Biology subjects

Li, T.

Publications and source records attributed to Li, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Biosynthetic additive manufacturing through mycelium-bacteria consortia

Lignocellulosic biomass is the most abundant renewable raw material on Earth, yet its structural and carbon-storage potential remains unrealized: microbial decomposition returns stored carbon to the atmosphere before it can be harnessed as a durable material. Distinct microbial processes, such as biosynthesis and biomineralization, offer a natural counterpoint, converting organic carbon into mechanically robust, persistent materials such as polymers and minerals. Here, we establish a biosynthetic additive manufacturing strategy through mycelium-bacteria consortia, by coupling fungal self-assembly with bacterial biomineralization inside fabricated three-dimensional scaffolds derived from lignocellulosic biomass. Trametes versicolor forms a continuous living mycelial network that serves as both a structural template and a transport pathway, guiding the spatial colonization of Sporosarcina pasteurii and enabling volumetric calcium carbonate deposition throughout the scaffold interior, overcoming the surface-limited mineralization of conventional microbial systems. Integration with helicoidal Bouligand architectures translates microscale mineral reinforcement into macroscale performance, increasing compressive Young's modulus by 7-14-fold and ultimate strength by 5-fold relative to unmineralized conventional mycelium-based living composites. The living mycelial network also enables autonomous self-healing and modular self-assembly through hyphal bridging without external adhesives or energy input. This work establishes a scalable route for converting and upcycling transient biomass carbon into durable living structural materials for sustainable construction.

bioengineering↗

bioRxiv2026

Disease-associated NK-cell state remodeling reveals transcriptional profiles predictive of clinical phenotypes

Natural killer (NK) cells adapt their cellular states to diverse tissue and inflammatory environments, yet how this plasticity manifests across pathological contexts and relates to patient-level disease phenotypes remains poorly defined. Here we established the Human NK-cell Atlas (HNKA) from over 1 million NK cells, including samples from 1,632 donors spanning 50 diseases. Within a shared NK-cell state architecture, analyses of state abundance and matched-reference exceedance distinguished disease-biased redistribution from transcriptional displacement. Fine-grained analyses localized disease-associated remodeling to specific NK-cell states, including CD56dim NK ISG15 in infection and autoimmunity and CD56bright NK ITM2C in tumors. These patterns were accompanied by recurrent interferon responses and state-specific regulatory activity. Cytokine perturbations recapitulated key transcriptional features of disease-associated NK-cell states. We developed NKceiver, a model based on state-specific NK-cell expression profiles for patient-level prediction. It distinguished 18 diseases and predicted COVID-19 severity and response to immune checkpoint inhibitors, with predictive performance retained in unseen patients and studies. Collectively, our results reveal that disease-associated remodeling within the diverse NK-cell state repertoire resolved by HNKA is biologically interpretable and clinically informative, supporting disease discrimination and prediction of clinical phenotypes.

immunology↗

bioRxiv2026

In Other Words: Learning When to Trust Generated Protein Function Descriptions

Generative protein-to-text models write function descriptions in free-form English but give no indication of which to believe. Indeed, free text is hard to evaluate. We introduce a large language model judge of equivalence of predicted vs. ''true'' function descriptions, validated against blinded expert curation. We also present ProtTale, our sequence-to-text model, that learns from the judge's verdicts to estimate its own reliability, pJay. On unseen Swiss-Prot enzymes, ProtTale and three other leading methods tie on accuracy but are right about different proteins. Here, ProtTale's unique correct predictions outnumber all other methods' combined. Scored from sequence alone, pJay is a plug-in filter, raising all models' performance. On short proteins, it raises precision for every tested method nearly twofold. We argue that generative annotation becomes useful not by being right more often, but by knowing when it can be trusted---a standard that every generative model in biology should meet.

bioinformatics↗

bioRxiv2026

NEIL2 regulates RNA polymerase II dynamics to suppress transcription replication conflicts in pancreatic cancer

