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Biology subjects

Lu, Z.

Publications and source records attributed to Lu, Z..

At least 19 recordsLinked to original sources

Coordinated Drift of Image Representations in Human EEG

Sensory representations drift over time in many animal systems, but evidence in humans remains limited. Moreover, how perception remains stable despite representational drift remains unclear. Here, we used THINGS-EEG2, a dataset with multiple sessions of repeated presentations of natural images, to test whether image-evoked EEG responses drift across recording sessions and whether this drift is geometrically constrained. We found that image-specific EEG response patterns drifted in a manner that was coordinated across channels and concentrated along dimensions that encoded image identity. Although this impaired cross-session decoding accuracy on average, its effects were heterogeneous with some image pairs becoming harder to distinguish and others becoming more separable. Critically, global distance statistics and the dimensionality of the image response space were preserved across sessions. Simulations show that downstream Hebbian networks can adapt faster to structured drift that preserves dimensionality than when drift is unstructured. These findings suggest that human sensory representations can change over time while remaining amenable to rapid compensation via unsupervised learning mechanisms.

neuroscience↗

Spatialsnake: a flexible workflow for spatial transcriptomics analysis across platforms

Background: Spatial transcriptomics technologies measure gene expression at different spatial resolutions and generate diverse data outputs. Existing workflows support a range of platforms and analyses, but combining methods and extending analyses to selected populations or tissue regions can require additional scripts and repeated data preparation. Findings: We developed Spatialsnake, a flexible workflow built on SpatialData and Snakemake for analysing processed outputs from Visium, Visium HD, Stereo-seq, Xenium and MERFISH. A common command-line interface supports single- and multi-sample analysis, with adjustable parameters and saved intermediate results. Users can select populations, tissue regions or distance-based neighborhoods, repeat clustering and annotation, and map refined labels back to the full dataset. Additional modules support cell-type composition estimation, spatial-domain identification, cell-cell communication inference, regulon analysis and sample-level comparisons. We demonstrate these functions using mouse-brain Visium and colorectal cancer Visium HD datasets. Joint analysis of three colorectal cancer sections retained 1,527,987 bins and enabled further analysis of 223,632 epithelial bins, linking epithelial subpopulation annotations to their locations within the complete tissue. Conclusions: Spatialsnake provides a unified workflow for spatial transcriptomics analysis across sequencing- and imaging-based platforms. Its flexible analysis modules support both whole-tissue analysis and further investigation of selected cell populations and tissue regions.

bioinformatics↗

CAI-Vax: Computational Design of Personalized mRNA Cancer Vaccine Constructs After Antigen Selection

CAI-Vax (Cancer Antigen Individualized Vaccine Design) arranges selected antigens and generates synonymous coding sequences for personalized mRNA vaccine constructs. We evaluated 357 vaccine-candidate peptides from 31 patients across four published cohorts. At the primary cumulative MHCflurry percentile-rank threshold of [≤]2%, HLA-aware search reduced predicted junction-spanning peptide-allele binder occurrences by 3.49 per junction relative to amino-acid-pattern optimization (paired Hodges-Lehmann estimate; nominal 95% interval 2.75-4.48; Holm-adjusted P = 7.45 x 10-). All 31 primary paired differences and the estimated effects in all 16 threshold-by-normalization settings favored HLA-aware search within the MHCflurry model used for optimization. Among 25 patients with an exact solution for the additive search objective, single-start greedy search found the minimum in 5 patients and the best individual heuristic in 16. Selecting each patients best result across all tested heuristics increased this to 19. MHCflurry and NetMHCpan EL identified identical tied best-plan sets in 6 of 31 patients after rescoring six frozen plans per patient. In a retrospective internal analysis, repeat-aware synonymous encoding reduced maximum 10-mer multiplicity in every patient, with mean codon-use-preference losses of 0.0041-0.0055 across cohorts; however, it performed worse than matched random encoding for 6-mers. These findings demonstrate that HLA-guided construct optimization can reduce predicted junctional binding within the optimization model, although the preferred antigen arrangement depends on the prediction model used. Experimental studies are needed to determine the biological and manufacturing relevance of these computational differences.

bioinformatics↗

DIRAS3 broadly suppresses signaling from diverse oncogenic KRAS hotspot variants through an inhibitory interface

