Biology subjects

Jiang, D.

Publications and source records attributed to Jiang, D..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Identification and characterization of host-modulating effectors encoded by the Cluster F1 mycobacteriophage NormanBulbieJr

NormanBulbieJr (NBJ) is a temperate siphovirus isolated on the host Mycobacterium smegmatis mc2155 that encodes 102 gene products, 60 of which have no known function (NKF). Based on gene content, NBJ is classified as a Cluster F, Subcluster F1 phage and shares 70% of its encoded gene phamilies with Girr, another F1 mycobacteriophage that was recently analyzed in a genome-wide overexpression screen and found to encode 29 diverse gene products capable of inhibiting growth of M. smegmatis. Similar functional screens in other mycobacteriophages have uncovered a growing repertoire of diverse, phage-encoded bacterial growth inhibitors, providing prime candidates for dissecting novel bacterial-phage interactions. An arrayed overexpression library encoding all 102 genes was constructed and systematically screened using a plate-based cytotoxicity assay, identifying 29 genes that inhibit mycobacterial growth. Because mycobacteriophage genomes are also known to encode systems involved in phage-phage competition, we conducted additional phage defense assays for a subset of NBJ genes in our library. This analysis confirmed homotypic immunity by the predicted immunity repressor and identified gp45 as a second defense factor that protects against Cluster F phages and promotes NBJ lysogen stability. Additional mechanistic analyses indicate that gp45 functions in a secretion-dependent manner, acting after phage adsorption to reduce productive infection and early phage transcript accumulation. Escape mutant and bacterial two-hybrid analyses implicate Cluster F tape measure proteins as the likely target of gp45, consistent with disruption of an early step in phage genome delivery. Finally, we extended our analysis to explore the essentiality of all identified host-modulating genes in the NBJ life cycle, using CRISPR-enhanced recombineering to generate phage deletion mutants, revealing two host modulators that are critical for lytic growth. Conducted as part of the SEA-GENES undergraduate research consortium, this study adds to a growing functional genomics resource and provides new insights into the complex interactions between phage gene products and the mycobacterial host cell.

microbiology↗

bioRxiv2025

A unified language model bridging de novo and fragment-based 3D molecule design delivers potent CBL-B inhibitors for cancer treatment

The rational design of small molecules is central to drug discovery, yet current artificial intelligence (AI) methodologies for generating three-dimensional (3D) molecules are often siloed, focusing on either de novo design or fragment-based design. The lack of a holistic framework limits AIs application across the complex and multi-step pipeline spanning from novel scaffold identification to lead compound optimization, and prevents AI from effectively learning from the entire process. Here, we introduce UniLingo3DMol, a language model for 3D molecular generation, empowered by fragment permutation-capable molecular representation alongside multi-stage and multi-task training strategy. This integrated design enables UniLingo3DMol to seamlessly span both de novo and fragment-retained molecular design, demonstrating superior performance over existing generation models in in silico evaluations across more than 100 diverse biological targets. We further leveraged UniLingo3DMol in the design of inhibitors targeting CBL-B, a crucial immune E3 ubiquitin ligase and attractive immunotherapy target. This strategy led to a lead compound demonstrating excellent in vitro activity and robust in vivo anti-tumor efficacy. Our findings establish UniLingo3DMol as a generalized and powerful platform, showing the strong potential to advance AI-driven drug discovery.

bioinformatics↗

bioRxiv2025

Dynamic epigenetic and transcriptional regulatory network in pepper fruit development and ripening

Pepper (Capsicum) is among the most widely cultivated and consumed vegetable crops worldwide. Although extensive studies in model fruit crops such as tomato have provided insights into the genetic and epigenetic regulation of fruit development and ripening, comparable knowledge in pepper remains limited. Here, we employ a multi- omics approach to investigate transcriptome and epigenome dynamics during pepper fruit pericarp development and ripening. Our analyses reveal coordinated changes in chromatin accessibility and histone modifications accompanying transcriptome reprogramming, with changes in H3K27ac closely associated with chromatin accessibility dynamics, and H3K27me3 dynamics potentially contributing to the transition from fruit growth to ripening. Moreover, construction of the transcriptional regulatory network underlying pepper fruit development and ripening suggests that several ripening regulators identified in the climacteric tomato may also play critical roles in governing ripening in the non-climacteric pepper. During ripening, DNA methylation, particularly in the CG and CHG contexts, undergoes global demethylation, especially at promoter regions, which is accompanied by increased chromatin accessibility and likely enhances transcription factor binding activity. We further demonstrate transcriptional and epigenetic regulation of carotenoid and ascorbic acid (vitamin C) biosynthesis pathways. Collectively, this study provides a comprehensive resource for mechanistic dissection and comparative analysis of fruit development and ripening, with practical implications for improving key fruit traits.

