Biology subjects

He, L.

Publications and source records attributed to He, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Scarless SARS-CoV-2 Genome Engineering and Variant Analysis

In addition to causing cold and flu-like symptoms, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can also cause chronic longer-term diseases. Antiviral drugs, especially used combinatorially, have the potential to reduce the severity of individual infections and prevent the development of chronic disease. One of the safest and most versatile reverse genetics systems for SARS-CoV-2 studies is a bacterial artificial chromosome (BAC)-based system harboring the WA1 strain full-length genome and attenuating deletions in the accessory open reading frame 3a and 7b proteins (ORF3a and ORF7b, respectively). Here, a scarless genome engineering technique called En Passant mutagenesis was used to change one amino acid in the viral main protease (Mpro P132) into the residue present in contemporary Omicron strains (H132), in order to more accurately study protease inhibitors and resistance mechanisms. This recombinant, attenuated viral system yields antiviral EC50 values for the active component of approved drugs including nirmatrelvir (Paxlovid) and ensitrelvir (Xocova) and, importantly, also enables a parallel assessment of drug efflux. For instance, the antiviral potency of nirmatrelvir improves 50-fold by inhibiting the P-Glycoprotein (P-Gp) transporter with ritonavir or tariquidar, whereas the potency of ensitrelvir is unaffected. This system also enables the safe isolation and characterization of viral variants with reduced sensitivity to drugs, as evidenced by Mpro M49L compromising the efficacy of ensitrelvir. Together, these systems combine to provide safe, reliable, and quantitative approaches for Mpro variant analysis and drug testing without the biosafety concerns of conducting these experiments using wildtype isolates.

microbiology↗

bioRxiv2026

A cross-modal generative model for incomplete and degradedprostate MRI with multicentre clinical validation

Missing or degraded sequences can limit prostate multiparametric MRI. We developed MSCNet, a sequence-conditioned cross-modal generative framework for reconstructing unavailable contrasts and restoring degraded acquisitions. Across ten completion tasks, task-specific MSCNet achieved mean structural similarity of 0.818 versus 0.798 for the strongest task-matched comparators; matched-capacity analyses showed larger differences in lesion fidelity and boundary preservation. In a blinded 1,000-case reader study, overall image quality met the prespecified non-inferiority criterion for DWI, ADC and T2W completion, but not T1W. In a separate 200-case diagnostic assessment, AUCs for clinically significant cancer were 0.860 with acquired images, 0.841 with MSCNet and 0.797 with baseline-generated images. A locked 186-case three-hospital cohort supported multicentre transportability. These retrospective results support quality-controlled cross-modal reconstruction as an adjunct to acquired prostate MRI.

bioengineering↗

bioRxiv2026

CreaSol(R) SSAT (Stabilized Tyrosol) Enhances Creatine on Muscle Performance and Anti-fatigue Capacity in Trained Mice

Tyrosol, a natural polyphenolic compound, has been identified as a potent cellular antioxidant. It mitigates oxidative stress-induced damage in skeletal muscle cells and facilitates the recovery of intracellular adenosine triphosphate (ATP), suggesting a beneficial role in maintaining cellular energy homeostasis. Creatine, widely used to enhance muscle strength by augmenting the phosphagen system, promotes intracellular ATP production but yields relatively modest improvements in endurance. In this study, we investigated the effects of combined supplementation of tyrosol (CreaSol) and creatine monohydrate (CM) on muscle endurance and strength in mice. Following a 4-week exercise training and intragastric intervention, muscle strength and exercise endurance were evaluated through four consecutive forelimb grip strength tests and exhaustive weighted swimming tests at 24-hour intervals. Compared with creatine monohydrate supplementation alone, the co-administration of CreaSol and creatine monohydrate significantly enhanced grip strength (+28.1%) and swimming endurance (+51.5%). More importantly, following consecutive exhaustive exercise, the combined group exhibited superior recovery capacity, demonstrating significantly attenuated declines in both strength and endurance compared to the creatine monohydrate-only group. We conclude that CreaSol not only effectively improves exercise performance in mice, but also significantly enhances the efficacy of creatine monohydrate in improving muscle strength and endurance, as well as reducing fatigue during consecutive high-intensity exercise.