Transcription replication conflicts (TRCs) arise from spatiotemporal interference between replication and transcription machinery and contribute to genome instability in cancer cells. In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic KRAS drives TRC formation, and base excision repair (BER) contributes to TRC resolution as an adaptive response. Here, we show that TRCs are enriched in pancreatic tumor sections from patients and are associated with malignant progression. We identify NEIL2, a bifunctional DNA glycosylase in the BER pathway, as a critical regulator of TRCs in PDAC cells. Mechanistically, NEIL2 loss causes aberrant RNA polymerase II (RNAPII) occupancy at transcription start sites and downstream of transcription end sites. Dysregulated RNAPII dynamics promote R-loop-dependent and -independent TRCs contributing to replication stress, DNA damage, and impaired cancer cell proliferation. Notably, the DNA-binding motif of NEIL2 necessary for canonical BER function is dispensable for TRC regulation. Together, these findings reveal an unrecognized role for NEIL2 in regulating RNAPII dynamics and mitigating TRCs in pancreatic cancer cells.

molecular biology↗

bioRxiv2026

Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control

Local tumor therapies rarely induce systemic immunity capable of controlling metastatic disease. Here, we engineer an mRNA lipid nanoparticle (LNP) platform to coordinate innate immune sensing and T cell activation in situ through co-delivery of an autoactivated cyclic GMP-AMP synthase mutant (cGASR241E) and membrane-tethered IL-12 (IL-12TM). cGASR241E mRNA LNPs autonomously generated cyclic GMP-AMP in vivo, activating host STING signaling and initiating antitumor responses. Co-administration with IL-12TM mRNA LNPs promoted localized cytokine production, reduced regulatory T cells, and restored effector function in tumor-infiltrating T cells. This combination elicited systemic antitumor immunity and suppressed distal tumors across multiple mouse models. The therapeutic efficacy required CD8+ T cells and IFNg; signaling in host, supporting a model in which innate DNA sensing is coupled to IL-12-mediated T cell functional reinforcement. In addition, the combination enhanced responsiveness to PD-L1 blockade. Together, these findings establish a clinically translatable strategy to integrate cGAS-STING activation with cytokine-driven T cell programming to drive systemic tumor control.

cancer biology↗

bioRxiv2026

Grow2Fold: mapping heterogeneous developmental growth to human brain folding

Cortical folding emerges through complex developmental processes, yet what organizes these processes into the characteristic folding patterns of the human brain remains unclear. Here, we developed an imaging-informed whole-brain modeling framework, Grow2Fold, that integrates developmental cortical regionalization, quantitative growth characterization, and mechanics-guided simulation to investigate how cortical growth shapes brain folding patterns. Using 836 fetal and neonatal MRI sessions from 747 participants spanning 21-45 postmenstrual weeks, we identified a reproducible and hierarchical spatiotemporal organization of cortical expansion characterized by coordinated regional growth trajectories. Rapid expansion occurs earlier around peri-central territories and progressively shifts toward frontal, parietal, and temporal association cortices. We encoded these imaging-derived trajectories into region- and age-specific growth laws and incorporated them into anatomically realistic whole-brain mechanical models. The resulting simulations recapitulate major sulcal landmarks and characteristic folding development across global and regional morphological measures. Comparing regional and uniform growth, we find that differential growth drives cortical instability, while heterogeneous developmental growth organizes this instability into anatomically recognizable folding patterns. Combined with subject-specific anatomy, these population-informed growth laws reproduce individualized longitudinal folding trajectories. Together, our results identify spatiotemporally patterned developmental growth as a key spatial constraint on cortical morphogenesis and establish a quantitative bridge from developmental imaging, through mechanical instability, to anatomically organized folding.

biophysics↗

bioRxiv2026

Benchmarking longitudinal local centiles for radiographic knee osteoarthritis prognosis

