Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 361 records · Page 20Linked to original sources

bioRxiv2026

Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor azenosertib (ZN-c3) mediates tumor control through both cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells and conventional dendritic cells. Mechanistically, HPV tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.

cancer biology↗

bioRxiv2026

Self-Terminating Bilayer Hydrogel Actuators via Enzyme-Programmed Mechanical Feedback

Autonomous soft materials that can actuate, perform a function, and then self-terminate without external intervention remain difficult to realize. Here, a bilayer hydrogel actuator fabricated by digital light processing-based 3D bioprinter is introduced that couples rapid thermoresponsive deformation with slower enzyme-programmed mechanical feedback to achieve self-regulated shape transformation and autonomous recovery. The system integrates a poly(N-isopropylacrylamide) actuation layer with a bovine serum albumin-poly(ethylene glycol) diacrylate enzyme-programmed layer loaded with trypsin. Above the lower critical solution temperature, deswelling of the actuation layer generates a strain mismatch across the bilayer and drives rapid closure. In parallel, proteolytic cleavage of albumin domains progressively softens the enzyme-programmed layer, reduces interlayer constraint, and acts as an intrinsic mechanical off-switch that relaxes curvature and restores the open state. This materials logic enables sustained enzyme release, time-dependent modulus loss, and autonomous shape recovery without staged external triggers. As a proof-of-concept, this platform is implemented as a gastrointestinal-retentive hydrogel gripper for localized intestinal enzyme delivery, where it exhibits thermally triggered gripping, millinewton-scale gripping force, autonomous reopening, and robust ex vivo retention on porcine small intestine under dynamic motion. These findings establish enzyme-programmed mechanical feedback as a general design strategy for self-regulated soft actuators and therapeutic materials with built-in functional lifetimes.

bioengineering↗

bioRxiv2026

Placental prostaglandin signaling disrupts barrier integrity and relays an acute inflammatory signal to the fetus.

Maternal inflammation during pregnancy is a major risk factor for adverse neurodevelopmental outcomes, yet the mechanisms linking maternal immune activation (MIA) to placenta-fetal brain axis dysfunction remain unclear. Using a poly-(I:C) mouse model, we show that MIA rapidly disrupts placental-blood barrier (PBB) integrity by disrupting pericyte-endothelium coupling within 48 hours, leading to increased placental permeability detected by in vivo MRI. We identify a prostaglandin E2 (PGE2)-dependent pathway involving cyclooxygenase-2 (COX2) and prostaglandin E-synthase (mPGES1) as a key mediator of this effect. Pharmacological inhibition of COX2 prevented MIA-induced structural and functional changes. In vitro explant studies confirmed that PGE2 acts via the EP3 receptor to disrupt pericyte-endothelium interactions, while ex vivo perfusion demonstrated that in addition to its local effects on PBB structure, placenta-derived PGE2 enters the fetal circulation. Finally, similar vascular alterations were observed in human placentas from pregnancies with severe maternal inflammation. These findings reveal a conserved inflammatory mechanism that compromises PBB integrity and may relay signals to the fetal brain, highlighting potential therapeutic targets for neuroprotection during prenatal inflammation. One Sentence SummaryMaternal immune activation during pregnancy disrupts placental vascular integrity through a COX2-dependent prostaglandin E2 pathway, which compromises the placenta-blood barrier and relays inflammatory signals to the fetus, identifying potential therapeutic targets for neuroprotection.

developmental biology↗

bioRxiv2026

Acute Degradation of Pumilio Proteins Uncovers a Biphasic Post-transcriptional Regulatory Hierarchy Controlling Embryonic Stem Cell Fate Decisions