plant biology↗

bioRxiv2025

Phosphatidylcholine Metabolism Controls Alveolar Progenitor Renewal and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease marked by alveolar type 2 (AT2) stem cell dysfunction and excessive matrix deposition, with no effective treatments. Recent advances have recognized that AT2 cells act as stem cells, in addition to their role in the production of pulmonary surfactants in the distal alveolar space. We and others have reported a failure of AT2 regeneration and a loss of AT2 cells in IPF. We recently further reported that there is a defect in lipid metabolism in IPF AT2 cells and we discovered a selective loss of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in AT2 cells from IPF, as well as in AT2 cells from bleomycin-injured mice. Pharmacological and genetic experiments confirm that LPCAT1 is required for AT2 cell renewal in 3D organoid assays. AT2 cell-specific Lpcat1 deletion resulted in reduced AT2 renewal, spontaneous lung fibrosis, and heightened susceptibility to bleomycin-induced fibrosis in mice in vivo. Expression-based high-content drug screening with an LPCAT1 knock-in cell line identified several drug families that upregulated LPCAT1 expression. We further confirmed that anti-malarial artesunate and PLA2 inhibitor ONO-RS-082 increased LPCAT1 mRNA expression, promoted AT2 renewal, and attenuated bleomycin-induced lung fibrosis in mice in vivo. Our findings establish LPCAT1 as a critical regulator of AT2 renewal and lipid metabolism in IPF, suggesting that reactivation of LPCAT1 could offer a novel therapeutic strategy for restoring alveolar progenitor function and mitigating lung fibrosis.

cell biology↗

bioRxiv2025

Pocket-based molecule generation with an SE(3)-equivariant language model leads to a potent and selective HPK1 inhibitor with in vivo efficacy

Deep learning shows promise in structure-based drug discovery, yet challenges persist in generating pharmacologically plausible molecules with valid 3D conformation and decent binding mode in the pocket. We introduce SE3-BiLingoMol, an SE(3)-equivariant Transformer for pocket-based 3D molecule generation, addressing two key limitations of existing language-model approaches. First, it uses Geometric Algebra Transformers for SE(3)-equivariant handling of continuous 3D coordinates. Second, a bidirectional attention mechanism mitigates conformational errors accumulated during autoregressive sampling. These innovations enable SE3-BiLingoMol to generate 2D drug-like, 3D geometrically valid molecules with superior binding modes. Validated on DUD-E dataset containing over 100 targets, the model achieved state-of-the-art performance in de novo design and optimization. We applied SE3-BiLingoMol to design potent and selective inhibitors for HPK1, a promising immunotherapy target. Through an iterative human-AI workflow, integrating AI generation with experimental validations (X-ray crystallography, bioassays), we identified Cmpd. 6. This novel tetracyclic compound demonstrates potent HPK1 inhibition, excellent cellular activity, favorable pharmacokinetics, and robust anti-tumor in vivo efficacy as monotherapy and with PD-1 blockade. Our work establishes a sophisticated generative AI framework for 3D molecule design and demonstrates its application in developing cancer immunotherapy. Highlights[bullet] SE(3)-Equivariant Language Model for Molecule Generation: We introduce a dual-channel SE(3)-equivariant language model that supports de novo molecule design and optimization, addressing key challenges in prior language model-based 3D molecule generation approaches. [bullet]Discovery of Potent HPK1 Inhibitors: Application of this model led to the discovery of highly selective HPK1 inhibitors with robust in vivo efficacy, resulting in a promising lead compound. [bullet]AI-Guided Rational Drug Development Paradigm: This work establishes a paradigm for AI-guided rational drug development, showcasing AI as a "co-pilot" that inspires drug designers with novel ideas in an "evidence-based context".