Despite major advances in KRAS-directed therapies, broadly suppressing oncogenic KRAS signaling across diverse hotspot variants remains an unmet challenge. Here, we identify an endogenous inhibitory mechanism that suppresses signaling across the major oncogenic KRAS hotspot classes while largely sparing basal wild-type KRAS, revealing activation-state-selective inhibition. We demonstrate that the imprinted tumor suppressor DIRAS3 directly engages activated KRAS through a functionally defined inhibitory interface that can be molecularly mimicked to broadly inhibit KRAS-driven signaling. Using genetically controlled RASless reconstitution models, complementary cancer cell validation, structure-function analyses, molecular dynamics-based membrane topology modeling, and ultrastructural imaging, we show that dual lipid modification constrains DIRAS3 membrane topology, enabling an 5-encoded inhibitory interface to engage activated KRAS, disrupt signaling-competent membrane assemblies, and suppress downstream signaling. Structure-function analyses establish this interface as a critical determinant of DIRAS3-mediated KRAS inhibition. A conformationally constrained 5 mimetic recapitulates full-length DIRAS3 activity, broadly suppressing MAPK and PI3K signaling across multiple oncogenic KRAS variants, including Q61 mutants with reduced sensitivity to current tri-complex RAS(ON) inhibitors. Mechanistically, immunoprecipitation shows that the 5 mimetic reduces KRAS association with both RAF1 and p110 similarly across G12 and Q61 mutants, whereas RMC-7977 reduces inhibition of p110 association with Q61 KRAS. The 5 mimetic also disrupts KRAS nanocluster organization and inhibits tumor growth in vivo. These findings identify a targetable inhibitory interface within DIRAS3 and establish mimicry of an endogenous KRAS suppressor as a mechanistically distinct strategy for broad KRAS inhibition.

cancer biology↗

EnsPlex: Integrative Protein Complex Prediction through Multi-source Complementary Structural Sampling and Topology-Aware Candidate Selection

Protein complex structure prediction depends on both the breadth of candidate coverage and the ability to select accurate models within a limited output budget. Most existing approaches emphasize only one stage. End-to-end models and molecular docking workflows generate candidate structures, whereas quality-assessment models primarily rerank a predefined candidate pool. A complete strategy must account for complementary sampling across generators, differences among scoring scales and the allocation of final candidate quotas. Here, EnsPlex is presented as a multi-source framework that couples structural sampling with candidate selection for protein-protein interaction complex prediction. EnsPlex combines conformation-expanded docking, AlphaFold-Multimer, AlphaFold3 and Boltz-1 to expand the sampled conformational space. Conformation-expanded docking comprises monomer conformational expansion followed by flexible HADDOCK docking. FACET is trained to predict candidate quality using DockQ and its component metrics as supervision. Across 102 antigen-antibody systems, EnsPlex achieved up to a 27.8% relative improvement in target success rate over AlphaFold3 with its built-in ranking under matched output budgets. FACET also improved within-source ranking in the internal candidate pools and in homology-filtered external data. These findings support the utility of EnsPlex for structure prediction in the evaluated antigen-antibody systems.

bioinformatics↗

Partial sleep deprivation diminishes and uncouples neuronal activity and energy metabolism in the live mouse hippocampus

Sleep disorders and wakefulness constitute a pronounced and pervasive health risk that contributes to numerous cerebral pathologies such as stroke, depression, and neurodegenerative disorders. The hippocampus (HC) plays vital roles in learning and memory and is especially susceptible to the pathological insults imposed by sleep deprivation (SD). While SD disrupts neuronal network signaling and triggers inflammatory processes, the impact of SD on metabolism within the HC presently remains poorly understood. In this study, we assessed the progressive and cumulative effects of partial SD in the live mouse HC CA1 region using two-photon microscopy. Using a custom-designed implantable cannula enabling direct HC visualization and administration of dyes and pharmacological agents directly to HC tissue, we longitudinally monitored spontaneous neuronal activity and partial pressure of oxygen (pO2) within HC CA1 tissue before and during a 7-day period of partial SD and after a 7- day period of recovery. Our results revealed a progressive decline in spontaneous neural activity, alongside sustained elevation in tissue pO2; during the 7-day partial SD period. Notably, after 7 days of recovery, neuronal activity did not return to baseline, and tissue oxygenation continued to increase. Our findings emphasize chronic SD's cumulative and enduring impairments to neuronal function and metabolism in the HC and reveal uncoupling between metabolic and functional recovery that outlasts the sleep restriction period.

