Biology subjects

Guo, J.

Publications and source records attributed to Guo, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease

MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. An endosomal recycling pathway regulated by the interaction of SORL1 with retromer is pathogenically disrupted in AD. Here we test the hypothesis, that the pathway might drive the neurodegenerative process, via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling SORL1's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, when taken together with other findings the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.

neuroscience↗

bioRxiv2026

Chromosome-level Atlantic switchgrass assemblies reveal a supernumerary B-Chromosome with transcriptional and evolutionary impacts

Supernumerary B-Chromosomes are extra genetic elements that frequently deviate from Mendelian inheritance to ensure their own survival. Their evolutionary origins and biological impacts within natural plant populations remain largely unexplored. Switchgrass (Panicum virgatum) is a model for studies of local adaptation, but reliance on a single reference genome has limited the detection of lineage-specific genomic content. We generated chromosome-level genome assemblies from the diverged Atlantic switchgrass subpopulation and discovered a previously undetected genomic element: a ~34 Mb supernumerary B-Chromosome, validated by Hi-C contact mapping and long-read depth, which indicates two to four B copies per nucleus. The B-Chromosome has a bipartite architecture including a gene-rich, single-copy proximal region (~8 Mb) and a repeat-rich, gene-poor distal region (~27 Mb) dominated by LTR/Ty3 (Gypsy) elements and punctuated by Mutator TIR peaks. High-resolution mapping reveals a highly rearranged chimera of fragments from multiple autosomes, biased toward the N-subgenome. Intact LTR retrotransposons on the B-Chromosome are younger than those on the A-Chromosomes, especially in its distal region, consistent with a B-Chromosome that arose and expanded within the Atlantic lineage. Population screening and phylogenetic analysis indicate that the B-Chromosome is largely restricted to the Atlantic subpopulation and likely has a single origin. In a typical family, 70% of open-pollinated progeny of B-positive maternal plants were B-positive, with substantial variation among families. Finally, B-Chromosome presence is associated with expression differences in A-Chromosome genes that differ between genetic backgrounds. Together, our results show how accessory chromosomes contribute to the evolutionary and genomic diversity of natural plant populations.

genomics↗

bioRxiv2026

HighFold-Lasso: Topology-Guided Prediction of Lasso Peptide Structures Using AlphaFold3

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked topology, in which the C-terminal tail is threaded through an N-terminal macrolactam ring formed by an isopeptide bond. This unique topology often confers high thermal stability and resistance to proteolytic degradation. However, the isopeptide linkage, threaded topology, and class-specific disulfide connectivity make lasso peptide structures difficult to reconstruct reliably using general-purpose structure prediction models. Here, we developed HighFold-Lasso, which combines custom covalent connectivity with lasso scaffold-guided adaptive low-noise initialization to enable conditional structure generation guided by lasso conformational priors. On a test set of 52 experimentally determined structures, HighFold-Lasso achieved a 100% lasso topology success rate, with a mean RMSD C-alpha of 1.942 Angstrom for the ring-loop region and 2.375 Angstrom for the full peptide. The framework supports modeling of the four classical lasso peptide classes (I-IV) and can represent noncanonical amino acids, providing computational support for structure-function studies and molecular engineering of lasso peptides.

bioinformatics↗

bioRxiv2026

Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS), the most prevalent chromosomal microdeletion disorder in humans (incidence ~1 in 4,000 live births), arises from hemizygous deletions of a 1.5-3.0 Mb region on chromosome 22. Notably, 20-30% of individuals with 22q11DS develop schizophrenia (SCZ) by early adulthood, making 22q11DS one of the strongest genetic risk factors for SCZ. However, the mechanisms by which the 22q11.2 deletion perturbs neuronal function and drive psychotic manifestations in 22q11DS remain poorly defined. In this study, we generated human 2D cortical neurons and 3D cortical organoids from induced pluripotent stem cells (iPSCs) derived from clinically well-characterized individuals with 22q11DS. Cellular and electrophysiological analyses revealed that 22q11DS neurons exhibit hyperexcitability, reduced glutamatergic synaptic transmission, and impaired homeostatic synaptic plasticity, which are pathophysiological hallmarks that may be relevant to the clinical, cognitive, and psychophysiological profiles of patients. Transcriptomic profiling of neurons and synaptosomes from 22q11DS cortical organoids uncovered dysregulated immune pathways and synaptic gene networks. Integrative mRNA-microRNA network analysis identified synergistic downregulation of hsa-miR-185-5p and hsa-miR-128-3p at synapses, driving aberrant regulation of immune and synaptic transcripts. Experimental knockdown of these microRNAs in control neurons recapitulated the molecular and functional phenotypes of 22q11DS neurons, thereby establishing a mechanistic link to synaptic dysfunction and impaired plasticity. Collectively, these findings delineate a multimodal mechanistic framework that bridges genetic vulnerability, synaptic pathology, and psychosis penetrance in 22q11DS, positioning dysregulated synaptic microRNAs as nodal regulators of neurodevelopmental networks and potential therapeutic targets.