physiology↗

bioRxiv2026

Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties

Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-{kappa}B. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-{kappa}B -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.

biochemistry↗

bioRxiv2026

Killer-cell dominance dichotomy governs tumor immune networks and stratifies inflamed cancers

Cancer immunotherapy benefits remain limited, even among "hot" tumors with high killer lymphocyte infiltration. Here, we investigated the population-level architecture of killer cells based on nearly 5,000 pan-cancer scRNA-seq samples, together with orthogonal validation by spectral cytometry and spatial transcriptomics. Unlike the prevailing "hot-cold" paradigm, which assumes coordinated infiltration of multiple cytotoxic lineages, we uncovered a conserved framework wherein terminal cytotoxic immunity in individuals or malignancies diverges into states dominated by either exhausted CD8+ T cells (Tex) or CD56dimCD16hi NK (NK1) cells. Despite the complexity of the tumor microenvironment, Tex-NK1 divergence governs the primary axis of tumor-intrinsic and tumor-extrinsic variance. Distinct from the conventional view that NK cells positively contribute to immunotherapy efficacy, NK1-skewed tumors, although highly cytolytic, are refractory to current immune checkpoint blockade regimens. This killer divergence defines a foundational axis of cancer immunity and provides a resource for prioritizing next-generation targets for NK-directed immunotherapy.

immunology↗

bioRxiv2026

Vascular normalization in breast cancer confers an endothelial immune suppressive gene expression profile

Tumors commonly exhibit a leaky vasculature and innate and/or adaptive immune cell infiltration. A recent study showed that a non-leaky and normalized mouse breast cancer vasculature after conditional deletion of the Shb gene in endothelial cells (EC) displayed a suppressive immune cell profile. To extend those findings further, regulation of immunomodulatory gene expression of normalized breast cancer EC was related to healthy human breast and human breast cancer EC gene expression. A considerable correlation was observed in the gene expression profiles of immunoregulatory genes between normal breast arterial EC and normalized (Shb-deficient) EC, and these changes did not primarily seem to involve gene products forming conduits for tumor leukocyte transendothelial migration but other aspects of immune suppression as for example cytokine expression. In addition to breast cancer, healthy lung and colonic EC exhibited an immune suppressive phenotype compared to their lung cancer and colorectal cancer counterparts. It is concluded that normalized EC may confer a non-leaky and immune suppressed phenotype, an insight that may be exploited to enhance the efficacy of immunotherapy.

Cancer Biology↗

bioRxiv2026

Pathogenic PTCD1 variants cause mitochondrial protein aggregation and cardiomyopathy

Disorders of mitochondrial oxidative phosphorylation affecting multiple respiratory chain complexes are among the most common causes of mitochondrial disease in humans. However, impaired energy metabolism alone does not fully account for tissue-specific vulnerability and disease progression, suggesting that additional molecular mechanisms contribute to disease pathology. We previously identified PTCD1 variants in a child with infantile cardiomyopathy associated with a combined respiratory chain deficiency. Here, we establish the pathogenicity of three PTCD1 (NM_015545.4) variants in which p.(Arg113Trp) and p.(Gly184Arg) segregate in cis whereas p.(Arg130*) is present in trans, demonstrating that disrupted mitochondrial proteostasis contributes to tissue damage in PTCD1 deficiency. PTCD1 patient cardiac tissue characterisation revealed impaired mitoribosome biogenesis, alongside increased aggregation of selective mitochondrial matrix proteins. Cell models expressing individual and combined PTCD1 missense variants, coupled with proteomics, recapitulated the protein aggregation, with the cis p.(Arg113Trp);p.(Gly184Arg) combination showing the most severe effect. Protein aggregation was accompanied by altered OPA1 processing and mitochondrial network remodelling. Our findings establish accumulating proteotoxic stress arising from impaired mitoribosome assembly as a pathogenic mechanism in post-mitotic tissues, driving PTCD1 cardiomyopathy.