Post-transcriptional regulation is critical for mammalian embryogenesis yet has been underexplored. We previously showed that RNA-binding Pumilio proteins (Pum1/2) are essential for early mouse embryogenesis and embryonic stem cell (ESC) functions. Here, using acute protein degradation systems combined with time-resolved RNA-seq and eCLIP, we delineate a two-phase regulatory hierarchy modulated by Pum1/2 in mouse ESCs. The first phase, occurring within 10 hours of Pum1/2 depletion, is predominantly the stabilization of over 100 Pum1/2-target mRNAs, while the second phase, occurring in subsequent 66 hours, propagates to over 1,000 mRNAs mostly through indirect regulatory effects. Functionally, Pum1/2 depletion delays transition from naive to formative pluripotency, impairs neuroectoderm differentiation, and enhances germline specification. Mechanistically, Pum1/2 directly repress mRNAs encoding PRC2 subunits, including Suz12, thereby constraining H3K27me3 deposition at neuroectodermal gene loci. These findings establish Pum1/2 as biphasic post-transcriptional regulators of pluripotency and lineage balance and link RNA stability control to chromatin-mediated silencing. HIGHLIGHTSO_LIAcute Pum1/2 degradation provides temporal resolution for profiling post-transcriptional regulation. C_LIO_LIPum1/2 destabilize more than 100 direct targets and modulate a biphasic network of over 1,000 mRNAs. C_LIO_LIPum1/2 loss delays pluripotency transition, suppresses neuroectoderm, and promotes germline fate. C_LIO_LIPum1/2 directly regulate Suz12 mRNA decay to modulate PRC2-mediated repression. C_LI

cell biology↗

bioRxiv2026

Zhi-Shi-Wu-Huang attenuates amyloid beta toxicity in Caenorhabditis elegans Alzheimer's disease models via modulating insulin DAF-16 signaling pathway

Alzheimers disease (AD) is a common neurodegenerative disorder primarily caused by Amyloid-beta (A{beta}) toxicity. Therefore, there is an urgent need to develop novel, effective, and safe drugs to treat AD. Traditional Chinese Medicine (TCM) has a long history of use in protecting against memory impairments. Recently, TCM has attracted growing attention from researchers as a source of potent neuroprotective compounds. In this study, we focus on four TCM herbs with multiple therapeutic properties: Valeriana jatamansi (V; 20 mg/mL), Acori tatarinowii (A; 10 mg/mL), Fructus Schisandrae (F; 5 mg/mL), and Scutellaria baicalensis (S; 2.5 mg/mL). The aim is to develop a neuroprotective anti-AD formulation, named "Zhi-Shi-Wu-Huang" derived from V, A, F, and S, and evaluate its efficacy in transgenic Caenorhabditis elegans models of AD. These four TCM herbs are among the most potent activators of the HSP-70 promoter, promoting the expression of heat shock protein 70 (HSP-70), which helps prevent protein misfolding and aggregation. Additionally, V, A, F, S, and the Zhi-Shi-Wu-Huang formula were found to reduce reactive oxygen species (ROS) production and enhance the expression of superoxide dismutase-3 (sod-3) and chymotrypsin-like proteasomes. Our findings demonstrate that both the individual extracts (V, A, F, S) and the Zhi-Shi-Wu-Huang formulation significantly reduce A{beta}-induced toxicity in transgenic worms by activating the insulin/DAF-16 signaling pathway.

neuroscience↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗

bioRxiv2026

A Niclosamide Prodrug SSL-0024 with Enhanced Bioavailability Suppresses Hepatocellular Carcinoma via Multi-Pathway Signaling Inhibition

BackgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for effective therapies. The FDA-approved anthelmintic, niclosamide, is a promising repurposed drug candidate for HCC; however, its clinical application in solid tumors is hampered by poor aqueous solubility and resulting low bioavailability. MethodsWe designed and screened eight novel niclosamide prodrug candidates for solubility, stability, and anti-proliferative activity in HCC cell lines. The lead compound, SSL-0024, was evaluated for pharmacokinetics and anti-tumor efficacy in an orthotopic patient-derived xenograft (PDX) model, and for cytotoxicity in patient-derived organoids (PDOs). Mechanistic studies assessed AKT-mTOR-STAT3 and other related signaling pathways. ResultsThe O-sulfate derivative, SSL-0024, demonstrated improved solubility and pH stability, and a sustained release of niclosamide over [~]48 h. Once-daily oral administration of SSL-0024 (100 mg/kg) achieved [~]60% tumor growth inhibition in PDX models at [~]46.8% of the niclosamide ethanolamine dose, with minimal toxicity. It also induced significantly greater cytotoxicity than sorafenib (p<0.05) in the PDO. Mechanistically, SSL-0024 suppressed major oncogenic pathways including AKT-mTOR-STAT3, RAF, and Wnt/{beta}-catenin. ConclusionsSSL-0024 overcomes key pharmacokinetic limitations of niclosamide while maintaining potent anti-tumor activity, supporting its further development as an orally bioavailable therapeutic candidate for HCC.

cancer biology↗

bioRxiv2026

SPICE: Fast parametric inference of significance for spatial associations between brain maps

Testing for spatial correlations between pairs of brain maps has emerged as a central task in neuroimaging studies. Determining the statistical significance of such correlations is challenging due to the presence of spatial autocorrelation in brain maps. Here we establish a novel parametric method, Parametric Spatial Test for Associations (PaSTA), to infer the significance of spatial associations between brain maps via covariance-variance modelling and effective degrees of freedom estimation. Our method is fast, reliable, and sensitive, enabling flexible significance testing of brain map correlations over arbitrary cortical surface and brain volumetric domains. We examine the sensitivity and specificity of PaSTA using simulated datasets with known ground truth and demonstrate its utility when applied to empirical brain maps. We extend PaSTA to approximately model modest nonstationarity in spatial autocorrelation and show that, our method yields improved false positive control and statistical power relative to existing approaches when brain maps are spatially heterogeneous.

neuroscience↗

bioRxiv2026

Hunting for Helminths: short- and long-read shotgun metagenomics for parasite detection in faecal samples

Soil-transmitted helminths (STHs) pose significant challenges to public health in endemic areas, necessitating reliable methods for their detection. Shotgun metagenomics enables simultaneous detection of STHs and microbes in a sample without prior knowledge of what is present. However, validation of shotgun metagenomics with known infection intensity or across different sequencing platforms has not been carried out for eukaryote parasites including STHs, and false positives remain a pervasive issue. We validated shotgun metagenomics as a method of STH detection in faecal samples. Using the Strongyloides ratti laboratory model of a STH infection we investigated how analytical methods (nucleotide-nucleotide matching, nucleotide-protein matching, marker gene detection, mitochondrial mapping), infection intensity and sequencing technology (short-read vs. long-read) affects sensitivity and specificity of detection. S. ratti was accurately detected at a standard laboratory dose, but low intensity infections were more difficult to detect. Only mitochondrial sequence mapping was 100% accurate at identifying S. ratti with no false positives. Overall, short-read outperformed long-read sequencing methods. We applied the same analytical methods to human faecal samples with confirmed infections for at least one of four STHs. Mitochondrial sequence mapping was also the most effective method for detecting STHs in human faecal samples, detecting 100% of Necator americanus and 92% of Ascaris spp. infections, but could not reliably detect STHs where DNA levels are expected to be low or variable. In conclusion, mitochondrial mapping was the most effective method of detection for sensitivity and specificity in both the laboratory system and human faecal samples. Our findings indicate that shotgun metagenomics should be approached cautiously using validated methods, particularly when infection intensity or DNA levels are expected to be low. Author SummarySoil-transmitted helminths (STH) such as the parasite Strongyloides, are important gastrointestinal parasites of humans and livestock. Accurate methods of detection for diagnostics and monitoring are important to implement suitable control and treatment strategies. Here we validate a shotgun metagenomics approach, where all DNA in a sample is sequenced, for detecting STH in faecal samples using a Strongyloides laboratory model for infection. Strongyloides was reliability detected in faecal samples at higher infection levels, but mitochondrial genome mapping of the sequences was the only analytical method that reliably detected Strongyloides at lower infections levels. These results were reflected in stool samples from humans infected with STH, where mitochondrial mapping was also the most reliable method. However, species that were associated with low levels of parasite material or DNA in the faeces including Strongyloides stercoralis, were more difficult to detect. We compared two sequencing methods: short-read Illumina and long-read Oxford Nanopore Technologies, but short-read outperformed long-read shotgun metagenomics. Contamination of bacteria sequences in parasite genome assemblies was problematic for analysis and contributed to false positive results. Future work should focus on specific targeting of eukaryote DNA either at the laboratory or bioinformatic stage to improve STH detection further.

