Biology subjects

Xu, C.

Publications and source records attributed to Xu, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Metagenomic analysis of the effects of European bison Bison bonasus (Linnaeus, 1758) presence on soil community structure and function in West Blean and Thornden Woods, Kent

The reintroduction of extinct or endangered species to restore ecosystem function is an essential aspect of rewilding. The Wilder Blean Project at West Blean and Thornden Woods in Canterbury, UK, is committed to rewilding natural processes and enhancing biodiversity in one of England's oldest and largest areas of ancient woodland. The introduction of European bison (Bison bonasus) is an important part of the project. However, how the reintroduction of large herbivores influences local biodiversity and ecosystem functions during the early stages of rewilding remains poorly understood. Soil samples were collected from the same sampling sites before and two years after bison were reintroduced and profiled by metagenomic sequencing using Oxford Nanopore Technologies sequencing platforms. The results showed that the alpha diversity of soil organisms did not change significantly before and after the introduction of European bison, while beta diversity showed modest shifts in community composition. The relative abundance of some nitrogen-fixing and photosynthetic microbial genera showed declines in the 2024 Bison Area, while the mycorrhizal fungus genus Rhizophagus was significantly less abundant than in the 2024 Control Area. Despite relatively stable taxonomic diversity, functional composition differed significantly between the 2022 and 2024 Bison areas and among the 2024 rewilding treatments, revealing a decoupling between taxonomic diversity and functional composition. Amino acid synthesis pathways and carbon metabolism pathways were significantly enriched. These findings highlight the potential of long-read Oxford Nanopore metagenomics to reveal functional shifts that may not be apparent from taxonomic diversity alone. Although these early-stage responses cannot yet predict long-term rewilding trajectories, continued longitudinal monitoring integrating microbial, soil physicochemical, and ecosystem-level measurements will be essential to determine the persistence and ecological significance of these functional shifts.

ecology↗

bioRxiv2026

An Integrated Spatially Resolved Mechanistic Model of Hierarchical Auxin-Cytokinin-Ethylene Crosstalk Underlying Root Growth Inhibition in Arabidopsis

Decoding how plants integrate multiple hormone signals to coordinate growth requires tools capable of resolving pathway interactions at cellular resolution in living tissue. Here we present ACE (Auxin-Cytokinin-Ethylene) and ACE2, proof-of-concept single-locus reporters to simultaneously capture activity of multiple hormones. Deploying ACE alongside well-established reporters, exogenous hormone treatments, and reverse-genetic perturbations of hormone biosynthesis, signaling, and transport in three-day-old etiolated Arabidopsis seedlings, we dissect the spatiotemporal hierarchy governing primary root elongation and root apical meristem (RAM) size. We demonstrate that both ethylene- and cytokinin-triggered root growth inhibition involve a boost of TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS1 (TAA1)-mediated auxin biosynthesis and AUXIN RESISTANT1 (AUX1)-dependent auxin redistribution. Two spatially distinct auxin responses underlie the respective root growth effects: ethylene expands TAA1-dependent auxin biosynthesis from the root vasculature into the epidermis and promotes AUX1-mediated auxin import into the transition and elongation zones to inhibit cell elongation, while cytokinin confines ethylene-dependent TAA1-boosted activity to the vasculature and drives auxin accumulation in lateral root cap cells to reduce RAM size. Together, these data establish a reciprocal regulatory loop between these hormones, positioning ethylene as a convergence node in auxin-cytokinin crosstalk, and cytokinin as a modulator of the ethylene-auxin interaction. Critically, the changes in cross-activated reporter patterns described for different genetic backgrounds, alongside quantitative assessment of hormone-specific inhibition of the mutants growth, were consistent with the multi-hormone network established over two decades of research, and added cell-type-resolved spatial detail and a proposed hierarchy for the etiolated seedling root. Finally, a second-generation reporter, ACE2, overcomes key technical limitations of ACE, expanding the platforms capacity toward a higher-order multi-hormone monitoring system. These resources expand the Arabidopsis genetic toolkit and provide a generalizable framework instrumental for dissecting multi-hormone signaling hierarchies at the cellular level.

plant biology↗

bioRxiv2026

Cross-attention and language models reveal the interpretability of functional predictions for the human olfactory receptor family