bioinformatics↗

bioRxiv2025

Spatial inheritance patterns across maize ears are associated with alleles that reduce pollen fitness

Significance StatementEarly studies noting uneven spatial distribution of progeny genotypes after pollination support a hypothesis where differences in pollen tube growth rate can bias inheritance. We used computer vision and statistical analysis to show alleles reducing maize pollen fitness are likely to produce statistically significant increasing, decreasing, or curvilinear spatial patterns from the apex of the inflorescence to the base, suggesting that differential pollen tube growth is not the only mechanism at play. SummaryOften, more pollen grains land on recipient flowers than there are ovules to fertilize. Consequently, the haploid male gametophyte engages in post-pollination competition, one way that pollen genotype can influence inheritance. The maize (Zea mays subsp. mays L.) inflorescence (ear), with its elongated stigma and style structures (silks), has a conspicuous spatial heterogeneity, with longer silks at the base of the ear than those at the apex. To evaluate the hypothesis that alleles with reduced pollen fitness influence the spatial distribution of progeny genotypes along the ear, we developed an updated phenotyping platform that maps mutant Ds-GFP kernel phenotypes on the ear via an implementation of the Faster R-CNN machine vision model (EarVision.v2) and a statistical pipeline that evaluates the relationship between kernel position and transmission ratio (EarScape). In our dataset (1384 ears) representing 58 Ds-GFP alleles, none with Mendelian inheritance (0/48) showed any significant pollen-conditioned spatial trend. In contrast, 50% of alleles with a pollen-specific transmission defect (5/10) exhibited significant spatial effects. An insertion into a gene encoding a putative actin-binding protein, base-to-apex gradient1* (bag1*), conditions increased mutant transmission at the ear apex relative to the base. Surprisingly, mutant alleles of two other pollen-expressed genes can generate the opposite pattern, decreased mutant transmission toward the ear apex; and two mutant alleles of the sperm-cell attachment factor, gamete expressed2 (gex2), can produce ears with transmission highest at both base and apex. We conclude that pollen fitness mutants have relatively common but heterogenous effects on the spatial distribution of progeny genotypes.

plant biology↗

bioRxiv2025

Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell homeostasis in idiopathic pulmonary fibrosis and reverses pulmonary fibrosis in mice

Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.

cell biology↗

bioRxiv2025

A spatial atlas of chemoradiation therapy in pancreatic cancer identifies cellular and microenvironmental determinants of persister populations

The molecular pathways involved in the response to radiation therapy in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. We aimed to elucidate the adaptive mechanisms and cellular interactions within PDAC to radiation therapy (RT). We constructed a transcriptomic landscape of the cellular subtypes and spatially resolved neighborhoods from 50 patient samples, including 16 longitudinally matched single cell RNA sequencing and 34 spatial transcriptomics specimens. To resolve shortcomings of cell-type mixtures in spatial data, we developed a novel statistical method called SpaCCI (spatially aware analysis of cell-cell interactions) to profile cell-cell interactions and ligand-receptor enrichment. This revealed CXCL12/TGF{beta}-driven persister cell niches where activated fibroblasts reprogram tumor- associated macrophages and spatially exclude stress-response CD8 T cells after RT. Persister cancer cells displayed transcriptional evidence of recalcitrance to metal-induced cell death pathways of ferroptosis and cuproptosis which were recapitulated in preclinical models. Our study reveals the selective pressures experienced by PDAC following RT that may help provide insight for future multimodal therapeutic strategies.

cancer biology↗

bioRxiv2025

Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

The KCNQ1+KCNE1 potassium channel complex forms the slow delayed rectifier current (IKs) critical for cardiac repolarization. Loss-of-function variants in KCNQ1 and KCNE1 cause long QT syndrome types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1+KCNE3, the structural basis of KCNQ1+KCNE1 remains unresolved. Using cryo-EM and electrophysiology, we determined high-resolution (2.5-3.4 [A]) structures of human KCNQ1+KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing seven "helix-to-loop" transitions in KCNQ1 transmembrane segments. These structural rearrangements: 1) stabilize the closed pore and the conformation of the intermediate voltage-sensing domain, thereby determining channel gating, ion permeation, and single channel conductance; 2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6, stabilizing channel opening; 3) create a fenestration capable of binding compounds specific for KCNQ1+KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for targeted LQTS therapy development.