neuroscience↗

CD24-dependent innate immune checkpoint targeting chimera disrupts TGF-β-driven immunosuppression to enhance anti-tumor therapy

The immunosuppressive tumor microenvironment (TME) poses formidable challenges for cancer immunotherapies. Among the complex TME landscape, the cytokine TGF-{beta}1 is an attractive soluble target for reinvigoration of anti-tumor immunity due to its pivotal function in immune cell suppression, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT) promotion, while immune checkpoint receptors exemplified by PD-1 and CD24 are promising surface targets. Though adaptive immune checkpoint inhibition is well established in clinical practice, TGF-{beta} blockade or innate immune checkpoint blockade is yet to be harnessed for tumor treatment. Here, leveraging CD24 overexpression on multiple tumor tissues and its unique recycling kinetics, we designed an innate Immune Checkpoint TArgeting Chimera (ICTAC) G01, a bifunctional CD24 antibody-TGF-{beta}1 receptor fusion protein that disrupts TGF-{beta}1 signaling by TGF-{beta}1 degradation instead of simple blockade and simultaneously inhibits the "don't eat me" CD24 signaling. We demonstrated that G01 effectively suppressed TGF-{beta}1-Smad signaling, reversed the EMT, and attenuated fibrotic collagen deposition. Additionally, it antagonized CD24 signaling to unleash robust antibody-dependent effector activity, further reprogramming the immunologically cold TME toward inflammatory phenotype. By selectively targeting malignant cells while sparing CD24-expressing B cells, G01 demonstrated a favorable safety profile. Notably, in patient-derived tumor fragments (PDTFs), G01 also inflamed the TME, underscoring its translational potential. Together, these results establish ICTAC as an effective strategy for tumor-specific receptor-mediated extracellular protein depletion, which supports its application for reversing TGF-{beta}1; and innate immune checkpoint-mediated tumor immunosuppression by concurrent targeting of both surface and soluble tumor-promoting factors.

immunology↗

Agentic transcranial functional ultrasound imaging: @fUS

Functional ultrasound (fUS) imaging provides deep, wide-field access to brain function, but instrument cost and complex acquisition and analysis workflows restrict its wider adoption. Here we introduce @fUS, an agentic transcranial imaging platform with an open architecture that integrates purpose-built hardware with executable experimental skills and persistent structured memory. The system combines 128-channel, 16-bit acquisition at 125 MHz with GPU-based processing and enables functional imaging through the intact scalp and skull of mice, with approximately 100-m spatial resolution and 10-Hz temporal sampling, providing a basis for longitudinal studies without cranial-window surgery. Its agent connects scientific objectives to experimental design, direct instrument control and data analysis, retaining context across interactions and supporting inspectable workflows through text and hands-free voice control. Neuroscience trainees with limited engineering experience independently configured the system within 30 min. Agent-assisted exploration of whisker-stimulation datasets revealed low-frequency vascular changes beyond conventional response mapping, supported by complementary two-photon measurements of single-vessel diameter. By combining transcranial imaging with accessible instrument control and analysis, @fUS provides a foundation for wider adoption and larger, more diverse neuroscience datasets. More broadly, it offers a framework for scientific instruments in which measurement, computation and experimental reasoning are developed as parts of the same system.

bioengineering↗

The diversity, evolution, and conservation of African plants

Africa hosts remarkable biodiversity across diverse biomes, yet its evolutionary history at continental-scale remains poorly understood. We integrate a time-calibrated phylogeny covering 93% of African vascular plant genera with continental-scale distribution data to jointly evaluate phylogenetic diversity (PD), endemism, and diversification rates (DR). We reveal a pronounced decoupling between DR and accumulated evolutionary history across Africa. Mountain, arid, and semi-arid areas emerge as centers of neo-endemism and elevated diversification, whereas lowland and humid regions, particularly the Guineo-Congolian zone, are dominated by older lineages with low recent diversification. Several DR hotspots do not overlap with Global Biodiversity Hotspots, indicating a mismatch between rapid diversification and accumulated evolutionary history. High net diversification and speciation rates during the last 15 million years were likely driven by cooling, aridification, and mountain uplift that created new ecological gradients and isolation barriers. These abiotic changes, interacting with lineage-specific traits, shaped African modern flora and highlight conservation gaps, especially in arid regions

evolutionary biology↗

AVMoments-EEG: A Large-Scale EEG Dataset of Naturalistic Audiovisual Event Perception

