatures, and pathways associated with reactive oxygen species production, oxidative phosphorylation, and TGF{beta} and interferon signaling similar to granulomas. This study revealed specific transcription patterns, immune responses and morphological alteration signaling in the early stage of HIV and Mtb infections.

microbiology↗

bioRxiv2024

Sirtuin2 blockade inhibits replication of Human Immunodeficiency Virus-1 and 1 Mycobacterium tuberculosis in macrophages and humanized mice

Coinfections with Mycobacterium tuberculosis (Mtb) and HIV-1 present a critical health challenge and require treatment for survival. We found that human M1 macrophages inhibit Mtb growth, while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, we found that HIV-1 augmented Sirt2 gene expression in M[FE]s. Therefore, we explored the therapeutic potential of sirtuin-modulating drugs in M[FE]s. Sirtinol, a Sirt2 inhibitor, significantly reduced HIV-1 growth in M0, M1, and M2-M[FE]s by >1 log10 over 7 days. Conversely, individual doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with resveratrol was neither synergistic nor antagonistic. Sirtinol upregulated iNOS and ATG5 mRNA in HIV-1 infected M[FE]s in a phenotype-dependent manner. In a humanized mouse model (Hu-NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, or in combination with combination antiretroviral therapy (cART), showed promising results; Sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel dual therapeutic strategy for treating HIV-1 and Mtb coinfections.

immunology↗

bioRxiv2024

Di-Gluebodies as covalently-rigidified, modular protein assemblies enable simultaneous determination of high-resolution, low-size, cryo-EM structures

Cryo-EM has become a routine structural biology method, yet elucidation of small proteins (<100 kDa) and increasing throughput remain challenging. Here, we describe covalently-dimerized engineered nanobodies, Di-Gluebodies, as novel and modular imaging scaffolds to address the challenges. They can simultaneously display two copies of the same protein or two distinct proteins, providing sufficient rigidity required by cryo-EM. We validate this method with multiple soluble and membrane targets, demonstrating that this provides a flexible and scalable platform for expanded protein structure determination.

synthetic biology↗

bioRxiv2024

A Novel Humanized Mouse Model for HIV and Tuberculosis Co-infection Studies

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. Further, co-infections with HIV and Mtb have severe effects in the host, with people infected with HIV being fifteen to twenty-one times more likely to develop active TB. The use of an appropriate animal model for HIV/Mtb co-infection that can recapitulate the diversity of the immune response in humans would be a useful tool for conducting basic and translational research in HIV/Mtb infections. The present study was focused on developing a humanized mouse model for investigations on HIV-Mtb co-infection. Using NSG-SGM3 mice that can engraft human stem cells, our studies showed that they were able to engraft human CD34+ stem cells which then differentiate into a full-lineage of human immune cell subsets. After co-infection with HIV and Mtb, these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally, Mtb caused infections in both lungs and spleen, and induced the development of granulomatous lesions in the lungs, detected by CT scan and histopathology. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections. Our results suggest that the humanized NSG-SGM3 mice are able to recapitulate the effects of HIV and Mtb infections and co-infection in the human host at pathological, immunological and metabolism levels, providing a dependable small animal model for studying HIV/Mtb co-infection.

immunology↗

bioRxiv2023

hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents

ObjectiveUrate transporter 1 (URAT1), a well-established urate-lowering therapeutic target for hyperuricemia and gout treatment, expresses in the kidney proximal tubule and is responsible for uric acid (UA) reabsorption. However, non-primate animal models currently used in pharmacological studies failed to evaluate URAT1 inhibitors effectiveness because their URAT1 has a very low UA affinity compared to human URAT1, resulting in a lag in targeting drug screening and novel therapy development for gout treatment. We established a human URAT1 (hURAT1) transgenic knock-in (KI) mouse model to assess uricosuric agents effectiveness and characterize URAT1-caused pathogenesis. MethodsWe generated hURAT1 transgenic mice using CRISPR/Cas9 knock-in technique. mUrat1 knockout was achieved by replacing exon 1 coding sequence with a human SLC22A12 CDS-pA cassette. Based on the above transgenic mice, a hyperuricemia model was further established by hypoxanthine administration. ResultsThe hURAT1-KI mice successfully expressed hURAT1 protein to the apical side of the kidney proximal tubule epithelium, where a native human URAT1 kidney localization in human body. Upon hypoxanthine challenge, the blood UA level was elevated in hURAT1-KI mice, exhibiting an approximately 37% increase compared to wild-type (WT) mice. The elevated blood UA level could be alleviated by hURAT1 inhibitor benzbromarone treatment in the hURAT1-KI mice whereas no response was observed in WT littermates. Therefore, hURAT1 transgenic mice responded well to inhibitors and can be used to evaluate the therapeutic effects. ConclusionThe hURAT1-KI hyperuricaemia mouse model would be valuable for preclinical evaluation of urate-lowering agents toward gout treatment and studying UA metabolic complexities in humans.

pharmacology and toxicology↗

bioRxiv2023

Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3 mediated IL-1β production in human macrophages and microglia