neuroscience↗

bioRxiv2026

A molecular clutch governs stator engagement and flagellar torque

Motile bacteria must continuously adjust their motility to navigate and colonize diverse environments, including mammalian hosts, yet the underlying mechanisms remain poorly understood. Here, using in situ single-particle cryo-electron microscopy, we determine near-atomic structures of the flagellar motor in the Lyme disease spirochete Borrelia burgdorferi and uncover a novel mechanism for controlling torque generation. We identify a distinct neutral state in which individual torque-generating MotA5B2 stator complexes remain incorporated in the motor but adopt an extended, tilted conformation disengaged from the rotor. Two conserved flagellar proteins, FliL and FlcA, form a transmembrane scaffold that retains 16 stator complexes, while FapA, a newly identified multidomain flagellar protein, binds the cytoplasmic base of the stator complex and stabilizes its rotor-disengaged conformation. Strikingly, rotor-engaged and rotor-disengaged stators coexist within individual motors, demonstrating that stator retention and torque engagement are separable states. Our findings establish a motor-retained neutral stator state and reveal a molecular-clutch mechanism that independently controls the engagement of individual stator units with the rotor, enabling rapid and precise regulation of flagellar torque and motility.

microbiology↗

bioRxiv2026

Assessing fish biodiversity and community structure in the Ganjiang River using eDNA metabarcoding

Hydropower development has emerged as a major driver of global environmental change, causing significant ecological damage to freshwater ecosystems and threatening aquatic biodiversity. However, the impact of cascade dams on fish communities in large river systems remains poorly understood, particularly in biodiversity hotspots such as China. Here, we used environmental DNA (eDNA) metabarcoding to assess the spatiotemporal patterns of fish diversity and community structure in the Ganjiang River, the largest tributary of the Yangtze River, in relation to cascade hydropower development. We collected water samples from 19 sites along the main stem and major tributaries in both wet and dry seasons, and analyzed the eDNA data using high-throughput sequencing and advanced bioinformatics pipelines. Our results revealed significant seasonal and spatial variations in fish diversity and community composition, with lower species richness and distinct assemblages in the impounded sections upstream of the dams compared to the downstream reaches. The fish communities were strongly influenced by environmental factors such as water temperature, pH, dissolved oxygen, and nutrients, which exhibited complex interactions with dam operation and land use practices. Spatial scale analyses further indicated that the impact of dams on fish diversity was most pronounced at the local scale, but also detectable at the regional scale. Our findings provide novel insights into the ecological consequences of cascade hydro-power development on fish communities and highlight the importance of considering spatial scales and environmental heterogeneity in assessing the impacts of human activities on freshwater biodiversity. Our study demonstrates the power of eDNA metabarcoding as a cost-effective and non-invasive tool for biodiversity assessment and conservation planning in large river systems facing multiple stressors and knowledge gaps.

ecology↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

When does post-ingestive dopamine signaling occur in humans?

The post-ingestive dopamine response is an integral determinant of subsequent eating behavior in animals yet measurement of the post-ingestive response to nutrients in humans has been elusive when assessed in the early post-ingestive period (30 minutes postprandially). We conducted secondary analysis comparing dopamine D2 receptor binding potential (D2BP) measured using [18F]fallypride positron emission tomography in two inpatient controlled feeding cohorts consuming standardized diet (50% carbohydrate; 35% fat; 15% protein) with similar characteristics and procedures but differing in time since last meal: confirmed overnight fast (n=57; 66.7% female; BMI 29.6{+/-}7.6 kg/m2; 31.9{+/-}7.2 years old) and 2-hours after a standardized meal reflecting 20% of energy requirements (n=43; 48.8% female; BMI 28.8{+/-}7.8 kg/m2, 31.3{+/-}7.7 years old). Compared to the fasted cohort, the 2-hour postprandial cohort exhibited significantly reduced whole striatal D2BP (p<0.0001) as well as in clusters in insular cortex, prefrontal cortex which remained after adjustment for age, sex, and insulin sensitivity. Voxelwise comparisons of the relationship between D2BP and BMI in the fasted and fed cohorts reveals clusters within dorsolateral and ventral striatum where dopamine level is dependent on postprandial state and adiposity. Given the similarities between protocol procedures and participant characteristics, our results suggest that the post-ingestive dopamine response to nutrients may be prominent in the extended post-ingestive period and warrant investigation within-subject.

