Biology subjects

Chen, J.

Publications and source records attributed to Chen, J..

At least 199 records · Page 11Linked to original sources

bioRxiv2026

Dysregulated tissue-resident lymphocytes drive age-associated emphysema by impairing alveolar regeneration

Aging is often associated with progressive tissue degeneration and chronic inflammation, yet the role of immune cells in mediating structural and functional decline in organs remains poorly defined. Here, we investigated immune-tissue interactions in the aged lung and identified emphysematous remodeling characterized by alveolar loss. Notably, aged lungs exhibited a marked expansion of tissue-resident lymphocytes (TRLs) with senescent features, accompanied by a significant reduction in alveolar stem/progenitor cell (AT2) abundance. In vivo adoptive T cell transfer and 3D immune-stem cell organoid assays revealed that these expanded TRLs suppressed AT2 growth via secretion of oncostatin M and interferon gamma. In vivo blockade of IL-7 receptor (IL-7R) reduced TRL accumulation in the lungs and ameliorated age-related emphysematous changes, including restoration of alveolar density. Our findings identify TRLs as key drivers of alveolar degeneration in aging and propose IL-7R inhibition as a therapeutic strategy to mitigate pulmonary decline. TeaserBlocking IL-7R clears harmful lymphocytes and helps rebuild the damaged air sacs of the aging lung.

cell biology↗

bioRxiv2026

CellChem: Cellular transcriptional responses reshape molecular representation space for efficient and multi-scale drug discovery

Despite decades of progress in computational drug discovery, deep learning-based molecular representation models remain largely structure-centric, assuming that chemical similarity approximates functional similarity. However, drug effects in cells are shaped not only by chemical similarity but also by molecular interactions in the cellular context. To capture this complexity, we introduce CellChem, a cellular-chemical representation-learning framework that learns cell-guided molecular representations of small-molecule actions within cells. By incorporating large-scale cellular transcriptional profiles during pretraining, CellChem reshapes molecular representation space from structure-centric to a balanced integration of structure and function. The learned CellChem molecular representations exhibit biologically meaningful geometric organization, such that distances between molecules encode not only structural similarity but also similarity in the cellular responses they elicit, independent of downstream tasks. Using downstream derivative models such as cell-guided compound-protein interaction prediction and drug-induced transcriptional response profile generation, CellChem supports highly efficient, multi-scale drug discovery, achieving significantly better performance than traditional models.

molecular biology↗

bioRxiv2026

The ABI5-WRKY45-LSU1 axis confers tolerance of Arabidopsis thaliana to cadmium

Abscisic acid (ABA) is involved in Cd tolerance in Arabidopsis, but the underlying mechanisms are unclear. In this study, we revealed that the ABI5-WRKY45-LSU1 axis confers the tolerance of Arabidopsis to Cd stress. Under Cd stress, the biosynthesis of ABA is increased, and the expression of transcription factor ABI5 is upregulated. Accordingly, the abi5-8 mutants show increased Cd sensitivity. ABI5 directly binds the ABRE element in the WRKY45 promoter to activate its transcription. Overexpression of WRKY45 rescues the Cd-hypersensitive phenotype of the abi5-8 mutant, placing WRKY45 downstream of ABI5. Transcriptome analyses identified LSU1 as a potential WRKY45 target. qRT-PCR, DUAL-LUC and EMSA experiments verified that WRKY45 binds the W-box cis-element in the LSU1 promoter to activate its expression. Overexpression of LSU1 enhances Cd tolerance by promoting the biosynthesis of non-protein thiols (NPT), glutathione (GSH), and phytochelatins (PC). Moreover, overexpression of LSU1 suppresses Cd sensitivity in the wrky45 mutant, confirming LSU1 acts downstream of WRKY45. On the other hand, we found that ATP sulfurylase 1 (APS1) interacts with LSU1 based in vitro and in vivo evidences. LSU1 stabilizes APS1, slows its degradation, and enhances APS1 activity, thus leading to increased NPT, GSH, and PC accumulation and improved Cd detoxification. Notably, overexpressing LSU1 did not rescue the Cd sensitivity of the aps1-1 mutant, indicating that LSU1 acts upstream of and depends on APS1. In short, we demonstrated a novel ABI5-WRKY45-LSU1 axis that regulates Cd tolerance through sulfur assimilation and phytochelatin synthesis. HighlightsO_LICadmium stress triggers ABA biosynthesis and ABI5 expression; ABI5 directly binds to ABRE motifs in the WRKY45 promoter and activates its transcription. C_LIO_LIWRKY45 transcriptionally activates LSU1, and LSU1 interacts with APS1 to stabilize it and elevate ATP sulfurylase activity, acting in an APS1-dependent manner. C_LIO_LIThe ABI5-WRKY45-LSU1 module enhances Arabidopsis Cd tolerance by boosting sulfur assimilation and GSH/PC-mediated Cd detoxification, rather than reducing Cd uptake. C_LI