The attention mechanism offers the possibility for data-driven discovery of biological principles. However, for important protein families such as human olfactory receptors, the extent to which attention can associate with biologically meaningful key regions lacks systematic validation. In this study, using human olfactory receptors (ORs) as a model, we constructed CrossVOI, a VOC-OR interaction prediction framework based on protein language models and cross-attention, achieving predictive performance superior to existing methods. Furthermore, we systematically analyzed the attention distributions of CrossVOI and found that attention not only focused on ligand-binding interfaces and evolutionarily conserved sites, but also to some extent identified certain dynamically regulated regions. In summary, we propose CrossVOI, currently the best-performing framework for VOC-OR interaction prediction, and analyze the interpretability of the attention mechanism for human ORs. This study provides insights into the interpretability of protein function prediction methods and is expected to contribute to the exploration of attention mechanisms in biological mechanisms, and provide assistance for large-scale screening and mechanistic analysis of olfactory receptors.

bioinformatics↗

bioRxiv2026

Functional and evolutionary insights into the emerging tet(X4)-carrying non-O1/O139 Vibrio cholerae from retail pork

The tigecycline resistance gene tet(X4) is prevalent in Enterobacteriaceae, particularly in Escherichia coli. To our knowledge, no study has reported the dissemination dynamics of tet(X4) in Vibrio spp. Herein, we isolated and characterized a first tet(X4)-positive non-O1/O139 Vibrio cholerae isolate from retail pork. Genomic sequencing identified a novel tet(X4) variant in the V. cholerae chromosome, harboring a G568A nucleotide substitution that resulted in an Ala190Thr (A190T) amino acid substitution in Tet(X4). While this Tet(X4)-A190T variant conferred lower phenotypic resistance to tetracyclines (including tigecycline) than the wild-type Tet(X4), its overall catalytic efficiency against these antibiotics was paradoxically enhanced despite a reduced substrate affinity. Genomic comparisons revealed that two copies of ISCR2 flanked the variant gene, and the structure was ISCR2-hp-hp-abh-tet(X4)G568A -ISCR2, which is highly homologous to the reported E. coli plasmids carrying tet(X4). In addition, it confirmed the presence of an ISCR2-mediated circular intermediate, proving this modules capacity for horizontal transfer of the tet(X4)G568A variant. Furthermore, the ISCR2-tet(X4) genetic structure carrying the G568A substitution was integrated within a chimeric SXT/R391-like integrative and conjugative element (ICE), which is also serving as a vehicle for genetic dissemination. As per our knowledge, this is the first report on the emergence of SXT/R391-like ICE carrying tet(X4) in Vibrio strains. Our finding demonstrates that the clinically relevant tigecycline resistance gene tet(X4), previously confined mainly to Enterobacterales from humans and livestock, is now actively spreading into environmental Vibrio populations. This cross-species transfer highlights a previously underappreciated ecological and public health concern in aquatic ecosystems.

microbiology↗

bioRxiv2026

Biological upgrading of C1-C2 products of electrocatalytic CO 2 reduction to C4-C6 carboxylates

BackgroundMicrobial chain-elongation by Clostridium kluyveri using the products (acetate and ethanol) derived from the electrocatalytic CO2 reduction reaction (CO2RR) represents a unique sustainable strategy for producing C4-C6 chemicals from CO2. However, direct integration of electrocatalytic effluents with anaerobic bioprocesses is often impeded by the physiological incompatibility between electrocatalytic product streams and microbial metabolism. Specifically, CO2RR effluents commonly contain formate, which cannot be utilized by C. kluyveri for chain elongation and therefore reduces the overall carbon efficiency of CO2 conversion to C4-C6 chemicals. Moreover, both formate and the elevated phosphate concentrations typical of electrochemical reaction solutions may inhibit microbial growth. ResultsWe show that formate at concentrations of up to 50 mM did not inhibit the growth of or the chain elongation by C. kluyveri. Based on this finding, we developed a modular two-step bioprocess. In the first step, the acetogen Clostridium ljungdahlii converts formate in CO2RR product mixtures into acetate, thereby generating additional substrates for second-step C. kluyveri-driven chain elongation, thus increasing the CO2RR carbon-conversion efficiency to C- C6 chemicals. To address the issue of C. ljungdahliis inhibition by high phosphate concentrations in electrocatalytic solutions, we explored the use of C. ljungdahlii biofilms for the first, i.e. the formate-conversion, step. C. ljungdahlii biofilms exhibit tolerance to concentrated electrolytes, enabling the conversion of up to 50 mM formate in CO2RR solutions. ConclusionsThe demonstrated two-step process constitutes the basis for the development of a robust and carbon-efficient biological process for the scalable upgrading of C1-C2 CO2RR products into higher-value C4-C6 chemicals.