neuroscience↗

bioRxiv2026

The PSInet Plant Water Potential Database: advancing new perspectives on plant water status, traits, and hydraulic processes

Water potential gradients drive water flow within and between soils and plants, and the internal plant water potential controls a wide range of physiological processes including photosynthesis, growth, and mortality. Notwithstanding this clear relevance for many critical aspects of ecosystem function, water potential data have historically been relatively inaccessible and unnetworked. The absence of a centralized repository for plant water potential time series limits our ability to integrate a wealth of ecophysiological information from other networks and from remote sensing. Closing this gap is necessary to address unresolved questions about plant responses to drought and heat stress, and to make confident predictions about plant and ecosystem function in a warming world. Here, we introduce the PSInet database -- a global collection of plant water potential time series from 285 datasets representing 523 species. We present the workflow that guided database development and evaluate its key features. Through a series of preliminary analyses, we then highlight the potential of the PSInet database for applications including: a) advancing plant water use strategy frameworks; b) disentangling the impacts of soil versus atmospheric drought stress; c) assessing the long-held assumption of pre-dawn equilibration of ecosystem water potential; d) understanding the risk of drought-driven mortality; and e) benchmarking remote-sensing data products and land-surface models.

plant biology↗

bioRxiv2026

MorphCell learns reconstructable shape representations with explicit scale control for 3D cell morphology

Three-dimensional (3D) cell morphology provides a measurable phenotype of cellular state and function, but representing it across biological systems and imaging modalities remains difficult. Existing approaches do not jointly provide transferable representations, complete surface reconstruction, geometric interpretation and explicit control of physical scale. Here we introduce MorphCell, a self-supervised framework that uses cell-surface point clouds to learn shape-driven representations independently of physical scale. MorphCell combines cross-view reconstruction pretraining with spherical self-reconstruction. The former captures geometric relationships between surface regions, whereas the latter recovers complete 3D morphology from individual representations. Pretrained on non-biological object surfaces, MorphCell transfers to cellular datasets without biological task-specific training and outperforms existing point-cloud representations in morphological classification. The learned representations capture both global contour and local surface variation, enabling geometric interpretation through reconstruction, biophysical descriptors and saliency analysis. By retaining physical scale as a separate variable for controlled fusion, MorphCell further reveals that shape and scale contribute differently across biological distinctions. This framework provides a general approach for representing, reconstructing and interpreting 3D cellular morphology across imaging modalities and biological contexts.

cell biology↗

bioRxiv2026

Passive thrust production in animal propulsion: exploitation of velocity gradients for energy conservation

Animals move through fluid environments that are rich in velocity gradients, yet how they exploit these flows to reduce locomotor costs remains elusive. We hypothesize that vertebrates utilize shear layers to passively produce thrust and establish a force equilibrium, thereby reducing locomotor cost. We discovered a shear-layer gait where fish preferentially position themselves within velocity gradients to maintain a steady posture and position at ~50% of their sustained maximum speed. Compared to the matching speed of uniform flow, fish moved into an adjacent velocity gradient reduced active propulsion effort by 98% and metabolic costs by 74%, reaching a resting state. The mechanism is a force equilibrium between viscous drag on the high-velocity side of the body and anteriorly directed suction forces on the low-velocity side, fundamentally a passive thrust production driven by the pressure gradients. Such discovery has direct applications in bioinspired propulsion design and broad implications for movement ecology.

physiology↗

bioRxiv2026

J-domain proteins stimulate PKL-mediated chromatin compaction at H3K4-hypomethylated genomic loci

Chromatin accessibility varies widely across distinct genomic regions in eukaryotes, yet the mechanisms governing these differential patterns remain poorly understood. Here, we identify a subfamily of functionally redundant J-domain proteins (JDPs) that assemble into a protein complex with PICKLE (PKL), an evolutionarily conserved CHD3-type chromatin remodeler, in Arabidopsis thaliana. JDPs are required not only for maintaining PKL protein stability but also for stimulating its nucleosome remodeling and ATPase activities. A previously uncharacterized histone-binding domain (HBD) within JDPs specifically recognizes the N-terminal tail of histone H3 when the H3K4me3 modification is absent. This interaction enhances PKL-mediated nucleosome sliding and ATPase activities in vitro, and promotes PKL-dependent chromatin compaction at H3K4me3-depleted genomic loci in vivo. The PKL-JDP complex drives chromatin compaction to repress developmentally regulated genes, thereby governing key developmental phase transitions, including the embryo-to-seedling transition and flowering. Collectively, these findings uncover a distinct mechanism by which the absence of H3K4me3 is sensed to initiate regional chromatin compaction, repress developmentally regulated genes, and facilitate key developmental transitions.

