Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

Geometric Deep Learning Reveals Ligandable and Cryptic RNA Binding Small Molecule Pockets (SMARTPocket)

RNAs are important therapeutic targets, however identifying ligandable small-molecule binding pockets remains a major barrier to RNA-targeted drug discovery. Here, SMARTPocket, an atomic-level geometric deep learning framework for predicting RNA-small molecule binding pockets directly from three-dimensional structure is introduced. SMARTPocket represents RNA as full-atom point clouds and uses transfer learning from more than 110,000 protein binding interface structures to overcome the limited number of experimentally elucidated RNA-ligand complexes. Across four established single-chain benchmarks and three broader curated benchmarks, SMARTPocket consistently outperforms existing RNA pocket predictors and general biomolecular modeling approaches. The model generalizes to apo RNA structures when conformational changes are modest, identifies cryptic ligandable pockets, and recapitulates experimentally validated binding sites in the SARS-CoV-2 frameshifting element and an RNA aptamer evolved to bind small molecules. SMARTPocket-guided docking further improves near-native RNA-ligand pose recovery and computational efficiency compared with blind docking. These results establish SMARTPocket as a generalizable framework for structure-based identification of ligandable RNA pockets and for accelerating discovery of RNA-targeted small molecules.

bioinformatics↗

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2026

MetaHarmonizer: robust biomedical metadata harmonization and a contamination control for inflated LLM performance on public benchmarks

Public biomedical repositories hold substantial reuse potential, but inconsistent metadata routinely blocks integration across studies. Recent LLM-based harmonization approaches address scale but suffer from non-determinism, hallucinated ontology terms, and, in their highest-accuracy configurations, dependence on proprietary APIs or labeled fine-tuning data. A more fundamental concern is that LLM accuracies on widely-used public benchmarks may substantially inflate transferable capability: under a contamination-controlled evaluation protocol we developed, the apparent LLM-only advantage on the GDC schema-mapping benchmark is inverted and three out of five LLMs recovers 80-100% of GDC identifiers from zero-schema context, suggesting direct memorization. Building on this insight, we present MetaHarmonizer, an automated metadata harmonization system designed to be robust by construction: SchemaMapper aligns attribute names across schemas, and OntologyMapper standardizes values to controlled vocabularies. Both modules implement a multi-stage cascade that escalates to more resource-intensive methods only when earlier stages fall short, with all candidates grounded in pre-defined controlled vocabularies to preclude hallucinated outputs and LLMs used only as bounded preprocessing components rather than inference-time dependencies. On the GDC schema-matching benchmark, SchemaMapper with the deployment-optimized LLM-generated alias dictionary achieved 71.6% Top-1 accuracy and the higher Recall@GT than Magneto bipartite variants, recovering significantly more ground-truth mappings; with the best performing alias dictionary, it reached the highest Top-1/Top-5/Recall@GT, and also matched the best Magneto reranker (fine-tuned LLM-reranker) on MRR; and it also outperforms LLM-only performance under contamination-controlled conditions. On four EFO benchmarks, OntologyMapper achieved 77.9-95.5% Top-1 accuracy, outperforming text2term by up to 16.4 pp and direct LLM inference (against the smaller corpus) by 19.2 pp because memorization is not a viable shortcut for this task. Across both modules, calibrated confidence scores separate correct from incorrect predictions (AUC 0.73-0.94), enabling principled human-in-the-loop triage. Inference is fully local, deterministic, and computationally efficient - seconds on schema mapping and under a minute for ontology mapping of up to [~]7,000 terms against the pre-indexed 33,230-term corpus. Released as a Python package with a domain-agnostic architecture, MetaHarmonizer provides a scalable foundation for improving the FAIRness of biomedical data and enabling cross-study integration, alongside an evaluation methodology applicable to any LLM-augmented bioinformatics benchmark built on public benchmarks.