biophysics↗

bioRxiv2025

Sludge liquefaction and stratification enable ultra-high digestion rate and resource recovery for waste activated sludge treatment

Most of the energy, nitrogen/N and phosphorus/P entering wastewater treatment plants (WWTPs) accumulates in waste activated sludge (WAS). While these resources are theoretically recoverable through anaerobic digestion (AD), conventional sludge AD faces long-standing challenges of low organic loading rate and limited N/P recovery. Here, building on an innovative sludge liquefaction and stratification technique, we present a novel process entitled SPREAD that boasts 10 times higher organic loading rates and recovers 5 folds of N/P resources, relative to conventional sludge AD. We develop an anaerobic digestion database (ADDB) for multi-omics analyses of digestion microbiomes, and pinpoint the mechanism underlying the exceptionally high organic loading rate and remarkable N/P recovery in SPREAD. Importantly, we identify a negative correlation between the Gibbs free energy ({Delta}G) and the relative abundance of methanogens, enabling identification of bottleneck steps for stimulation and augmentation of methanogenic digestion. Our study provides a game-changing technology for the treatment and resource recovery from WAS and opens a new avenue for sustainable management and carbon/energy-neutrality of WWTPs.

bioengineering↗

bioRxiv2025

PepPCBench is a Comprehensive Benchmark for Protein-Peptide Complex Structure Prediction with AlphaFold3

Peptides mediate up to 40% of protein-protein interactions (PPIs), offering high specificity and the ability to target binding sites inaccessible to small molecules, making them promising candidates for drug development. Accurate modeling of protein-peptide complexes is crucial for understanding fundamental biological processes and for advancing peptide-based drug design. However, due to the high conformational flexibility of peptides, predicting their interactions with proteins remains a significant challenge. Recent advancements in artificial intelligence (AI), exemplified by all-atom protein folding neural networks (PFNNs) such as AlphaFold3 (AF3), have expanded predictive capabilities beyond proteins to encompass protein-peptide complexes. Nevertheless, existing evaluations of these methods are often limited in scope and lack systematic, multi-dimensional, and fair comparisons of PFNN performance in protein-peptide complex prediction. Here, we introduce PepPCBench, a comprehensive benchmark framework specifically developed to evaluate AF3s capabilities in predicting protein-peptide complexes. This study utilizes a carefully curated dataset named PepPCSet, which is excluded from the AF3s training or validation sets. This dataset includes 261 protein-peptide complexes with peptide lengths ranging from 5 to 30 residues. Our benchmark results indicate that AF3 outperforms other PFNNs in prediction accuracy and structural validation. However, its performance remains insufficient for practical peptide drug discovery, indicating room for improvement. It is expected that PepPCBench can provide some valuable insights into the enhancement of protein-peptide complex structure prediction and the development of peptide-based therapeutics. The dataset and pipeline protocols are available at https://github.com/zhaisilong/PepPCBench.

bioinformatics↗

bioRxiv2025

A general evolutionary model for the emergence of novel characters from serial homologs

Repeated structures are widespread across multicellular organisms, such as vertebrae, segments, and cell types. These structures, also known as serial homologs, share ancestral states and developmental underpinnings yet also provide the materials for novel adaptive phenotypes. It remains largely unclear why some repeated structures diverge quickly, while others remain constrained. One reason for this uncertainty is the lack of a generalized model for the evolution of repeated structures under different scenarios that links developmental, genetic, and selective constraints to expected and observed patterns of evolution. Here, we introduce a model that incorporates key structural features of gene regulatory networks and selection and investigate how responses to multivariate selection depend on developmental constraints. We show structural features of developmental networks determine when repeats can respond independently to selection and when divergence is limited. Simulations recover broad expectations of phenotypic evolution under directional selection inferred from empirical data. We further show that, in the face of fluctuating selection, strong developmental constraints lead to reduced fitness over time and attenuated fitness fluctuations. Together, our results provide general insights into the principles of evolution of repeated structures and offer a modeling framework for the evolution of a broad range of key phenotypic characters.

evolutionary biology↗

bioRxiv2025

PET imaging of an antisense oligonucleotide in the living non-human primate brain using click chemistry