plant biology↗

bioRxiv2026

Intranasal Fritillaria taipaiensis nanovesicles alleviate acute lung injury via the lung-brain axis

Acute lung injury (ALI) is a severe inflammatory syndrome frequently complicated by brain injury, which worsens outcomes. Here, we explored whether regulation of the lung-brain axis represents a therapeutic strategy for the management of ALI. We show that intranasal administration of Fritillaria taipaiensis-derived exosome-like nanovesicles (Ft-ELNs) ameliorates LPS-induced ALI and ALI-associated hypothalamic inflammation in mice. Ft-ELNs preferentially accumulate in the lungs, inhibiting TRPV1 in both the lungs and the hypothalamus to establish the lung-brain axis. In parallel, Ft-ELNs primarily regulate systemic humoral immunity by inhibiting the VEGFR1/PI3K/AKT/NF?B signaling pathway. In vitro experiments further confirmed that Ft-ELNs are efficiently internalized by alveolar epithelial MLE-12 cells, exerting protective effects by suppressing VEGFR1 expression. Mechanistically, we identified Ft-miR1 of Ft-ELNs as the key functional effector that directly targets the Flt1 3'UTR to inhibit VEGFR1 expression. These data suggest that Ft-ELNs attenuate lung-brain axis inflammation by targeting VEGFR1 and may hold potential as novel therapeutic agents for the treatment of severe ALI.

immunology↗

bioRxiv2026

Computer vision-aided locomotor behavioral analysis identifies therapeutic motor signatures in a mouse model of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction. Traditional open-field tests quantify spontaneous locomotor parameters; however, fine mouse motor signatures, particularly disease stage-specific changes in HD motor symptoms and pharmacodynamic responses to therapeutic treatments. Here, we employed a computer vision-aided behavioral flow analysis designed to quantify fine, HD-relevant motor dysfunction in the zQ175DN HD mouse model, ranging from early HD-like motor signatures to well-defined motor deficits. Markerless pose estimation and Keypoint-MoSeq segmented standard top-view open-field recordings into recurrent behavioral syllables, which were then organized into higher-order clusters and transition networks. Disease stage-dependent changes in syllable occurrence, syllable duration, behavioral-state composition, and transition structure were identified. These analyses are not possible with traditional open-field assays. Syllable-duration features provided the strongest genotype discrimination, and HD-like motor features were also characterized by hub remodeling and transition-network disorganization. These features were integrated into an HD motor dysfunction (HDMD) score based on age- or HD progress-matched wild-type (WT) -standardized absolute deviations. The HDMD score distinguished HD mice from WT across multiple symptomatic stages and correlated with HD pathology and disease severity. Effect-size and power analyses suggested improved efficiency for detecting potential therapeutic effects. This framework requires only standard top-view recordings and may also support retrospective analysis of existing open-field video datasets. Overall, the HDMD framework provides a practical strategy for identifying fine motor changes in HD mice, aiding study design and preclinical efficacy assessment in HD drug development.

neuroscience↗

bioRxiv2026

MOLECULAR BASIS FOR PINK1 MATURATION

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a key regulator of mitophagy, has been linked to the pathogenesis of Parkinson's disease (PD). PINK1 recruits Parkin, an E3 ubiquitin ligase, triggering mitophagy in response to mitochondrial damage. During mitophagy, the quantity, stability, and activity of PINK1 must be strictly regulated; however, the mechanisms governing these parameters under cellular stress are still unclear. Herein, we determined the structural basis for PINK1 maturation mediated by heat shock protein 90/cell division cycle 37/FK506-binding protein 51 (HSP90/CDC37/FKBP51) chaperone complex. We identified PINK1-associated proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and determined the structures of the complexes using Cryo-Electron Microscopy (Cryo-EM). Results showed that FKBP51 potentially interacts with a conserved leucine-proline-phenylalanine (LPF) motif on the activation loop of PINK1 and negatively regulates PINK1 functions in mitophagy. A PINK1 mutation located at the FKBP51 recognition site is linked to mitophagy deficiency, which can be partially rescued by specific inhibition of FKBP51. These findings reveal a general mechanism for PINK1 recognition by the HSP90/CDC37/FKBP51 chaperone complex and suggest a potential approach for upregulating PINK1 activity, which is impaired in PD.