molecular biology↗

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↗

bioRxiv2026

Telomere-to-telomere assembly and haplotype analysis of tetraploid Dendrobium officinale illuminate Orchidaceae polyploid evolution and mycorrhizal symbiosis genes

Dendrobium officinale is a typical epiphytic orchid. We report the telomere-to-telomere (T2T) genome assembly for D. officinale, representing the first T2T reference genome within the Orchidaceae family. The assembly is anchored to 19 chromosomes and contains 38 complete telomeres and 15 characterized centromeres. We further generated haplotype-resolved assemblies of the autotetraploid genome, identifying 12,761 sets of tetra-allelic genes. Based on synonymous substitution analysis, we inferred that the autotetraploidization event occurred approximately 0.86 million years ago. A systematic analysis of the SWEET gene family across the genus Dendrobium revealed that the gene family size is shaped primarily by epiphytic types and environmental factors. In D. officinale from Langshan, eight SWEET genes were specifically expressed in roots, suggesting they may play specialized roles in the root mycorrhizal system, potentially contributing to the D. officinales ability to recruit and maintain fungal partners. Together, these resources provide valuable foundations for studies of orchid evolution, functional genomics, and molecular breeding.

bioinformatics↗

bioRxiv2026

Positive Affect Modulates Early Valuation and Conflict Processing in Social Decision-Making

Social decision-making relies on dynamic affect-cognition interactions across distributed brain networks, yet how incidental positive affect modulates these mechanisms at a millisecond timescale remains unclear. This study investigated the impact of music-induced positive emotion on the neural dynamics of decision-making in the Ultimatum Game. Fifty-six participants were assigned to either a happy music group or an active control (rain sound) group. Fifty-six participants were assigned to either a happy music group or an active control (rain sound) group, while electroencephalography was recorded to capture rapid neural dynamics. Behaviorally, happy music accelerated reaction times (RTs) and decoupled the ERP-RT correlations observed in the control condition. Neurally, positive affect amplified event-related potential amplitudes during early conflict detection (220-280 ms) and late valuation (520-560 ms) stages. Multivariate pattern analysis further revealed that happy music enhanced the neural separability and temporal stability of decision states (accept vs. reject). Moreover, using support vector regression based on functional network features, we found that decision acceptance rates were predicted with significantly higher accuracy in the happy music group (R = 0.60) compared to controls (R = 0.41). Crucially, feature weight analysis indicated a topological shift in decision strategy: while the control group relied on frontal-central edges (implicating executive control), the happy music group was characterized by central-temporal connections (suggesting integrative processing). Collectively, these findings provide novel evidence that incidental emotion intervenes at the millisecond timescale to bias social choices, offering a dynamic network-based account of the affect-cognition interaction.

neuroscience↗

bioRxiv2026

Toward Computationally Complete Spatial Omics

Multimodal spatial omics has transformed biology by mapping molecular complexity within intact tissues, yet current technologies remain limited in the number of modalities measured simultaneously and often produce lower-quality data than single-modality assays. We present COSIE, a computational framework that generates high-resolution, multilayered molecular landscapes across tissue sections, individuals, and platforms. COSIE integrates histology, epigenome, transcriptome, proteome, and metabolome into a unified representation. Applied to 12 datasets spanning 10 spatial technologies, eight modalities, and nine tissue types, ranging from thousands of spots to millions of cells, COSIE outperforms existing methods. It resolves tissue structures, enhances noisy measurements, predicts unmeasured modalities, and captures dynamic processes. In human tumors, COSIE identifies invasive subregions linked to clinical outcomes and predicts spatial gene expression in TCGA samples using only histology images. By transforming fragmented data into comprehensive spatial maps, COSIE advances computationally complete spatial omics and the creation of digital tissue twins for biomedicine.