Determination of a drugs biodistribution is critical to ensure it reaches the target tissue of interest. This is particularly challenging in the brain where invasive sampling methods may not be possible. Here, a pretargeted imaging methodology is disclosed that utilizes bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide in the living brain following intrathecal dosing. A novel PET tracer, [18F]BIO-687, bearing a click-reactive trans-cyclooctene (TCO) was discovered and tested in conjunction with a Malat1 antisense oligonucleotide (ASO) conjugated with a methyltetrazine (MeTz). PET imaging in rats demonstrated that the tracer possesses good kinetic properties for CNS imaging and can react to form a covalent linkage with high specificity to the MeTz-conjugated-ASO in vivo. Further, the amount of tracer reacted by cycloaddition with the Tz was determined to be dependent on the concentration of ASO-MeTz in tissue, as determined through comparison of the imaging signal with the LC-MS of the tissue homogenate. The system was evaluated in cynomolgus monkeys, with PET imaging showing favorable tracer kinetics and specific binding to the ASO in vivo. These results demonstrate that the tracer [18F]BIO-687 can image intrathecally-delivered ASO distribution in the brain, and future studies should leverage this technology to evaluate ASO distribution in human subjects to study distribution. One Sentence SummaryDistribution of an intrathecally administered antisense oligonucleotide can be imaged using a pretargeted approach in the living brains of non-human primates.

neuroscience↗

bioRxiv2025

Advanced Manufacturing of Coil-Reinforced Multilayer Vascular Grafts to Optimize Biomechanical Performance

Small diameter vascular grafts require a complex balance of biomechanical properties to achieve target burst pressure, arterial compliance-matching, and kink resistance to prevent failure. Iterative design of our multilayer vascular was previously used to achieve high compliance while retaining the requisite burst pressure and suture retention strength for clinical use. To impart kink resistance, a custom 3D solution printer was used to add a polymeric coil to the electrospun polyurethane graft to support the graft during bending. The addition of this reinforcing coil increased kink resistance but reduced compliance. A matrix of grafts were fabricated and tested to establish key structure-property relationships between coil parameters (spacing, diameter, modulus) and biomechanical properties (compliance, kink radius). A successful graft design was identified with a compliance similar to saphenous vein grafts (4.1 {+/-} 0.4 %/mmHgx10-2) while maintaining comparable kink resistance to grafts used currently in the clinic. To explore graft combinations that could increase graft compliance to match arterial values while retaining this kink resistance, we utilized finite element (FE) models of compliance and kink radius that simulated experimental testing. The FE-predicted graft compliance agreed well with experimental values. Although the kink model over-predicted the experimental kink radius values, key trends between graft parameters and kink resistance were reproduced. As an initial proof-of-concept, the validated models were then utilized to parse through a targeted graft design space. Although this initial parameter range tested did not yield a graft that improved upon the previous balance of graft properties, this combination of advanced manufacturing and computational framework paves the way for future model-driven design to further optimize graft performance. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/633374v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@faca56org.highwire.dtl.DTLVardef@f9dccforg.highwire.dtl.DTLVardef@fbb5corg.highwire.dtl.DTLVardef@d5c021_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Single amino acid mutations in histone H3.3 illuminate the functional significance of H3K4 methylation in plants

Although numerous data have revealed correlations between histone modifications and chromatin activities such as transcription, proofs of their causal importance in gene expression regulation remain limited. Sequence variants within each histone family expand chromatin diversity and may carry specific modifications, further raising the question of how histone modifications coordinate with different variants. Here, we investigate the regulatory role of lysine 4 (K4) of Arabidopsis histone H3 by point mutating K4 in two major H3 variants, H3.1 and H3.3. K4 is essential for the function of H3.3 but not H3.1 in plant development. H3K4 methylation levels decrease drastically upon K4 mutation in H3.3, and the associated transcriptome changes are similar to those observed in a mutant lacking SDG2, a major enzyme responsible for depositing H3K4 trimethylation (H3K4me3). Moreover, H3.3K4 and SDG2 are required for de novo gene activation and RNA Pol II elongation. H3K4 methylation is preferentially accumulated on H3.3 compared to H3.1, likely due to the close association of the H3.3 deposition and H3K4 methylation machineries. Furthermore, we reveal the diverse impacts of K4 nearby residue mutations on H3K4 methylation and H3.3 function. Collectively, these findings suggest that H3.3 serves as a critical substrate for H3K4 methylation, which is important for gene expression regulation. In addition, our work highlights the potential of using plants as a platform to directly investigate the importance of histone amino acids and their modifications.