biophysics↗

bioRxiv2026

A modular architecture of human cellular aging across organs and diseases

Aging is a heterogeneous biological process in which different cellular systems undergo molecular remodeling at distinct rates, yet whether human cellular aging follows an organized architecture across organs remains unclear. Here, we integrate a multi-organ human single-cell transcriptomic atlas with plasma proteomic profiles from approximately 50,000 participants to reconstruct cellular aging states at population scale. By projecting cell-type-enriched molecular signatures onto circulating proteins, we characterize aging patterns across 128 organ-cell type pairs and identify 14 cellular aging modules comprising conserved cross-organ programs and organ-specific aging states. These modules reveal cellular identity as a dominant organizing axis of human aging that transcends anatomical boundaries. Module-level aging states uncover substantial inter-individual heterogeneity, with 34% of individuals exhibiting extreme aging deviation in at least one cellular module. Cellular aging modules exhibit distinct temporal trajectories, with structural and tissue-resident modules showing earlier remodeling than immune lineages. The modular organization of cellular aging is reflected in disease susceptibility, with accelerated aging of specific modules, particularly epithelial aging, showing broad associations with disease burden and mortality. Longitudinal analyses further demonstrate the stability and clinical relevance of cellular aging states, whereas lifestyle, metabolic and pharmacological factors show selective relationships with individual aging programs. Together, our study establishes a modular framework for understanding human cellular aging and reveals an organization of biological aging that may help explain individual differences in healthspan.

cell biology↗

bioRxiv2026

Chromatin state shapes site-specific A-to-I RNA editing

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism that diversifies the transcriptome. While ADAR enzymes catalyze this reaction, the upstream mechanisms that determine why individual adenosines are edited at markedly different efficiencies remain poorly understood. Here, we integrated multi-omics datasets from human cell lines and mouse embryonic tissues and developed machine learning models that distinguish high-and low-frequency editing sites based on local epigenetic features. Across species, tissues, and developmental stages, H3K36me3 consistently emerges as the strongest negative predictor of editing frequency, whereas the histone variant H2A.Z.1 shows a positive association. Functional validations in H2AFZ-knockdown cells reveal that H2A.Z.1 preferentially facilitates editing at high-frequency sites (76.3% of sites decreased, mean {Delta} =-0.07), whereas SETD2-knockout-mediated loss of H3K36me3 selectively derepresses editing at low-frequency sites (86.9% upregulated, [~]2.7-fold increase). These findings establish chromatin state as an upstream regulatory layer that modulates RNA editing independently of editing enzyme abundance and reveal opposing roles for H3K36me3 and H2A.Z.1 in shaping RNA editing landscapes. Together, our study provides a conceptual framework linking epigenetic regulation to post-transcriptional RNA modification, suggesting that chromatin-mediated regulation contributes to the establishment of site-specific RNA editing programs across mammalian genomes.

genetics↗

bioRxiv2026

Lipid Imbalance Generates Golgi Whorls that Sequester Small GTPases

Small GTPases are generally viewed as organizers of organelle identity, with different families recruited to specific membranes by compartment-selective targeting mechanisms. Here, we identify a membrane state that reverses this relationship. Excessive peptide S-palmitoylation at Golgi generates multilamellar, filipin-poor whorls that recruit ARF, Rab, and Rho family GTPases normally associated with distinct cellular compartments. The whorls simultaneously excluded Golgi transmembrane residents, coat proteins, ER proteins, a GPI-anchored protein, and other palmitoylated proteins, demonstrating that they were selective membrane compartments rather than nonspecific protein aggregates. Preventing myristoylation of ARF6 or geranylgeranylation of Rab11a strongly reduced recruitment, whereas prenylation alone was insufficient, indicating recognition of a composite membrane-targeting code. Lowering cellular cholesterol promoted whorl formation, whereas cholesterol supplementation suppressed it. Chemically distinct lipid perturbations generated GTPase-positive Golgi whorls, suggesting convergence on a shared membrane-remodeling state. As whorls accumulated, endocytic recycling and anterograde trafficking declined, survival signaling decreased, and viability became poorly reversible. These findings show that lipid imbalance can redirect small GTPases across normal organelle boundaries, converting Golgi-derived membranes into selective sinks for trafficking regulators.

cell biology↗