synthetic biology↗

bioRxiv2026

Modular counterplays shape condensation and signaling of chimeric antigen receptor

Chimeric antigen receptor-engineered T (CAR T) cell therapy has achieved remarkable clinical efficacy against hematological malignancies but exhibits limited therapeutic outcomes in solid tumors, where immune checkpoint signaling is highly active. Here, we demonstrate that the second-generation CD28-CD3{zeta} (28Z) CAR undergoes liquid-liquid phase separation with the Src-family kinase LCK to assemble a signaling condensate crucial for CAR activation. PD-1, but not LAG3 or CTLA4, disrupts these CAR-LCK condensates through competitive binding to CAR rather than through its canonical phosphotase-dependent inhibitory pathway. Incorporation of a CD3{varepsilon} cytoplasmic module into the CAR introduces additional LCK interactions that reinforce CAR-LCK condensation, thus limited PD-1 incorporation and stabilize signalosome assembly. Consequently, the CD3{varepsilon}-engineered CAR (E-CAR) resists PD-1-mediated condensates disassembly, preserves immunological synapse organization, and sustains proximal signaling following PD-L1 engagement. E-CAR T cells are therefore resistant to PD-1-mediated functional suppression and maintain potent antitumor activity against PD-L1-positive solid tumors. Together, these findings identify disruption of CAR signaling condensates as a previously unrecognized mechanism of PD-1-mediated inhibition and establish CD3{varepsilon} modular signalosome engineering as a rational engineering strategy to overcome immune checkpoint suppression.

immunology↗

bioRxiv2026

Catch-bond engineering surpasses high-affinity maturation for T cell receptor therapies against solid tumors

The sensitivity of T cell receptors (TCRs) has traditionally been attributed to their affinity, a principle that has long underpinned both T cell biology and TCR engineering. Currently, high-affinity maturation remains the predominant strategy employed to enhance TCR sensitivity; however, this approach has been associated with severe off-target toxicities in clinical settings. In this study, using the only FDA-approved TCR-T therapy as a clinical reference, we demonstrate that force-induced catch bonds, rather than static affinity, primarily determine TCR sensitivity and facilitate the development of more effective TCR engineering strategies. Among polar and charged amino acids, histidine was determined to be the most effective residue for pinpointing engineering hotspots. TCRs engineered to form catch bonds exhibited superior performance compared to the FDA-approved TCR subjected to high-affinity maturation, improving the efficacy of TCR-T cell therapies against solid tumors without eliciting off-target toxicity or alloreactivity. Mechanistically, a correlation was observed between TCR sensitivity and the strength of catch bonds, whereas no such relationship was found with affinity. The duration of T cell-tumor cell interactions, immunological synapse formation, and the intensity of subsequent signaling are governed by catch bonds rather than by affinity. Structural and computational investigations have demonstrated that force-induced reconfiguration of the ligand-receptor interface, along with the formation of a novel hydrogen bond network, augments the specificity of interactions between the TCR and antigenic peptides. Furthermore, bispecific T cell engagers utilizing the TCR scaffold also formed catch bonds with tumor antigens, indicating intrinsic mechanosensory properties of the extracellular domains of TCRs and suggesting a novel therapeutic modality based on catch-bond-engineered TCRs.

immunology↗

bioRxiv2026

High-resolution transcriptomic profiling of Arabidopsis thaliana across a 37°C-40°C thermal gradient