plant biology↗

bioRxiv2024

Computational constraints underlying theemergence of functional domains in thetopological map of Macaque V4

V4, an intermediate visual area in the ventral visual stream of primates, is known to contain neurons tuned to color, complex local patterns, shape, and texture. Neurons with similar visual attribute preferences are closely positioned on the cortical surface, forming a topological map. Recent studies based on multielectrode arrays and calcium imaging revealed the macaque V4 has neuronal columns tuned to specific natural image features, and these columns are clustered into various functional domains. There are domains tuned to attributes generally associated with object surface properties such as texture or color, as well as domains associated with the shape and form of object boundaries reminiscent of the blobs and inter-blobs in the primary visual cortex. Here, we explored the computational constraints underlying the development of the V4 topological map. We found that the map learned based on self-organizing principles constrained by neuronal columns tuning and retinotopy position can account for many characteristics of the observed V4 map, including the interwoven organization of texture and shape processing clusters. These anatomical clustering, with the implied local recurrent connectivity, might facilitate a modular parallel processing of surfaces and boundaries of objects along the ventral visual system.

neuroscience↗

bioRxiv2024

Single-dose avian influenza A(H5N1) Clade 2.3.4.4b hemagglutinin-Matrix-M nanoparticle vaccine induces neutralizing responses in nonhuman primates

With the recent rise in cases of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b infection in humans and animals, there is an associated increase in the risk of human-to-human transmission. In this study, we characterize recombinant A(H5N1) A/American Wigeon/South Carolina/22/000345-001/2021 (A/AW/SC/2021) clade 2.3.4.4b vaccine. Purified recombinant A/AW/SC/2021 HA trimers upon formulation with Matrix-M adjuvant, saponin-cholesterol-phospholipid icosahedral particles, non-covalently anchored to the vertices of the Matrix-M forming A(H5N1) HA-Matrix-M nanoparticles (H5-MNPs). In naive mice, two intranasal (IN) or intramuscular (IM) doses of A/AW/SC/2021 H5-MNP vaccine induced robust antibody- and cell-mediated immune responses, including neutralizing antibodies against A(H5N1). In non-human primates (NHPs) primed with seasonal influenza vaccine, a single IM or IN dose of the A/AW/SC/2021 H5-MNP vaccine induced geometric mean serum A(H5N1) clade 2.3.4.4b pseudovirus neutralizing titers of 1:1160 and 1:54, respectively; above the generally accepted seroconverting neutralizing titer of 1:40. Immunization with H5-MNP vaccine induced antibody responses against conserved epitopes in the A(H5N1) HA stem, vestigial esterase subdomain, and receptor binding site. This novel A(H5N1) H5-MNP IN and IM vaccine was immunogenic in rodents and NHPs as a potential A(H5N1) pandemic single-dose vaccine.

microbiology↗

bioRxiv2024

Land plant-specific H3K27 methyltransferases ATXR5 and ATXR6 control plant development and stress responses

The colonization of land by plants relies on numerous evolutionary innovations crucial for terrestrial adaptation. These include advances in sexual reproduction and the ability to properly respond to various environmental stresses, which involve precise control of their regulatory genes. A notable genetic innovation in land plants is the emergence of histone lysine methyltransferases ATXR5/6, which specifically catalyse the repressive histone H3 lysine 27 monomethylation (H3K27me1). However, the significance of the evolution of these enzymes in land plants remains unclear. In this study, we investigate the importance of ATXR5/6 by generating strong atxr5;atxr6 double mutants in Arabidopsis. Our results show that ATXR5/6 are essential for plant reproductive development and play a critical role in supporting normal plant growth by repressing the transcription of stress responsive genes. In addition, ATXR5/6 are necessary for maintaining H3K27 trimethylation (H3K27me3), likely by providing H3K27me1 as a substrate for further methylation. We also demonstrate that the function of ATXR5/6 in regulating reproductive development and responsive genes is conserved in the monocot rice. We propose that land plants may have evolved ATXR5/6 to assist in the transcriptional regulation necessary for terrestrial adaptation.

plant biology↗