bioinformatics↗

bioRxiv2026

OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era

Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term "Alzheimers disease", OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery. HighlightO_LIOmicVerse 2.0 consolidates 694 methods spanning 11 omics domains into agent-callable high-level APIs. C_LIO_LIRebuildR automatically reconstructs and evolves R/Bioconductor methods as Python-native implementations under output-equivalence gates. C_LIO_LIOmicOS establishes a state-of-the-art omics agent harness, ranking first on general omics benchmarks across models and substantially improving the analytical capability of local open-source models. C_LIO_LICompositional use of ecosystem modules nominates a colon epithelial axis associated with Alzheimers disease risk. C_LIO_LIExternal algorithm packages supporting automatic iterative evolution can be integrated into the OmicOS ecosystem. C_LI

bioinformatics↗

bioRxiv2026

Hypermutability of ultraconserved histone genes and its contribution to human disease

Histone genes are among the most evolutionarily conserved sequences in eukaryotes, reflecting their essential role in nucleosome architecture. Intriguingly, our analysis reveals unexpectedly high germline mutation rates in replication-dependent histone genes across vertebrates. We provide multiple lines of evidence suggesting that this hypermutability is largely driven by off-target mutagenic effects of AID/APOBEC enzymes, representing an unintended fitness cost associated with vertebrate immune system innovation. To characterize the impact of these mutations, we develop HistMTR, a paralog-aware missense constraint framework that outperforms existing tools in predicting the pathogenicity of histone mutations. Applying this framework to large-scale human genomic data, we demonstrate that both coding and regulatory histone mutations contribute to a spectrum of diseases, including developmental disorders and reproductive failure. Analyses of allele transmission ratios and the distribution of fitness effects indicate intense ongoing negative selection against deleterious histone mutations in humans. Together, these findings uncover a hidden vulnerability of ultraconserved histone genes and establish HistMTR as an important framework for characterizing the underappreciated role of histone mutations in human disease.

evolutionary biology↗

bioRxiv2026

Oxidized protein states define metastatic fitness in lung cancer

AbstractReactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10*Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo. These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

Cancer Biology↗

bioRxiv2026

Duplication of superoxide dismutase and a mutation in aquaglyceroporin mediates the sensitivity of Plasmodium falciparum to cryptosporin, a natural product derived from Acaromyces ingoldii

Cryptosporin, a fungal metabolite, exhibited potent antimalarial activity against both asexual blood stage Plasmodium falciparum and liver-stage Plasmodium berghei with minimal human HepG2 toxicity. Unlike atovaquone, cryptosporins mechanism is independent of mitochondrial electron transport. Minimum inoculum of resistance showed a low risk of resistance development. RNA-Seq analysis revealed the upregulation of genes associated with sexual development including many canonical markers such as Pfs25, and PfCCp3, suggesting a stress response that is also seen when parasites are treated with artemisinin. In vitro evolution and whole genome sequencing analysis identified a mutation (F138Y) in PfAQP (PF3D7_1132800) and duplications of the two superoxide dismutase genes, PfSOD-1 (PF3D7_0814900) and PfSOD-2 (PF3D7_0623500). CRISPR/Cas9 editing confirmed that the F138Y mutation in PfAQP was sufficient to confer resistance to cryptosporin. Alignment of the P. falciparum structure with that of HsAQP3 suggests the mutation may impact transport of hydrogen peroxide and the transition between open and closed conformations. Indeed, studies with BY4742 {Delta}fps1 yeast expressing PfAQP showed that the permeability of PfAQP was not affected by cryptosporin and that it is likely not a direct target. Taken together, this study highlights the role of PfAQP in the resistance development of cryptosporin. In addition, cryptosporin likely induces high levels of oxidative stress which results in the duplications of oxidative dismutase genes as part of the parasites defense response. These findings highlight the role of PfAQP in mediating drug resistance, the mechanism of which warrants further research.

genetics↗

bioRxiv2026

mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment.