Cartilage thickness on MRI is a structural biomarker of osteoarthritis (OA), yet anatomical variation and aging can mask early disease, including changes occurring 12-36 months before incident OA. We propose longitudinal local centile maps that use normative growth charts as prior information and integrate a knee's earlier scans to identify cartilage that is thinner or thicker than expected. We built the reference charts from 5,045 scans of 957 persistently radiographically normal knees in the Osteoarthritis Initiative. Under participant-separated nested cross-validation, longitudinal centile profiles achieved higher 12- and 24-month AUCs for predicting incident radiographic OA than regional PCA, radiomics, cross-sectional centile features, and raw-map deep features across most classifiers. These conventional descriptors added little when combined with centile profiles, and cross-sectional centiles added little beyond longitudinal centiles. Deep centile features achieved the best AUCs (0.954 [95% CI 0.931-0.974] at 12 months and 0.969 [0.949-0.985] at 24 months; balanced accuracy 0.917 and 0.931) and outperformed raw-map deep features in all 12 classifiers after correction for multiple comparisons. No representation consistently improved 36-month prediction. Longitudinal centiles transform cartilage thickness maps into reference-based deviation maps: deep longitudinal centile features provide the highest predictive accuracy, while regional longitudinal centile profiles provide interpretable prognosis with the second-highest accuracy.

bioengineering↗

bioRxiv2026

Olfactory-mediated host tracking and rapid local adaptation in a seed-feeding wasp

Understanding how specialized herbivores track divergence among their hosts is central to evolutionary biology. Congruent genetic structure between hosts and herbivores is often interpreted as evidence of long-term codivergence, but similar patterns may also arise when herbivores rapidly adapt to pre-existing host differentiation. Here, we integrate population genomics, host volatile profiling, and behavioral assays to examine host-associated divergence in the obligate seed-feeding wasp Megastigmus daduheensis and its conifer host Cupressus chengiana across three river valleys on the eastern Qinghai-Tibet Plateau. Despite strong phylogeographic congruence between each of the three wasp and host lineages, calibrated demographic analyses indicate that wasp divergence occurred during the early Holocene, substantially later than the Pliocene-Pleistocene divergence of host lineages. This temporal mismatch is inconsistent with strict long-term codivergence and instead supports rapid host tracking in a topographic complex region. Host lineages differed in volatile organic compound profiles, and behavioral assays showed that wasps were preferentially attracted to volatiles from their local host lineages. These results identify olfactory-mediated host recognition as a plausible mechanism promoting host fidelity and reinforcing host-associated genomic and behavioral differentiation. Our findings show that apparently concordant host-herbivore divergence can emerge over compressed evolutionary timescales through rapid local adaptation, highlighting how ecological differentiation can accumulate within species through host tracking.

evolutionary biology↗

bioRxiv2026

Immune Reconstitution and Antigenic Exposure History Shape Virus-Specific Humoral Immunity in People with HIV

CD4+ T-cell recovery is widely used to assess immune reconstitution in people with HIV, but its relationship to virus-specific humoral immunity across pathogens remains unclear. We characterized neutralizing activity against SARS-CoV-2, HIV-1, and influenza viruses in ART-treated, virologically suppressed individuals spanning distinct CD4+ T-cell levels. BA.5 was the dominant SARS-CoV-2 neutralization target across CD4 strata, whereas D614G neutralization increased with greater immune reconstitution. This gradient was largely absent for the antigenically divergent NB.1.8.1 and XFG variants. HIV-1 neutralization was inversely associated with CD4+ T-cell count, while influenza showed strain-dependent patterns. Neutralization-to-protection bridging preserved a CD4-associated gradient for D614G but not for highly immune-evasive variants. These findings show that immune reconstitution does not translate uniformly into antiviral humoral function. Instead, antibody profiles reflect host immune status, prior antigenic exposure, and viral antigenic evolution, supporting pathogen-specific functional assessment alongside conventional immune monitoring.

immunology↗

bioRxiv2026

Inflammation-induced of Clec18a inhibits immune responses via Trpm7-dependent Cbl activation