Thermal adaptation is critical for organismal viability, with acquired thermotolerance (AT) in Arabidopsis thaliana typically conferred by acclimation temperatures between 34{degrees}C and 37{degrees}C, while acclimation at 40{degrees}C fails to protect against lethal heat stress. To elucidate the transcriptional mechanisms underlying the loss of AT at higher temperatures we performed RNA-seq profiling of Arabidopsis seedlings across a single-degree thermal gradient from 37{degrees}C to 40{degrees}C. Our analysis reveals that all of these temperatures result in a robust heat shock response, characterized by the upregulation of genes involved in protein folding and stress responses. However, each temperature elicits a distinct transcriptional signature. These findings demonstrate that temperature-specific fine-tuning of the heat shock response occurs within this narrow range and that these differences may dictate the successful acquisition of thermotolerance. This dataset provides a valuable resource for understanding the molecular architecture of heat-stress adaptation and the distinct transcriptional states associated with different thermal regimes.

plant biology↗

bioRxiv2026

Neuronal stop-codon readthrough is associated with ribosome pausing and alters protein localization in Drosophila

Stop-codon readthrough (RT) diversifies proteomes and is particularly prominent in neurons, suggesting its importance in nervous systems. However, the regulatory logic that specifies neuronal RT and the structural and cellular consequences of the resulting C-terminal protein extensions remain poorly understood. Here we leverage neuron-specific ribosome profiling datasets in Drosophila to construct an in vivo atlas of 163 neuronal RT transcripts. Sequence- based modeling distinguished RT from non-RT transcripts and highlighted an extended post-stop region enriched for stable predicted RNA structures. Beyond these cis-associated features, ribosome-footprint analysis revealed pronounced stop-codon pausing on RT transcripts, accompanied by upstream periodic peaks from the stop codon consistent with ribosome queuing. At the protein level, neuronal RT appended polypeptides enriched with polar residues and intrinsically disordered regions (IDRs). Finally, an in vivo dual-color reporter showed that RT of the RNA-binding protein Bru3 alters localization from the nucleus to cytoplasmic granules. Together, our results suggest that neuronal RT is associated with structured post-stop RNA regions that reshape termination dynamics and can produce IDR-rich C-terminal protein extensions with distinct subcellular localization.

molecular biology↗

bioRxiv2026

Integrin-engaged Cellular Patches Mechanically Impose a Mitochondrial Respiratory Bottleneck to Suppress Cancer Cell Motility

The nanoscale organization of cell-adhesive ligands is increasingly recognized as a determinant of cell behavior, yet whether it directly regulates cellular metabolism remains unclear. Here we show that supramolecular clustering of integrin-binding ligands regulates mitochondrial respiratory capacity through integrin-mediated mechanotransduction. Supramolecular ligand clustering induces integrin redistribution and cytoskeletal remodeling, leading to mitochondrial reorganization and a selective constraint on oxidative phosphorylation. This respiratory limitation functionally constrains tumor cell migration and invasion and cannot be overcome by restoring cytoskeletal contractility, whereas replenishing mitochondrial metabolic substrates effectively rescues motility. In a HeLa xenograft model, the integrin-binding supramolecular system suppresses tumor growth and reduces extracellular matrix deposition. These findings identify mitochondrial respiratory capacity as a critical downstream effector of integrin mechanosignaling and establish extracellular ligand organization as a previously unrecognized driver of mechanically encoded metabolic regulation.

biophysics↗

bioRxiv2026

Transfer learning reveals species-specific olfactory preferences in Diptera and informs pest management strategies

The interaction between volatile organic compounds (VOCs) and odorant receptors (ORs), termed VOI, constitutes the molecular basis for species to recognize chemical information in the environment. Characterization of subtle differences in VOI relationships among closely related species is crucial for understanding the rapid evolution of ORs and for identifying species-specific chemical cues relevant to pest management. However, progress in this field has been constrained by both the scarcity of experimental data and limitations in computational prediction accuracy. To address this, we developed a virtual screening-enhanced transfer learning strategy that integrates large-scale molecular docking data with sparse functional experimental data. The resulting VOI prediction model was validated through functional experiments on the pest species Bactrocera dorsalis, demonstrating its cross-species predictive capacity. Using this model, we investigated the relationship between ecological niches and olfactory sensitivity in Diptera insects from multiple perspectives, with an emphasis on patterns that may inform pest behavioral research. The models predictive reliability was further supported by its consistency with known olfactory trends: it recapitulated the preferential responses of fruit flies and mosquitoes to esters and aromatics, respectively, and reproduced the previously reported negative correlation between olfactory and visual capacities in Drosophila. As a proof-of-concept application, we compared hematophagous and non-hematophagous mosquitoes, revealing overlapping chemical spaces but distinct patterns in their specifically recognized compounds. This study provides a reliable VOI prediction framework that reveals species-level olfactory preference patterns in Diptera, offering a computational pipeline to accelerate the discovery of behaviorally active compounds for species-specific pest monitoring and control.