IntroductionResistance to immunotherapy remains a major clinical challenge in TP53-mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K/AKT/mTOR signaling in TP53-mutant HNSCC and its role in disease progression, we investigated whether the mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes. MethodsWe evaluated the effects of mTOR inhibitor everolimus in TP53-mutant, anti-PD-1-resistant syngeneic HNSCC cell lines and syngeneic tumor models. Tumor microenvironment (TME) changes, including immune cell infiltration, immune checkpoint expression, and key pathways associated with immune suppression and angiogenesis were assessed to define the mechanisms underlying TME remodeling. ResultsEverolimus significantly suppressed tumor growth in syngeneic HNSCC models. At the cellular level, everolimus significantly increased intratumoral CD8+ T cell and dendritic cell (DC) infiltration while reducing the accumulation of regulatory T cells (Tregs). Mechanistically, everolimus induced a cytokine/chemokine response, marked by increased TNF-/CXCL10 expression, leading to enhanced immune infiltration. Everolimus also inhibited the HIF-1/VEGFA angiogenic axis, a central driver of immune exclusion and myeloid-derived suppressor cell (MDSC) recruitment. Furthermore, everolimus treatment attenuated PD-1/PD-L1 signaling by reducing PD-1 and PD-L1 expression, respectively, in T cells and tumor cells, thereby restoring T-cell cytotoxic competence. DiscussionThese findings demonstrate that mTORi with everolimus reverses multiple mechanisms of immune resistance in TP53-mutant HNSCC by promoting immune cell recruitment, suppressing immunosuppressive pathways, and enhancing anti-tumor T cell activity. Collectively, these results support mTORi as a mechanistically rational strategy for reprogramming immune resistance in TP53-mutant HNSCC and provide a strong preclinical rationale for combining everolimus with immune therapy in patients who are likely to fail immunotherapy.

cancer biology↗

bioRxiv2026

Extracellular salicylic acid activates immune signaling through cell-surface receptors

Salicylic acid (SA) is a central immune hormone that accumulates in both intracellular and extracellular compartments during pathogen infection. While intracellular SA signaling is well established, whether extracellular SA (eSA) directly activates immune responses remains unknown. Here we show that eSA functions as an extracellular signal potentially perceived by the plasma membrane-localized lectin receptor kinases LecRK-I.8 and LecRK-VI.2 in Arabidopsis. The extracellular domains of both receptors bind SA with micromolar affinity, SA rapidly induces LecRK-I.8 phosphorylation, and the kinase activities of LecRK-I.8 and LecRK-VI.2 are required for downstream signaling. Moreover, mutagenesis of a computationally predicted binding pocket in LecRK-VI.2 abolishes SA binding and immune function, providing evidence for receptor-mediated perception. Genetic analyses further demonstrate that LecRK receptors are required for SA-induced resistance, transcriptional reprogramming, and phosphoproteomic responses. Together, these findings expand current models of SA signaling by revealing a potential receptor-mediated cell-surface perception mechanism for a classical immune hormone.

plant biology↗

bioRxiv2026

Multiscale modeling of the subcutaneous administration of peptides

With the increasing prevalence of subcutaneous administration of peptides, understanding their release and absorption is key to designing formulations with desired pharmacokinetics. Though the absorption of monoclonal anti-bodies (mAbs) has been widely explored through computational modeling, that of peptides remains poorly understood, as key features of peptide absorption, including concentration-dependent oligomerization and reversible binding with serum albumin and extracellular matrix, have not been captured. In this work, we present a first-of-its-kind approach to simulating subcutaneous administration of peptides that couples a high-fidelity tissue-level poroelastic model with a systemic compartment pharmacokinetic model. While accounting for competing binding and oligomerization tendencies of peptides, the model not only captures the process of injection but also tracks the absorption over subsequent days. We demonstrate the model using a single-dose administration of semaglutide and validate it against experimentally observed pharmacokinetic parameters. The results show the distribution of the different forms of the injected peptide throughout the body and describe the role of binding in sustaining its release. The model also reveals novel mechanisms, such as albumin-bound monomers enveloping the plume and the balance of oligomerization and binding in early stages of peptide absorption.