Innate immune responses must be tightly controlled to maintain immuno-homeostasis. However, the regulatory mechanisms underlying the activation and early stages of the innate immune response remain poorly defined. Here, we found the soluble C-type lectin Clec18a is up-regulated in multiple inflammatory diseases, including sepsis and influenza, and secreted within minutes upon activation in multiple immune cells, including macrophages, dendritic cells (DCs), and T cells. Clec18a-myeloid-knockout mice exhibited reduced survival and exacerbated inflammation than the wild-type. However, exogenous recombinant Clec18a administration alleviated inflammation both in vitro and in vivo. Mechanistically, we identified macrophage-inducible C-type lectin (Mincle) as the receptor of Clec18a. Clec18a-Mincle binding triggers Trpm7-dependent calcium influx, which activates the ubiquitin E3 ligase Cbl and leads to Mincle-Cbl-MyD88-Trpm7 complex formation and degradation. Cbl deficiency, calcium inhibition and Trpm7 knockdown abrogated Clec18a-mediated immune suppression. Thus, our study revealed Clec18a as a critical checkpoint on the initiation of innate immune response through an intrinsic crosstalk between CLR and TLR signaling.

immunology↗

bioRxiv2026

AAV-mediated TBR1 supplementation ameliorates behavioral and electrophysiological abnormalities in Tbr1-haploinsufficient mice

TBR1 haploinsufficiency causes a neurodevelopmental disorder associated with intellectual disability and autistic features, but the therapeutic potential of postnatal gene replacement remains incompletely defined. Here, we evaluated adeno associated virus (AAV) mediated human TBR1 replacement in Tbr1 haploinsufficient mice. A single retroorbital injection of AAV.PHP.eB expressing human TBR1 under the human synapsin promoter was administered at postnatal day 3 at a dose of 2 E11 vector genomes. Compared with control vector treated mutants, treated mice exhibited increased TBR1 protein abundance and TBR1, CTIP2, and parvalbumin positive cell counts in selected brain regions. Treatment improved sociability, social transmission of food preference, and buried food seeking. Electroencephalographic (EEG) recordings showed attenuation of elevated relative theta power and improved theta suppression and gamma enhancement during social interaction. However, anterior commissure abnormalities persisted, correction of other EEG abnormalities was incomplete, and sleep wake proportions showed no significant treatment improvement. These findings demonstrate that neonatal TBR1 replacement improves selected behavioral and electrophysiological outcomes despite persistent anatomical abnormalities. These findings support further development of gene replacement for TBR1 haploinsufficiency and highlight EEG measures as candidate biomarkers for monitoring treatment response.

neuroscience↗

bioRxiv2026

A climate-resilient microalga, Desmodesmus ecotolerans sp. nov., for biophotovoltaic applications

Microalgae are promising biological platforms for sustainable energy production because they can convert photosynthetic activity into electricity in biophotovoltaic (BPV) systems. Identifying strains that grow well at elevated temperatures and under reduced irradiance is an important step toward BPV applications in seasonally variable environments. Microalgae were isolated from Seondong Lake (Seoul, Republic of Korea) during three sampling periods and screened for growth at different temperatures. Among 45 isolates, KHUC-11 showed the highest weighted growth index based on growth rates at 25, 30, and 35 under dark conditions and was selected for further characterization. Phylogenetic reconstruction of the 45S rRNA gene cluster, internal transcribed spacer 2 (ITS2) secondary-structure comparison, and morphological characterization supported the description of KHUC-11 as Desmodesmus ecotolerans sp. nov. D. ecotolerans produced more biomass than Chlamydomonas reinhardtii CC-125 under both moderate- and low-light conditions. Under low light, its final dry biomass concentrations were 1.81 and 1.58 times those of CC-125 under mixotrophic and photoautotrophic conditions, respectively. Despite its smaller cell size, D. ecotolerans showed higher photosynthetic performance than CC-125, and screen-printed electrode (SPE)-based electrochemical assays demonstrated enhanced anodic current generation and CV-derived estimated power output. Taken together, these findings identify D. ecotolerans as a novel climate-resilient Desmodesmus species with bioelectrochemical properties that support further evaluation for BPV applications.