cell biology↗

bioRxiv2026

MZF1-mediated GAPDH overexpression drives glycolytic reprogramming and neuroendocrine progression in advanced prostate cancer

Drug resistance to the androgen receptor (AR) antagonist is a critical obstacle in the clinic for advanced prostate cancers. Especially, AR antagonist treatment-induced neuroendocrine progression represents a lethal and therapy-resistant subtype. Although transcriptional and epigenetic lineage plasticity have been extensively implicated in treatment-induced neuroendocrine progression, the contribution of metabolic adaptation remains incompletely understood. Here, we identified a previously unrecognized metabolic reprogramming mechanism induced by AR antagonists in castration-resistant prostate cancer (CRPC) models. AR antagonist treatment markedly enhanced glycolytic activity and induced glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Genetic depletion of GAPDH suppressed AR antagonist-induced glycolytic activation, altered transcriptomic and metabolic programs, reduced neuroendocrine-associated marker expression, and inhibited xenograft tumor growth. Mechanistically, GAPDH promoter pulldown coupled with mass spectrometry, siRNA screening, and chromatin immunoprecipitation assays identified myeloid zinc finger-1 (MZF1) as a key transcription factor for Enzalutamide-induced GAPDH gene expression. Pharmacological inhibition of GAPDH using koningic acid (KA) or penta-O-galloyl-{beta}-D-glucopyranose (PGG) significantly suppressed tumor growth and attenuated neuroendocrine-associated molecular programs in CRPC cell-derived xenograft and patient-derived t-NEPC xenograft models. Collectively, our findings identify an AR antagonist-induced MZF1-GAPDH signaling axis that promotes glycolytic activation and neuroendocrine-associated metabolic adaptation during treatment resistance. These results support targeting GAPDH-dependent metabolic reprogramming as a potential therapeutic strategy for treatment-resistant prostate cancer. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/729867v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@10480b2org.highwire.dtl.DTLVardef@9d2ed8org.highwire.dtl.DTLVardef@16e8705org.highwire.dtl.DTLVardef@1627ad2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Artery Like Smooth Muscle Drives Contractile Function in Dural Venous Sinuses

The dural venous sinuses are the main conduit for cerebral blood flow to drain from the head back to the heart. Pathology of these sinuses has significant impacts on cerebral blood volume and intracranial pressure, indicating that these veins have an important role in cerebral hemodynamics. Active and modifiable mechanisms of sinus diameter control may present an opportunity for physiological or pathological regulation of venous blood flow. Here, we characterized the molecular and anatomical properties of dural vascular smooth muscle cells (SMCs) using RNA-sequencing and immunohistochemistry, demonstrating that artery-like SMCs are exclusive to sinus vessels. An ex vivo pressurized sinus preparation from mice was used to functionally characterize the vasodynamics of the sinus and its corresponding bridging veins. We found that the sinus contains dynamically contractile SMCs and constricts to both pressure and contractile agonists, while the bridging veins do not. We further demonstrated that these sinus SMCs exhibit dynamic calcium signaling that is responsive to contractile stimuli. These results reveal a contractile SMC phenotype localized to dural venous sinuses and demonstrate that sinus vessels possess active, artery-like mechanisms for regulating cerebral venous outflow.