pharmacology and toxicology↗

bioRxiv2026

Short T1 Fraction as a Marker of Myelin Content: Evidence from Postmortem MRI and Histology

PurposeTo investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth. MethodsMulti-inversion-time MRI data were acquired from four postmortem brain hemisphere specimens from donors with Alzheimers disease on a clinical 3T scanner, and from five dissected tissue blocks containing white matter hyperintensities (WMHs) on a preclinical 3T system. Short-T1 fraction maps were generated using inverse Laplace transform to isolate short-T1 components and were compared with T2-based myelin water imaging metrics through joint T1-T2 correlation analysis. Short-T1 fraction maps from the tissue blocks were further compared with myelin-stained histology. In addition, in vivo short-T1 fraction data were acquired from two elderly volunteers with WMHs to demonstrate translational feasibility. ResultsPostmortem MRI revealed reduced short-T1 fractions in WMHs. T1-T2 correlation analysis showed that the short-T1 fraction was closely associated with the short-T2 (myelin water) component. Strong correlations were observed between short-T1 fractions and optical densities from both Luxol Fast Blue- and myelin basic protein-stained histological sections, supporting the link between the short-T1 signal and myelin content. Consistent findings were also observed in vivo, where significant reductions in short-T1 fractions were detected within WMHs. ConclusionThe short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a clinically translatable biomarker of myelin integrity.

neuroscience↗

bioRxiv2026

Discovery of ARQ-501 as a potent PafA inhibitor that elevates KatG levels to potentiate isoniazid in mycobacteria

The prokaryotic ubiquitin-like protein (Pup) conjugation system (PPS), which is essential for Mycobacterium tuberculosis (Mtb) virulence but absent in humans, presents an attractive drug target. Here, we report the discovery of ARQ-501, a quinone-based, covalent, substrate-competitive inhibitor of the Pup ligase PafA. ARQ-501 exhibited potent anti-mycobacterial activity against Mtb under host-mimicking stress conditions and within macrophages. We further identified the catalase-peroxidase KatG, essential for activation of the frontline prodrug isoniazid (INH), as a pupylation substrate. ARQ-501 inhibits KatG pupylation, causing its accumulation and creating a selective synergy with INH. This quantity over quality mechanism successfully rescued INH activation by the clinically prevalent KatG S315T mutant in enzymatic assays and enhanced INH efficacy against clinical S315T isolates to variable degrees. This work identifies a novel class of PafA inhibitors and a previously unrecognized role of pupylation in regulating KatG, offering a potential therapeutic avenue to combat drug-resistant tuberculosis.

microbiology↗

bioRxiv2026

Gut Microbiota Dysbiosis Drives Myocardial Hypertrophy Through GBP2b/GBP1-Mediated Immune Reprogramming and Exosomal Signaling in Chronic Colitis

BACKGROUNDPatients with inflammatory bowel disease (IBD) are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. IBD is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction. METHODSA chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA-seq, co-immunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing. RESULTSChronic DSS colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide (LPS) translocation, bone marrow chimera experiments demonstrated that hematopoietic TLR4 signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified guanylate-binding protein 2b (GBP2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of LPS-TLR4 signaling. Upon LPS stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 and FIS1 to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling, and cardiac dysfunction. CONCLUSIONSThese findings establish the LPS-TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with IBD. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIPatients with inflammatory bowel disease have an increased risk of cardiovascular dysfunction that cannot be fully explained by traditional cardiovascular risk factors. C_LIO_LIGut microbiota dysbiosis and chronic innate immune activation are hallmarks of inflammatory bowel disease, but their direct contribution to cardiac remodeling remains unclear. C_LI What New Information Does This Article Contribute?O_LIChronic colitis-associated gut microbiota dysbiosis induces systemic immune cell metabolic and mitochondrial reprogramming that is sufficient to drive cardiomyocyte hypertrophy and cardiac dysfunction. C_LIO_LIHematopoietic Toll-like receptor 4 signaling links colitis associated gut microbiota to immune metabolic dysfunction and cardiac impairment, establishing a causal gut-immune-heart axis. C_LIO_LIGuanylate-binding protein 2b (GBP2b/GBP1) is identified as a critical downstream effector that promotes mitochondrial fission, oxidative stress, immune cell cardiac infiltration, and exosome-mediated cardiac remodeling. C_LI