microbiology↗

bioRxiv2026

Microbes on the Mind: Multi-modal Neuroimaging Reveals Gut-Brain Axes in Infants

The gut microbiome develops from birth and is associated with cognition and mental health, but its relationship with early brain maturation remains unclear. We studied 223 typically developing infants aged 0-3 years using multimodal MRI and paired fecal shotgun metagenomics. Microbiome-wide association analysis linked microbial features to cortical morphology, white-matter microstructure, and functional networks. Regularized canonical correlation analysis identified structural-metabolic and functional-taxonomic covariance patterns. Sparse partial least-squares analysis recapitulated both full-sample CCA patterns and their defining structural and functional phenotypes, providing cross-method corroboration. Longitudinal canonical-score slopes did not significantly covary, whereas earlier neuroimaging CCA1 scores predicted microbiome CCA1 scores 1-6 months later in bidirectional autoregressive cross-lag models. These observational results identify coordinated developmental patterns and temporal ordering without establishing causality.

developmental biology↗

bioRxiv2026

Soil microenvironment and microbial community composition jointly regulate carbon accrual in agricultural soils

Much of the persistent soil organic carbon (SOC) pool is microbial in origin: microorganisms process plant carbon into biomass and their necromass can associate with mineral surfaces, contributing to long-term carbon persistence. This has generated interest in microbial interventions such as inoculation to restore carbon in degraded croplands, yet their efficacy remains uncertain. The uncertainty reflects a more fundamental, unresolved question: are microbially-mediated carbon transformations governed principally by the composition of the microbial community or by the soil microenvironment? To disentangle these drivers, we conducted a reciprocal microbial community transplant experiment, introducing communities of contrasting origin from locally adjacent grassland and cropland soils into sterilised grassland and cropland soils, and incubating them for eight months with regular organic inputs. This design decouples the inoculum from the microenvironment, allowing their individual and interactive contributions to be quantified. Fungal assembly was influenced more by the inoculum, consistent with dispersal limitation, whereas bacterial assembly was governed more by the microenvironment, consistent with environmental selection. Despite receiving the same organic carbon inputs, grassland and cropland recipient soils showed distinct SOC trajectories, indicating that the soil microenvironment strongly constrained net carbon retention. Within this constraint, community composition also mattered: introducing grassland rather than cropland communities increased fungal diversity and fungal necromass and led to better SOC outcomes, expressed as net gain or reduced loss. These results show that SOC accrual emerges from interactions between the soil microenvironment and microbial community composition, with fungal community assembly particularly associated with necromass accumulation and carbon retention. They highlight the need to consider both soil conditions and microbial community composition when developing strategies to enhance SOC accrual.

ecology↗

bioRxiv2026

Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration

MCAM/CD146 is an immunoglobulin-superfamily receptor expressed on endothelial cells, immune cells and numerous carcinomas. Although MCAM has long been associated with metastatic progression, recent work has revealed context-dependent inhibitory effects on transendothelial migration, leaving unresolved how MCAM engagement of basement membrane laminins alters cell migration. Here, we report multiple cryo-electron microscopy structures of human MCAM bound to laminin. We show MCAM engages laminin on a surface centered on the first two laminin globular domains (LG1-2) and that this epitope directly overlaps with the interface used by integrin. Consistent with structural competition, MCAM occupation of laminin abolishes integrin-dependent cell migration. Structure-guided mutation of the MCAM-laminin interface disrupts laminin binding and eliminates MCAM-mediated inhibition. These findings establish that MCAM and integrin compete for a shared interface on laminin and define a structural mechanism by which MCAM occupancy can suppress laminin-dependent migration. The structure resolves a central ambiguity in MCAM biology and provides a framework for developing biologics that selectively modulate pathological cell migration.