genomics↗

bioRxiv2026

Metabolic compensation via gluconeogenesis explains the non-essentiality of glycogen phosphorylase as an insecticidal target in Plutella xylostella

Glycogen phosphorylase (GP) catalyzes the rate-limiting step of glycogenolysis and occupies a central position in insect carbohydrate metabolism, supplying precursors for chitin biosynthesis. Acyl urea compounds structurally related to benzoylphenylurea (BPU) insecticides are potent inhibitors of mammalian GP, raising the question of whether insect GP could serve as an independent insecticidal target. Here, we systematically evaluate this possibility in the diamondback moth Plutella xylostella. We show that a mammalian GP inhibitor (GPI) potently inhibits recombinant PxGP (IC50 = 2.96 nM), while the BPU insecticide diflubenzuron (DFB) does not. Molecular docking and MM/GBSA analysis predict that this selectivity reflects differential side-chain engagement: GPI is predicted to occupy the allosteric site at the dimer interface via contacts with seven residues spanning both subunits ({Delta}G = -34.63 kcal/mol), whereas DFB's difluorobenzoyl moiety is predicted to remain solvent exposed without productive protein contacts ({Delta}G = -29.29 kcal/mol). Despite potent in vitro inhibition, GPI exhibits no insecticidal activity, and RNAi-mediated knockdown of PxGP (confirmed by enzyme activity measurements showing ~29% reduction in per-larva GP-a activity) does not impair development or survival. We provide evidence that insects compensate through a multi-layered metabolic response: upregulation of gluconeogenic enzymes (PEPCK, G-6-Pase), selective upregulation of glycogen branching enzyme (GBE) but not -amylase, and changes in protein content suggestive of catabolic substrate mobilization. Fitness assessment reveals transient larval weight loss (24-48 h) with complete recovery of pupal weight, adult wing morphology, and female fecundity, indicating that the metabolic compensation response is ultimately effective in sustaining development. These findings suggest that GP is functionally non-essential under these conditions, likely through a combination of gluconeogenic compensation and the availability of alternative carbon sources, and highlight the importance of considering metabolic network redundancy in target-based insecticide design.

biochemistry↗

bioRxiv2026

Automated high-throughput fabrication of patient-specific vessel-on-chips enables a generative AI digital twin--Cascade Learner of Thrombosis (CLoT) for personalized thrombosis prediction

We developed an integrated platform combining high-throughput automated biofabrication, systematic patient-derived tissue experiments, and specialized artificial intelligence to enable patient-specific computational "digital twins" for thrombosis prediction. Our automated manufacturing platform fabricates 80 fully assembled, patient-specific vessel-on-chips within 10 hours from clinical imaging--a [~]100-fold improvement over manual methods--achieving sub-micron precision through novel two-stage pneumatic motion control and integrated optical feedback. Using these chips, we systematically captured thrombosis across 491 high-fidelity videos spanning 6 patient-derived vascular geometries, 5 distinct anatomical injury sites, and 14 anticoagulant/antiplatelet interventions, establishing a "physical twin" experimental corpus. We trained CLoT (Cascade Learner of Thrombosis), a conditional video diffusion model efficiently adapted via lightweight Low-Rank Adaptation (LoRA) to generate realistic thrombosis videos conditioned on patient-specific geometry, injury location, and drug treatment. Rigorous benchmarking against state-of-the-art commercial models (Sora, Wan, Kling, Seedance, Hailuo, Hunyuan) reveals CLoT achieves 7.38-fold superior temporal biological consistency and 5.3-fold higher spatial morphological fidelity. Prospective validation on unseen patients demonstrates >90% temporal accuracy. This integrated paradigm--combining automated fabrication with domain-specialized generative AI--establishes proof-of-concept for personalized medicine enabled by digital twins trained on human-derived vascular anatomy, enabling pre-treatment antithrombotic evaluation while providing a replicable template for translating tissue engineering into clinical practice.