physiology↗

bioRxiv2026

Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability

Coronaviruses (CoVs) replicate unusually large RNA genomes that necessitate proofreading by the 3'-to-5' exoribonuclease (ExoN) formed by nonstructural proteins 14 (nsp14) and 10 (nsp10). Previous studies suggested that inactivation of the ExoN catalytic site in severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is lethal, leaving unresolved whether the virus can tolerate impaired proofreading activity. Here, we investigated the functional requirement for ExoN in SARS-CoV-2 replication by combining a continuous fluorescence-based biochemical assay with an optimized single-bacmid reverse genetics system. Mutational analysis of residues involved in RNA binding or catalysis revealed graded effects on ExoN activity in vitro. Alanine substitution of Lys9, a residue positioned near the RNA-binding interface, did not reduce ExoN activity, whereas charge reversal at this position (K9E) impaired activity more strongly than alanine substitutions of the catalytic motif I residues D90 and E92 (D90A/E92A). Correspondingly, recombinant SARS-CoV-2 carrying K9A was readily recovered, whereas the D90A/E92A mutant was recovered only after an extended delay and K9E could not be rescued despite repeated attempts. The D90A/E92A mutant exhibited reduced replication while maintaining the engineered ExoN substitutions during serial passage. Deep sequencing of viral populations revealed a marked increase in genome-wide sequence variation in the D90A/E92A mutant, demonstrating a stable mutator phenotype. Together, these findings indicate that SARS-CoV-2 can tolerate substantial impairment of ExoN activity but depends on a minimal activity threshold for viability. This system provides a platform for defining how SARS-CoV-2 proofreading controls genome stability, viral fitness, and sensitivity to antiviral strategies that exploit reduced replication fidelity. ImportanceCoronaviruses have unusually large RNA genomes because they encode a proofreading enzyme that removes copying errors during replication. It has been unclear whether SARS-CoV-2 can survive when this proofreading function is strongly weakened, because earlier studies suggested that loss of the enzymes catalytic activity is lethal. We show that SARS-CoV-2 can tolerate substantial impairment of proofreading, but only when residual exonuclease activity remains above a minimal threshold. A virus with impaired proofreading replicates less efficiently and accumulates mutations across its genome, whereas a more severe defect prevents virus recovery. These findings clarify how coronavirus proofreading balances genome stability with viral fitness and provide a useful system for studying how reduced replication fidelity affects viral evolution, antiviral sensitivity, and attenuation. Defining this activity threshold may also help guide antiviral strategies that target coronavirus proofreading.

microbiology↗

bioRxiv2026

Allosteric Biosensors Unravel GTPase-Effector Feedback

Fluorescent biosensors that report protein conformation in vivo have been invaluable for understanding how the spatio-temporal dynamics of signaling controls cells. However, for GTPases these biosensors report the activated conformation using reagents that block the binding of downstream proteins, generating dominant negative effects and altering normal cell physiology. We present here a generalizable design to make GTPase biosensors (AlloRac1 and AlloCdc42), in which a circularly permuted fluorescent protein is inserted into a conserved loop allosterically connected to the effector binding site, generating activity-dependent fluorescence without blocking ligand interactions. The Rac1 biosensor showed that effector interactions led to increased Rac1 activation, indicating an auto-regulatory positive feedback made visible by the new biosensor design. This feedback regulated the kinetics and localization of Rac1 activity, including Rac1 activity gradients that controlled motility. Feedback was generated through Rac1 interaction with the effector Pak1, which led to further activation of Rac1 by the guanine exchange factor {beta}-Pix. The new biosensor approach enables quantitative imaging of previously obscure spatio-temporal dynamics in GTPase regulation.

cell biology↗

bioRxiv2026

Near telomere-to-telomere Linum genomes reveal a lineage-specific DNA transposon associated with chromosome architecture remodeling