biophysics↗

bioRxiv2026

Rapid Shift Toward Pulsed Field Ablation and Precision Risk Stratification in High-Impact Atrial Fibrillation Research

Conventional bibliometrics rely on lifetime citations, obscuring immediate shifts in cardiovascular research paradigms. To track emerging trends in atrial fibrillation management, we performed a comparative bibliometric analysis of the 50 highest-cited original research articles per year in OpenAlex topic T10065 across consecutive 2023 (Class of 2025) and 2024 (Class of 2026) publication cohorts. Articles were ranked using a fixed 18-month post-publication citation window, and extracted concepts were normalized into 719 canonical topics and 32 parent themes using large language model curation. Concept frequency tracking demonstrated a swift technological shift, with pulsed field ablation showing the largest topic frequency increase (+0.08, from 0.30 to 0.38) to become the leading canonical topic in 2024, displacing conventional thermal pulmonary vein isolation (-0.18, 0.40 to 0.22). Simultaneously, stroke prevention focus shifted toward refined predictive modeling, with increases in Risk Stratification and Predictive Models (+0.08, 0.30 to 0.38) and CHA2DS2-VASc scoring (+0.08, from 0.10 to 0.18). High-impact atrial fibrillation research is rapidly pivoting toward non-thermal ablation safety profiling and precision risk stratification, highlighting the utility of fixed-window concept mining for capturing real-time scientific evolution. Online explorer of the result is available at https://pri.pepkio.com.

bioinformatics↗

bioRxiv2026

A conformational switch governs the dual role of liquid-liquid phase separation in amyloid fibrillization

Biomolecular condensates provide dynamic environments that store and organize proteins, yet the fundamental principles determining whether condensation promotes or suppresses irreversible protein aggregation remain unclear. Here, we show that the receptor-interacting protein kinase 3 (RIPK3) RHIM domain follows distinct self-assembly pathways into condensates or amyloid fibrils depending on its conformational state. We find that predominantly folded proteins undergo liquid-liquid phase separation (LLPS), forming reversible condensates that kinetically suppress fibril formation. Partial unfolding instead promotes direct fibrillization that bypasses LLPS, whereas induced condensate formation via increasing ionic strength or addition of molecular crowder delays amyloid formation. In contrast, when the protein is predominantly unfolded, LLPS accelerates fibrillization through condensate-interface-mediated nucleation. These findings establish protein conformation as a determinant of whether condensates suppress or promote amyloid assembly, revealing a dual role for phase separation in regulating functional amyloid formation and providing a framework that connects condensate dynamics with cellular functions.

biophysics↗

bioRxiv2026

EM3DFold: accurate de novo protein and nucleic acid model building for cryo-EM maps using language model-powered deep learning

Cryo-electron microscopy (cryo-EM) has become one of the most powerful techniques for macromolecular structure determination. However, accurate model building from cryo-EM maps remains challenging, particularly for nucleic acids. Here, we present EM3DFold, a unified de novo model-building framework for accurate structure determination of proteins, nucleic acids, and protein-nucleic acid complexes from cryo-EM maps using a density-aware, large language model-powered three-track attention (TTA) network. The TTA network effectively integrates sequence, density, and structural information to enable accurate all-atom model building. EM3DFold was extensively evaluated on independent benchmarks of 298 experimental cryo-EM maps at < 4.0 [A] resolutions, and achieves an unprecedentedly high median accuracy of 75% completeness (88% coverage and 94% sequence accuracy) for 178 nucleic acid maps, 90% completeness (95% coverage and 96% sequence accuracy) for 124 protein-nucleic acid complexes, and 95% completeness (97% coverage and 98% sequence accuracy) for 120 protein-only targets, substantially outperforming state-of-the-art methods including ModelAngelo, EM2NA, CryoREAD, and EMProt. In addition, EM3DFold also produces models with superior model-to-map fit and stereochemical quality, providing a robust and reliable solution for automated cryo-EM model building. The EM3DFold package is freely available at https://github.com/huang-laboratory/EM3DFold.

bioinformatics↗