bioengineering↗

bioRxiv2026

Genetically Programmed Shape-morphing of Engineered Living Materials

Engineered living materials (ELMs) promise genetically programmable functions by coupling biological regulation to synthetic material responses. Here, we introduce genetically encoded, reversible shape-morphing in a peptide-crosslinked polyethylene glycol (PEG) hydrogel whose network density is modulated by opposing enzymatic pairs that induce crosslinking or hydrolysis. This molecular programmability alternates the hydrogel between deswelling and swelling/disintegration and produces 2 - 5-fold changes in mechanical properties. By fabricating a bilayer hydrogel with an inert layer, these molecular modulations are translated into a reversible and directional motion with angular bending motions exceeding 80{degrees}. Further, by embedding genetically engineered bacteria or interfacing mammalian cells, producing the relevant enzymatic cues, the reversible shape-morphing of these ELMs is programmed at the genetic level. We further demonstrate genetically programmed, autonomous reversible bending in a bilayer hydrogel controlled by out-of-equilibrium counteracting biochemical reactions with dynamically changing respective reaction rates. This work establishes a concept where coordinated polymer/peptide material engineering and synthetic biology yield autonomous shape-morphing ELMs, opening avenues toward biohybrid soft robotics, adaptive microfluidic systems, and dynamic biomedical interfaces.

synthetic biology↗

bioRxiv2026

Histone neutralization protects the ischemic brain against stroke-associated pneumonia

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients and mice exposed to middle cerebral artery occlusion, we show that stroke-associated pneumonia markedly worsens clinical stroke outcome. In mice, pneumonia induced 3 days after stroke impaired neurological recovery and increased brain neutrophil infiltrates, blood-brain barrier breakdown, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Neutrophils were critical mediators of pneumonia-induced blood-brain barrier breakdown and microvascular thrombosis. Notably, administration of a neutralizing anti-histone antibody during pneumonia--unlike degradation or blockade of neutrophil extracellular trap formation or myeloperoxidase inhibition--restored long-term neurological recovery and prevented brain atrophy in stroke-associated pneumonia mice. This study identifies extracellular histones as key drivers of secondary inflammatory brain injury and establishes histone neutralization as a therapeutic strategy with an extended treatment window in the post-acute stroke phase. One Sentence SummaryNeutralizing extracellular histones reverses pneumonia-driven secondary brain injury and restores long-term recovery after ischemic stroke.

neuroscience↗

bioRxiv2026

Multiscale confidence quantification for virtual spatial transcriptomics with UTOPIA

Virtual spatial transcriptomics (ST) methods predict gene expression or cell types from histology images, extending molecular readouts beyond the limited regions or samples directly measured by ST platforms. However, the statistical reliability of these predictions remains unclear. Here, we present UTOPIA, a model-agnostic framework for multiscale confidence quantification in virtual ST. UTOPIA assigns statistically calibrated confidence scores to predictions across spatial resolutions and biological granularities, ranging from single genes to metagenes and from specific cell types to broader cell classes. UTOPIA controls false discovery rates for detecting genes, metagenes, or cell types while accounting for local tissue context. We show that prediction confidence depends critically on both spatial resolution and biological granularity, with reliable inference often emerging only at coarser, biologically meaningful scales. Across multiple ST platforms and in both in-sample and out-of-sample settings, UTOPIA enhances interpretability, prevents false biological conclusions, and enables more trustworthy downstream analyses of virtual ST.

genomics↗