bioinformatics↗

bioRxiv2026

Aberrant chromatin looping by NUP98-HOXA9 is constrained by CTCF and facilitated by cohesin

The acute myeloid leukemia (AML) fusion protein NUP98-HOXA9 (NHA9) drives leukemogenesis by promoting aberrant chromatin loop formation through phase separation, yet the mechanisms underlying these interactions remain unclear. To address this, we dissect the interplay between NHA9 and individual loop extrusion factors using in situ Hi-C, CUT&RUN, RNA-seq, and Auxin-inducible degradation of CTCF or RAD21. CTCF was found to be dispensable for NHA9 loop formation, although CTCF binding constrained a subset of loops that emerged only upon CTCF depletion. In contrast, cohesin played a distance-dependent role where short-range NHA9 loops formed independently of RAD21, while long-range loops were strongly cohesin-dependent. Despite this requirement, RAD21 showed minimal enrichment at NHA9 loop anchors, indicating that NHA9 does not function as a canonical cohesin barrier. Instead, these findings support a non-canonical model in which cohesin transiently facilitates interactions between distal NHA9-bound loci, which are subsequently stabilized through NHA9 phase separation. Together, this work reveals a distinct mechanism of oncogenic chromatin looping in which NUP98-HOXA9 cooperates with canonical loop extrusion machinery to reprogram genome architecture in AML.

Molecular Biology↗

bioRxiv2026

A human developmental and adult brain atlas benchmarks dopaminergic stem cell models and cell therapy candidates

Parkinsons disease (PD) is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons1. Stem cell-derived mDA neurons hold promise for disease modelling2,3 and are currently in clinical trials for cell replacement therapy4-6. However, systematic benchmarking has been limited by the lack of a unified high-resolution reference and methods that quantify incomplete or mixed lineage specification in vitro7. We establish a single-cell and spatial atlas of the human developing diencephalon-midbrain-hindbrain axis resolving 93 cell subtypes, including 39 lacking prior single-cell characterization and 4 entirely novel populations. Using this atlas as a reference, we integrate 19 hPSC-derived mDA datasets, both published2,8-25 and unpublished, to build the Human Dopaminergic Neural Atlas (HDNA) spanning 2D, 3D, and graft models, including those used in clinical trials. To classify cells and quantify lineage fidelity, we develop CapybaraBrain, a marker-driven non-negative decomposition framework that assigns each cell continuous identity scores across all 93 developmental programs, enabling systematic discrimination of discrete, transitioning, and cross-lineage hybrid states26. We uncover a pervasive landscape of off-target populations reflecting relaxed transcriptional boundaries in vitro, including a previously unrecognized TH-PITX2 midbrain neuronal population, and we validate atlas-predicted latent lineage plasticity through inducible genetic fate mapping in mouse models. We further define maturation-associated transcriptional programs by harmonizing adult mDA subtype atlases, revealing that dopaminergic identity and maturation are partially decoupled across protocols. Finally, projecting PD patient-derived tri-cultures onto the HDNA uncovers genotype- and cell-type-specific transcriptional dysregulation. Together, these integrated atlases and computational framework establish a unified standard for benchmarking differentiation fidelity, exposing off-target states, and guiding next-generation PD models and cell therapies.