Chromosome number variation and structural reorganization are key drivers of plant evolution, yet their genomic basis remains unclear due to incomplete representation of repetitive regions in existing assemblies. The Linum genus exhibits exceptional karyotypic diversity (n = 7-43), providing a powerful system to investigate chromosome evolution. Here, we generated near telomere-to-telomere (T2T) genome assemblies for four species, including cultivated flax (L. usitatissimum cv. CDC Bethune; n = 15), its wild progenitor (L. bienne; n = 15), and two related species (L. decumbens and L. grandiflorum; n = 8). Together with published genomes of L. lewisii (n = 9) and L. tenue (n = 10), these enabled reconstruction of chromosome evolution across six lineages. Phylogenomic analyses revealed a shared ancestral whole-genome duplication (WGD) associated with the n = 9 karyotype, followed by lineage-specific WGDs and divergent diploidization. The transition from n = 8 to the derived n = 15 flax lineage not only occurred without chromosome length expansion, but also with genome size reduction, indicating extensive internal restructuring. Comparative analyses showed that this restructuring was associated with lineage-specific expansion of a single DNA transposon family (TE_00003234; hAT), which is highly enriched in expansive pericentromeric regions that are characterized by low gene density and nucleotide diversity, suppressed recombination, segregation distortion, and extensive synteny disruption, unlike the LTR retrotransposon-rich pericentromeres typical of most plant genomes. These findings support a model in which lineage-specific DNA transposon expansion is associated with remodeling of pericentromeric architecture and large-scale chromosome restructuring following polyploidization.

genomics↗

bioRxiv2026

Multiscale Mechanisms of Human Memory Modulation by Deep Brain Stimulation

The highly variable effects of deep brain stimulation (DBS) on cognition highlight a fundamental gap in our understanding of how external perturbations interface with the brains ongoing, task-engaged state. The current study addressed this challenge by combining intracranial EEG recordings with hippocampal DBS stimulation in human participants during spatial sequence memory task. We found 50 Hz stimulation targeting hippocampal white matter enhanced memory performance, whereas 5 Hz stimulation targeting hippocampal gray matter impaired memory. These opposing behavioral outcomes were both governed by two dissociated mechanisms: a region-specific modulation of theta rhythms in an engagement-dependent fashion, and a global modulation of the fidelity of memory representations across the cortex. Our results suggest targeted stimulation can concurrently fine-tune specialized circuits and govern the brains global state, which not only offers a novel roadmap for understanding how external inputs shape human cognition, but also helps to design precise, state-dependent neuromodulation therapies.

neuroscience↗

bioRxiv2026

The antipsychotic drug clozapine suppresses autoimmunity driving psychosis-like behavior in mice

Antipsychotic drugs are the first-line treatment for psychosis yet their mechanism of action remains poorly understood, largely due to the challenge to faithfully model psychosis preclinically. Here, we focus on the emerging concept that psychosis can be caused by brain autoimmunity and present a novel mouse model of anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis, a condition that manifests with psychosis and autoanti-bodies against the NMDAR. We devised a new mRNA-based approach to immunize mice against the NMDAR. Immunized mice developed psychosis-like behaviors that were caused by anti-NMDAR autoantibodies leading to phagocytosis of NMDARs by brain microglia. The antipsychotic drug clozapine rescued psychosis-like behaviors and, remarkably, reduced anti-NMDAR autoantibody levels and antibody-mediated phagocytosis of NMDARs. The immunomodulatory effects of clozapine were confirmed in a mouse model of systemic lupus erythematosus. Our results demonstrate that clozapine suppresses autoimmunity driving psychosis-like behaviors, raising the possibility that immunomodulation contributes to antipsychotic drug action. HIGHLIGHTSO_LImRNA immunization against the NMDAR induces psychosis-like behavior in mice C_LIO_LIAnti-NMDAR autoantibodies are sufficient for psychosis-like behavior C_LIO_LIMicroglial phagocytosis of NMDARs mediates psychosis-like behavior induced by anti-NMDAR autoanti-bodies. C_LIO_LIClozapine reduces anti-NMDAR autoantibodies, microglial phagocytosis and psychosis-like behavior, consistent with immunomodulation as a potential mechanism of antipsychotic drug action. C_LI

neuroscience↗

bioRxiv2026

MAMGL: A memory-augmented meta-graph learning framework for adolescent major depression disorder diagnosis