pathology↗

bioRxiv2026

The bacterial swarming factor SwrD forms hexameric rings reminiscent of DNA binding proteins.

Prokaryotic swarming is a collective surface-associated behavior that supports rapid colonization, biofilm formation, and host interactions. Swarming requires enhanced flagellar motor (FM) torque generation under high-load conditions. In many bacteria, this adaptation is achieved through increased stator unit recruitment and coordinated transcriptional regulation of motility genes. Genetic studies have implicated several relatively poorly characterized proteins in swarming, including SwrD, a component of the fla-che operon whose loss impairs torque generation in Bacillus subtilis. Intriguingly, SwrD is conserved in spirochetes that experience high viscous loads but do not exhibit canonical swarming, suggesting a broader functional role in FM regulation. Here, we structurally and biophysically characterize SwrD from B. subtilis and the spirochete Borrelia burgdorferi. In both cases, we show that SwrD assembles into a hexameric ring-like structure featuring a highly charged, disordered peripheral tail. Whereas SwrD displays structural similarities to DNA-binding proteins, key DNA interaction motifs are not conserved in SwrD. Deletion of swrD in B. subtilis results in pronounced swarming defects and altered expression of fla-che operon transcripts. In silico interaction analyses further identify the stator protein MotA as a high-confidence SwrD interactor, but this interaction could not be validated biochemically. Conserved SwrD residues mediate subunit interactions or locate to the hexamer periphery where they may mediate functionally important interactions.

biochemistry↗

bioRxiv2026

An SE(3)-equivariant Crystal Structure Prediction Framework for Prospective Identification and Development of Bioactive Nucleoside Self-Assembling Materials

Flexible organic small molecules can assemble into supramolecular biomaterials whose properties are intrinsically governed by their crystal structures, yet experimental structure determination remains difficult to scale during molecular modification and materials optimization. Crystal structure prediction (CSP) provides a potential solution, but its prospective power is limited for flexible molecules owing to incomplete conformational sampling and the difficulty of identifying experimentally realized structures from large candidate sets. Here, an SE(3)-equivariant deep-learning workflow, SE3CSP, is developed for organic crystal structure prediction. By learning molecular conformations, unit-cell parameters and packing patterns from experimentally resolved crystal structures and integrating these predictions with MACE-based structure optimization, SE3CSP establishes an end-to-end pipeline from two-dimensional molecular representations to three-dimensional crystal structures. Using nucleosides as representative flexible self-assembling building blocks, SE3CSP achieves an overall prediction accuracy of [~]57%, substantially outperforming the benchmark MACE-based Genarris 3.0 workflow ([~]14%). Furthermore, a prospective prediction strategy is developed in which an SE3CSP-predicted density window ({+/-} 0.15 g/cm3) is applied prior to energy ranking and structural deduplication, enabling all experimentally realized structure to be consistently ranked within the top 1-2% of all generated candidates. Beyond structure prediction, SE3CSP-derived energy landscapes provide insight into potential single-crystal-to-single-crystal transformations and enable the identification of a nucleoside supramolecular material with dynamic breathing porosity, which is further developed as an adsorptive platform for inflammatory mediator removal with excellent anti-inflammatory performance and biocompatibility. These results establish SE3CSP as a practical framework for prospective CSP and highlight its utility in guiding the discovery and design of bioactive self-assembled materials.