Developmental Biology↗

bioRxiv2026

Heat stress induces persistent placental dysfubction and fetal growth restriction via the ERS-MAPK-apoptosis axis

Maternal heat stress (HS) is an emerging risk factor for adverse pregnancy outcomes, yet how gestational heat exposure causes persistent placental dysfunction remains unclear. In the present study, we established a murine HS model (38.5{degrees}C, 2.5 h/day, E0-E12.5) followed by thermal recovery to E17.5. HS reduced fetal weight during early gestation and caused persistent fetal growth restriction after recovery, despite partial placental weight restoration. Histological analyses revealed early reductions in the junctional and labyrinth zones, followed by sustained labyrinthine deficiency and compensatory junctional zone expansion. Consistently, HS impaired placental vascularization, with reduced vessel length and area, decreased CD31 and -SMA abundance, and altered angiogenesis-related gene expression. HS also triggered oxidative stress, weakened antioxidant capacity, disrupted anti-inflammatory signaling, reduced tight junction protein expression, and compromised barrier integrity. Mechanistically, HS induced excessive endoplasmic reticulum stress, accompanied by increased CHOP, phosphorylated ERK, and cleaved caspase-3. In conclusion, our data unveil a heat-induced placental insufficiency program that restricts fetal growth through vascular, redox, barrier, and ERS-MAPK-apoptotic remodeling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/730306v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c73748org.highwire.dtl.DTLVardef@fe7b3eorg.highwire.dtl.DTLVardef@14d5e6dorg.highwire.dtl.DTLVardef@72572f_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2026

(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both {micro}- and {delta}-opioid receptors in astrocytes. Chronic stress reduces {micro}-{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased {micro}-{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the {micro}-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic {micro}-{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.

neuroscience↗

bioRxiv2026

DOC Release and Physiological Response of Zostera marina Under Light and Nutrient Gradients

The seagrass bed, known as an important blue carbon ecosystem, not only has robust carbon sequestration capacity, but also releases the fixed organic carbon into the water column in the form of dissolved organic carbon (DOC). Zostera marina is the main constructive species of the seagrass meadows of northern China, but the regulatory mechanism of its DOC release in response to environmental changes still remains unclear. Adult Z. marina was used as the experimental material in this research to investigate the effects of light intensity and nutrient concentration on its DOC release, and to observe its physiological responses. By using a total organic carbon (TOC) analyzer, dissolved oxygen monitoring, transmission electron microscopy (TEM), and transcriptome analysis, we explored how light and nutrients affect DOC release and the underlying physiological mechanisms in Z. marina. The results showed that both elevated light intensity and short-term nutrient enrichment promoted organic carbon release from Z. marina to the environment. Increased light enhanced the net primary productivity (NPP) of Z. marina, while the magnitude of DOC release increased more than NPP itself. Nutrient enrichment reduced NPP while raising the proportion of DOC released by Z. marina. Transcriptome analysis showed that nutrient enrichment significantly affected pathways, including flavonoid biosynthesis and fatty acid degradation. This study demonstrated that changes in light and nutrients can significantly influence DOC release and carbon allocation patterns in Z. marina, providing a theoretical basis for blue carbon accounting and ecological restoration evaluation in seagrass beds.

plant biology↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

The Magnaporthe oryzae Effector AvrPii Attenuates Rice Immunity by Targeting the Calcium-Associated ANK Protein AVIN8

Rice blast, caused by the fungus Magnaporthe oryzae, poses a severe threat to global rice production. Although numerous M. oryzae effectors have been identified, the molecular mechanisms remain poorly understood. The effector AvrPii triggers ETI upon recognition by NLR receptor Pii and has been shown to target host exocytosis and oxidative metabolic pathways to suppress immunity. Here, we identify AVIN8 (AvrPii-interacting protein 8) as a new target of AvrPii. AVIN8 is an ankyrin-repeat (ANK) protein localized to the plasma membrane and nuclear envelope, with sequence similarity to known ANK calcium channels. AVIN8 expression is induced during early M. oryzae infection. Overexpression of AVIN8 enhances blast resistance, whereas its silencing increases susceptibility. AVIN8 promotes chitin-triggered ROS production in a Ca2+-dependent manner. In contrast, AvrPii impairs Ca2+ influx and chitin-triggered ROS burst. Our findings reveal a virulence strategy in which M. oryzae effector AvrPii hijacks the Ca2+ influx-associated ANK protein AVIN8 to suppress early calcium and PTI signaling in rice.

plant biology↗