BackgroundAdolescent major depressive disorder (AMDD) is a prevalent and heterogeneous psychiatric condition that emerges during a critical period of brain development. Neuroimaging-based biomarkers derived from resting-state functional magnetic resonance imaging (rs-fMRI) hold promise for objective diagnosis; however, pronounced inter-individual variability and limited sample sizes pose major challenges for robust model development. MethodsWe propose a memory-augmented Meta-Graph Convolutional Network (BrainMetaGCN) to classify AMDD using rs-fMRI functional connectivity. Individual functional connectivity matrices were constructed by parcellating rs-fMRI time series into cortical regions of interest and computing pairwise correlations. A meta-graph generator dynamically learned subject-specific graph structures, which were processed by lightweight graph convolutional layers. A memory neural network was incorporated to encode population-level prototypical connectivity patterns and generate individualized representations via attention-based retrieval. Model performance was evaluated across multiple independent datasets and compared with state-of-the-art deep learning approaches. Additionally, network interpretability was examined through cortical hierarchy analysis and functional enrichment of discriminative network components. ResultsThe proposed BrainMetaGCN consistently outperformed baseline models, including convolutional and transformer-based approaches, achieving higher accuracy, area under the receiver operating characteristic curve, sensitivity, and specificity. Memory-module-derived functional networks exhibited clear modular organization and showed a significant positive correlation with cortical functional hierarchy, supporting their neurobiological validity. Functional enrichment analyses implicated synaptic transmission, axon guidance, receptor tyrosine kinase signaling, and immune-related pathways, suggesting neurodevelopmental and neuroimmune mechanisms underlying AMDD. Ablation analyses confirmed that memory augmentation and dynamic meta-graph construction were critical for robust performance under small-sample conditions. ConclusionsThis study introduces a robust and interpretable memory-augmented graph learning framework for AMDD classification. By effectively balancing individual specificity and population-level generalization, BrainMetaGCN advances neuroimaging-based precision diagnosis and provides new insights into the neural and biological mechanisms of adolescent depression.

neuroscience↗

bioRxiv2026

Unbiased Single-Cell Transcriptome-Proteome Co-Profiling Reveals Malignant Dormancy and Post-Transcriptional Buffering of CTCs

Leptomeningeal metastasis is driven by rare cerebrospinal fluid circulating tumor cells (CSF-CTCs). However, the mechanisms underlying their adaptation to chemotherapeutic stress remain elusive, primarily because transcriptomics alone poorly predicts functional protein states. Here, we present scMAPS, a single-cell multi-omics method that employs magnetic-assisted partitioning cell lysates to enable unbiased transcriptome-proteome co-profiling without loss-prone physical splitting and precision device. By coupling scMAPS with our custom CLEAP (CTC Label-free Enrichment and Accurate Picking) system, we performed the first deep multi-omics profiling of rare clinical CSF-CTCs before and after localized chemotherapy, detecting an average of 2,547 proteins and 7,821 genes per cell. The integrated CLEAP-scMAPS pipeline reveals a coordinated prioritizing survival over proliferation malignant dormancy phenotype and identified post-transcriptional buffering as the primary driver of treatment resistance. Our platform enables the comprehensive molecular phenotyping of rare clinical specimens, providing a highly versatile framework for decoding complex post-transcriptional regulatory networks.