Understanding how the human brain processes dynamic audiovisual events requires datasets that combine naturalistic stimulation, high temporal resolution, and systematic experimental manipulation of sensory information. Here, we introduce AVMoments-EEG, the first large-scale, high-temporal-resolution human EEG dataset designed to characterize neural responses to naturalistic audiovisual events. Across 10 participants, we recorded 64-channel scalp EEG during free viewing of 3-second naturalistic video clips derived from the Audiovisual Moments in Time dataset. The stimulus set comprised 896 training videos (56 videos in each of 16 event types), each presented three times, and 64 held-out test videos (4 videos in each of 16 types), each presented 40 times in each of three conditions: (1) intact audiovisual input, (2) intact visual input with scrambled audio, and (3) intact auditory input with scrambled visual input. This design yielded 10,368 trials per participant and combines broad stimulus coverage with highly repeated test stimuli. AVMoments-EEG enables temporally resolved investigation of naturalistic event processing and modality-specific audiovisual contributions, while providing a benchmark for video-to-EEG encoding, EEG-based decoding, and brain-model alignment. The dataset offers a resource for studying dynamic event perception, multisensory processing, and the temporal correspondence between human neural responses and artificial neural network representations.

neuroscience↗

Img2EEG: A Scalable and Interpretable Encoding Framework for Simulating Human EEG Responses to Visual Inputs

Understanding how visual information processing unfolds over time requires models that not only predict neural responses but also expose the representations that support them and generalize beyond sampled stimulus spaces. Here we introduce Img2EEG, a participant-specific image-to-EEG encoding framework that integrates hierarchical visual and semantic representations to generate temporally resolved multichannel EEG responses. Trained on THINGS EEG2, Img2EEG generalized to unseen images while preserving stimulus-specific and participant-specific response structure. Controlled perturbations of internal representations and visual inputs revealed distinct temporally structured contributions of visual and semantic information, and in silico experiments reproduced classic human neural responses, such as the face-sensitive N170, while enabling targeted representational interventions. Scaling Img2EEG to 1.28 million ImageNet images produced over 12 million synthetic EEG responses that supported cross-dataset visual reconstruction and improved the behavioral alignment of an artificial vision model. Img2EEG provides an interpretable and scalable framework for experimentally manipulable modeling of visual neural dynamics.

neuroscience↗

CryoFlex characterizes structural motion between conformations directly from cryo-EM density maps

Heterogeneous cryo-EM reconstruction methods can resolve multiple conformational states, but understanding their functional implications often requires determining which regions move between states and quantifying their displacement magnitudes. Comparing atomic models can quantify motion, but flexible regions are often incompletely modeled. Direct map comparison is limited by variable map quality and ambiguous correspondence between displaced density features. Here, we present CryoFlex, a method that estimates the direction and magnitude of structural motion directly from reconstructed density maps of selected states. The resulting motion analysis supports functional interpretation and guides downstream structure processing. CryoFlex localized and quantified structural motion across diverse map pairs, including those with incomplete atomic-model coverage or weak local density. Against C; displacements, CryoFlex achieved an endpoint error of about 1 angstrom. In separate benchmarks, it outperformed registration baselines on clean and noisy inputs. Thus, CryoFlex complements heterogeneous reconstruction workflows with direct quantification of structural motion between reconstructed states.

bioinformatics↗

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations generally outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

Shared and distinct temporal representations of Chinese words across imaged, silent, and overt speech

How internal speech relates to overt speech remains a fundamental question in speech production: do different forms of speech preserve a common neural representation of the intended word, or does that representation change as speech becomes articulated? We used time-resolved electroencephalography to characterize representations of 10 Chinese words during imagined, silent, and overt speech. Word identity was reliably decodable in all three modes, but its temporal dynamics differed: imagined-speech representations peaked earlier and were less temporally stable, whereas silent and overt speech showed stronger and more sustained representations. Cross-mode decoding revealed word-discriminative information shared across all three mode pairs, with substantially stronger generalization between silent and overt speech. However, direct comparison of word-level representational geometry revealed robust correspondence only between silent and overt speech, indicating that transferable information across modes does not necessarily imply preservation of the broader relational structure among words. Representational similarity analyses further showed distinct visual-form, semantic, and phonetic dynamics across speech modes, with late visual-form and phonetic information contributing uniquely to the geometry shared by silent and overt speech. Controlling for time-matched surface electromyography preserved the overall silent-overt neural correspondence and within-mode phonetic representations, while eliminating the unique phonetic contribution to their shared geometry, suggesting that peripheral articulation accounts for part, but not all, of this common structure. Together, these findings show that imagined, silent, and overt speech share word representations at different levels and suggest that representational geometry and temporal stability are progressively reorganized as internal speech is translated into articulation.