bioengineering↗

bioRxiv2026

Intrinsic space-time couplings governing multi-scale cortical dynamics

The neocortex covers a vast expanse of the mammalian brain and represents the principal target of clinical neuromodulation; however, the global principles of neocortical operation have been challenging to identify. In this regard, a limitation has been tracking activity with cortex-wide spatial coverage while maintaining access to the millisecond temporal resolution of neuronal firing-- a crucial combination not achievable with existing recording technologies. Here we introduce and apply conformal immersion microscopy, enabling activity tracking across the entire dorsal cortex with millisecond temporal resolution and 100 {micro}m spatial resolution (thus spanning five orders of magnitude in time and four in space), at sufficient sensitivity to resolve single-trial activity beyond 100 Hz. Drawing on physics-based frameworks, we apply multiscale analysis to identify a fundamental frequency-dependent coherence length that partitions the neocortex into discrete dynamical elements with well-defined propagation speeds, boundaries, and scale-invariant dynamics. These dynamical elements were found to be conserved from sub-threshold to suprathreshold (neuronal firing) regimes of neural activity, and were robust to diverse pharmacological, optogenetic, and genetic interventions. However, it was possible to identify and establish conditions allowing elemental boundaries to be selectively overridden, and to allow perturbation of specific elements even while conserving global dynamical architecture. Together, these findings enable measurement of intrinsic spatiotemporal parameters governing the dynamical organization of neocortex, which may provide a foundation for mechanistically-informed basic and translational understanding.

neuroscience↗

bioRxiv2026

MeCP2 is Necessary in Cerebellar Purkinje Cells for Precise Network Dynamics During Associative Motor Learning

Loss-of-function variants of MECP2 cause Rett syndrome; however, their impact on cerebellar computations for learning remains poorly understood. Here, we show that Mecp2 deletion specifically in Purkinje cells does not broadly disrupt cerebellar-dependent behaviors but selectively compromises those that require precise timing, coordination, and associative updating in the cerebellar cortex. Mecp2 loss altered the emergence of learning-related Purkinje cell activity in vivo and disrupted their intrinsic and synaptic properties that support adaptive cerebellar output. These findings identify MeCP2 as a critical player in Purkinje cell function to regulate cerebellar learning signals and suggest that Rett syndrome-related motor dysfunction reflects impaired adaptive computation rather than a generalized loss of motor capacity.

neuroscience↗

bioRxiv2026

Identification of Reductases Catalyzing Benzyl Alcohol Formation during Salicylic Acid Biosynthesis in Plants

Salicylic acid (SA), a central hormone in plant immunity, is biosynthesized via a recently elucidated phenylalanine-derived pathway in most seed plants. This pathway requires benzyl alcohol as a key substrate for the formation of the SA precursor benzyl benzoate. However, how benzyl alcohol is produced in plants was unclear. Here, we identify a two-step conversion of benzoyl-CoA to benzyl alcohol via benzaldehyde in Nicotiana (N.) benthamiana. From a forward genetic screen for SA-deficient mutants, the and {beta} subunits of heterodimeric benzaldehyde synthase (BalS) involved in the conversion of benzoyl-CoA to benzaldehyde were found to be required for SA biosynthesis in N. benthamiana. Further reverse genetic analysis revealed that the NADPH-dependent benzaldehyde reductase (BalR1) acts downstream of BalS to convert benzaldehyde to benzyl alcohol. Interestingly, OsBalR1, but not OsBalS or OsBalS{beta}, is required for maintaining high basal SA levels in rice, suggesting the presence of redundant benzoyl-CoA-reducing activities or alternative biosynthesis routes for benzyl alcohol production. Together, this work defines the missing enzymatic steps in phenylalanine-derived SA pathway and provides insights into the evolutionary diversification of SA production strategies in plants.

plant biology↗