cell biology↗

bioRxiv2026

Convergent cortical temporal axis: common cortical oscillatory modes

Brain dynamics provide the most direct substrate for neural function and representation. Extensive prior work has demonstrated that the human brain is organized into hierarchical structures across molecular, cellular, microstructural, and macroscale network levels. However, whether these hierarchies can be directly linked through shared patterns of neural dynamics remains unresolved, and clear evidence from data-driven analyses is still lacking. A central open question is whether brain dynamics vary along a single continuous dimension, or whether they are instead composed of a limited number of reproducible coordination modes that could provide a unifying basis for cross-scale integration. Here, using source-resolved resting-state magnetoencephalography (MEG), we adopt a fully data-driven approach that imposes no a priori assumptions about cortical hierarchy or gradient structure. By characterizing full-spectrum power relationships across cortical regions, we identify a set of stable and reproducible spectral coordination modes. These modes capture how multiple frequency components jointly co-vary across space, defining distinct dynamical configurations rather than conventional band-limited oscillations or continuous gradients. The identified spectral coordination modes exhibit pronounced spatial differentiation across the cortex, distinguishing regions dominated by narrowband rhythmic activity from those characterized by broadband or multi-frequency coordination. Importantly, these modes do not correspond to predefined hierarchical axes, nor can they be reduced to existing MEG gradients or functional connectivity organizations. Instead, they emerge directly from the data, revealing a finite set of shared organizational patterns underlying cortical dynamics. Multimodal analyses further demonstrate that individual spectral coordination modes show selective associations with neurotransmitter system distributions, laminar microarchitecture, and cell-type-specific gene expression, suggesting that these dynamical patterns may serve as linking mechanisms between micro- and macroscale brain organization. Computational modeling supports this interpretation, showing that differences in local circuit parameters are sufficient to generate distinct spectral coordination states without invoking a single global dynamical hierarchy. Across the adult lifespan, these coordination modes exhibit frequency- and region-specific reorganization, indicating multiple parallel trajectories of dynamical aging. In Parkinsons disease, alterations are observed in specific spectral coordination modes, particularly within higher-order cortical regions, suggesting that the disorder preferentially disrupts distinct dynamical configurations rather than inducing a global breakdown of cortical dynamics. Together, these findings indicate that large-scale brain dynamics are not organized along a single pre-existing hierarchical axis, but instead are structured by a limited number of data-driven spectral coordination modes. This framework provides a new dynamical perspective for linking brain organization across modalities and scales, and offers a principled avenue for understanding systematic changes associated with aging and neurological disease.

neuroscience↗

bioRxiv2026

Bacillus velezensis GFZF-23 Alleviates Colitis through Microbiome Restoration and β-Sitosterol-Mediated Metabolic Reprogramming

BackgroundA major hurdle in probiotic development for inflammatory bowel disease (IBD) is the inability to disentangle their direct effects on the host from those mediated through the resident microbiota. Here, we establish a reverse screening platform in gnotobiotic zebrafish to overcome this limitation. ResultsWe isolated Bacillus velezensis (B. velezensis) GFZF-23 from long-surviving gnotobiotic zebrafish and demonstrated its potent protective effects against DSS-induced colitis. The strain significantly attenuated intestinal damage and inflammatory responses in both germ-free and conventional hosts. Multi-omics analysis revealed that B. velezensis GFZF-23 employs environment-specific strategies. In the presence of a microbiome, it restored community homeostasis by enriching beneficial taxa, such as Faecalibacterium. Strikingly, in germ-free conditions, GFZF-23 did not simply reverse disease-associated markers but actively reprogrammed host metabolism, with particular enrichment in the linoleic acid pathway. Functional assays confirmed that {beta}-sitosterol serves as a critical effector metabolite driving this protection. ConclusionsThis work establishes B. velezensis as a promising therapeutic candidate and provides a robust framework for deconvoluting the direct and indirect effects of potential probiotics. Our findings highlight metabolic reprogramming as a vital, underappreciated mechanism in precision microbiome therapeutics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/710680v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@10868e6org.highwire.dtl.DTLVardef@11f1532org.highwire.dtl.DTLVardef@1a88631org.highwire.dtl.DTLVardef@1020b33_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