Activation of the NACHT, LRR family pyrin domain containing 3 (NLRP3) inflammasome complex is an essential innate immune signalling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labelling, affinity purification and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-IL-1{beta} levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1{beta} cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1{beta} production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

biochemistry↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

Genomic insights into post-domestication expansion and selection of body size in ponies

Horses domestication revolutionized human civilization by changing transportation, farming, and warfare patterns. Despite extensive studies on modern domestic horse origins, the intricate demographic history and genetic signatures of pony size demand further exploration. Here, we present a high-quality genome of the Chinese Debao pony and extensively analyzed 385 individuals from 49 horse breeds. We reveal the conservation of ancient components in East Asian horses and close relationships between Asian horses and specific European pony lineages. Genetic analysis uncovers Asian paternal origin for European pony breeds, and these pony-sized horses share a close genetic affinity due to the presence of a potential ancestral ghost pony population. Additionally, we identify promising cis-regulatory elements influencing horse withers height by regulating genes like RFLNA and FOXO1. Overall, our study provides insightful perspectives into the development history and genetic determinants underlying body size in ponies and offers broader implications for horse population management and improvement. TeaserDecoding pony genetics: exploring origins and size determinants sheds light on their historical and biological impacts.

genomics↗

bioRxiv2023

Construction of a multi-tissue cell atlas reveals cell-type-specific regulation of molecular and complex phenotypes in pigs

The systematic characterization of cellular heterogeneity among tissues and cell-type-specific regulation underlying complex phenotypes remains elusive in pigs. Within the Pig Genotype-Tissue Expression (PigGTEx) project, we present a single-cell transcriptome atlas of adult pigs encompassing 229,268 high-quality nuclei from 19 tissues, annotated to 67 major cell types. Besides cellular heterogeneity within and across tissues, we further characterize prominent tissue-specific features and functions of muscle, epithelial, and immune cells. Through deconvoluting 3,921 bulk RNA-seq samples from 17 matching tissues, we dissect thousands of genetic variants with cell-type interaction effects on gene expression (ieQTL). By colocalizing these ieQTL with variants associated with 268 complex traits, we provide new insights into the cellular mechanisms behind these traits. Moreover, we highlight that orthologous genes with cell-type-specific regulation in pigs exhibit significant heritability enrichment for some human complex phenotypes. Altogether, our work provides a valuable resource and highlights novel insights in cellular regulation of complex traits for accelerating pig precision breeding and human biomedical research.

genetics↗

bioRxiv2023

Two haplotype-resolved genomes of highly heterozygous AAB allotriploid bananas provide insights into subgenome asymmetric evolution and banana wilt control

Bananas (Musa spp.) are one of the most important tropical fruits and staple food, which are of great significance to human societies. Plantain and Silk are two important banana subgroups, which are both triploid hybrids (AAB) between the wild diploid Musa acuminata and M. balbisiana. In this study, we reported the first haplotype-resolved genome assembly of Plantain and Silk bananas with genome size of approximately 1.4 Gb. We discovered widespread asymmetric evolution in the subgenomes of Plantain and Silk, which could be linked to frequent homologous exchanges (HEs) events. This is the first study to uncover the genetic makeup of triploid banana and verify that subgenome B harbors a rich source of resistance genes. Of the 88,078 and 94,988 annotated genes in Plantain and Silk, only 58.5% and 59.4% were present in all three subgenomes, with >50% genes containing differently expressed alleles in different haplotypes. We also found that Plantain is more resistant to banana Fusarium wilt, exhibiting a much faster defense response after pathogenic fungi infection. Many differentially expressed genes in abscisic acid, ethylene, jasmonic acid and salicylic acid pathways were identified in Plantain. Our analysis revealed that MpMYB36 promotes the biosynthesis of secondary cell wall and deposition of lignin by directly binding to the promoter of MpPAL and MpHCT, which allows Plantain to inhibit the penetration of early infection. Moreover, the insertion of the key carotenoid synthesis gene (CRTISO) may be the potential genetic basis for the richness of carotenoids in Plantain. Our study provides an unprecedented genomic basis for basic research and the development of elite germplasm in cultivated bananas.

plant biology↗

bioRxiv2023

A MSTNDel273C mutation with FGF5 knockout sheep by CRISPR/Cas9 promotes skeletal muscle myofiber hyperplasia via MEK-ERK-FOSL1 axis

Mutations in the well-known Myostatin (MSTN) produce a "double-muscle" phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of the MSTN often produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, a MSTNDel273C mutation with FGF5 knockout sheep, in which the MSTN and FGF5 dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon of MSTN, resulting in cysteine-depleted at amino acid position 273, and the FGF5 double allele mutation led to inactivation of FGF5 gene. The MSTNDel273C mutation with FGF5 knockout sheep highlights a dominant "double-muscle" phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, the MSTNDel273C mutation with FGF5 knockout mediated the activation of FOSL1 via the MEK-ERK-FOSL1 axis. The activated FOSL1 promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the expression of MyoD1, and resulting in smaller myotubes. In addition, activated ERK1/2 may inhibit the secondary fusion of myotubes by Ca2+-dependent CaMKII activation pathway, leading to myoblasts fusion to form smaller myotubes.

cell biology↗