neuroscience↗

Interstitial macrophages drive chronic lung allograft dysfunction

Despite immunosuppressive regimens targeting adaptive immunity, chronic lung allograft dysfunction (CLAD) remains the major obstacle to durable lung allograft survival. Here, we identify colony-stimulating factor 1 receptor (CSF1R)-expressing interstitial macrophages as critical orchestrators of CLAD. Using lung tissue from patients with CLAD and a mouse model of mismatched lung transplantation, we show that both donor-derived tissue-resident and recipient- monocyte-derived interstitial macrophages spatially co-localize within peribronchial immune aggregates in patients with CLAD. These interstitial macrophages express distinct cytokine programs that include those implicated in the recruitment of T and B cells. Pharmacological inhibition of CSF1R after lung transplantation in mice reduced interstitial macrophage abundance and attenuated CLAD pathology. Our findings identify donor- and recipient-derived interstitial macrophages as upstream regulators of CLAD and suggest CSF1R as a therapeutic target for its prevention and treatment.

immunology↗

Knee Joint Biomechanics During Lunges at Different Tibial Angles and External Loads: A Musculoskeletal Analysis with Finite Element Insights

ObjectiveThis study investigates knee joint biomechanics during lunges under varying tibial angles and external loads using musculoskeletal modeling and finite element analysis. The goal is to provide a biomechanical basis for understanding knee loading patterns and optimizing sports training and rehabilitation. MethodsTwenty-six healthy young men performed lunges under tibial inclination angles relative to the ground (60{degrees} and 90{degrees}) and two external load conditions (bodyweight and an additional 98 N external load). Kinematic and kinetic data were captured using motion capture and force plates. Musculoskeletal models were used to estimate joint moments, range of motion, and stiffness, with data analyzed using two-way repeated-measures ANOVA. Finite element analysis was performed at 90{degrees} tibial angle to evaluate tissue stress and displacement. ResultsThe joint moment at a 60{degrees} tibial angle was much higher than at a 90{degrees}. External load showed significant effects on knee stiffness, with lower rotational stiffness in the horizontal plane (P < 0.001) and lower coronal plane stiffness at 90{degrees} (P = 0.012) under the 98 N external-load condition, indicating reduced resistance to angular displacement in these planes. Under the 90{degrees} tibial-angle condition with external load, peak stress and displacement were concentrated in the posterior horn of the meniscus, with a maximum displacement of 3.12 mm. ConclusionThe anterior tilt of the tibia increased sagittal-plane knee loading, while external load mainly reduced joint stiffness in the coronal and horizontal planes. Under the 90{degrees} loaded condition, the concentration of stress and displacement in the posterior horn of the meniscus suggests a mechanically unfavorable loading pattern rather than direct evidence of injury risk. These findings may provide useful biomechanical information for load management during lunge-based training and rehabilitation.

bioengineering↗

Distinct mitochondrial phenotypes align with visual and semantic representations across human cortex

Cortical regions differ in the information they represent, but whether this functional specialization is accompanied by corresponding differences in cellular and molecular organization remains unknown. Here, we combined precision 7T fMRI, image-to-brain encoding models, a recently developed human mitochondrial atlas, and cortical transcriptomics to test whether visual and semantic representations occupy distinct molecular environments. Across two independent combinations of visual and semantic feature models, variance uniquely attributable to visual information was negatively associated with both mitochondrial density and mitochondria-specific respiratory capacity. In contrast, variance uniquely attributable to semantic information was positively associated with mitochondrial density but showed no reliable association with respiratory capacity. Genome-wide transcriptomic analyses revealed convergent differences in mitochondrial and broader cellular programs associated with the two representational axes. These findings establish a cross-scale correspondence between the information represented by human cortex and its regional energetic and molecular architecture.

neuroscience↗