molecular biology↗

bioRxiv2026

Canalized gene regulatory networks stabilize floral polymorphism and enable modular transgressive expression

O_LIFloral polymorphisms frequently persist across heterogeneous environments despite ongoing gene flow, yet the regulatory mechanisms maintaining discrete phenotypes remain unclear. We tested whether alternative flower-colour morphs in Stellera chamaejasme L. are maintained by canalized gene regulatory architectures that stabilize expression around morph-specific optima. C_LIO_LIWe used a pan-transcriptomic and eco-evolutionary framework integrating genome-wide gene expression profiling, co-expression network analysis, functional enrichment, ortholog-based phylogenomics, and variance-based modeling of regulatory canalization and transgressive expression to quantify regulatory variation across morphs. C_LIO_LITranscriptomic variation was structured primarily by morph identity rather than geography, indicating consistent morph-associated regulatory programs. Parental morphs showed reduced within-morph variance in gene co-expression modules, consistent with strong regulatory constraint at the network level. In contrast, a naturally occurring mosaic morph exhibited extensive non-additive and predominantly transgressive expression, with most genes falling outside the parental range. This transgressive signal was modular, with most networks remaining stable while a subset showed elevated variance and disrupted inheritance. Functional analyses further reveal that floral pigmentation is embedded within broader metabolic and stress-response pathways, linking color polymorphism to coordinated physiological states and ecological differentiation. C_LI

plant biology↗

bioRxiv2026

SIMO - Single Section Integrative Multi-Omics - spatial mapping of metabolites and lipids combined with region-specific proteomics in a single tissue slice

Technological advances in biomedical sciences have accelerated multi-omics research, enabling high-resolution spatial mapping of diverse molecular compound classes. However, integrating spatial omics often requires serial tissue sections, limiting the alignment correlation across modalities. We present a single-section integrative multi-omics (SIMO) workflow that combines metabolite and lipid imaging with histopathology and region-specific proteomics. Using MALDI-MSI, tissue staining, and laser microdissection (LMD), SIMO delivers comprehensive metabolic, lipidomic, and proteomic insight from the same sample. Using mouse cardiac tissue we develop, control, and validate the methodology resulting in [~]60 imaged lipids and [~]60 imaged metabolites at 20 {micro}m pixel size and subsequently spatial proteomics by LMD, detecting over 5,000 proteins from the same tissue. To demonstrate the capabilities of the workflow in preclinical context, we apply SIMO to a metastasizing melanoma PDX model, identifying over 100 spatially localized lipids and metabolites, and over 5,000 proteins across metastases and non-tumor tissues in liver. SIMO enables precise ROI selection, statistical comparison of protein regulation, and alignment of metabolic and lipidomics pathways across spatial omics and region-specific proteomics, demonstrating its value as a spatial multi-omics platform.

biochemistry↗

bioRxiv2026

A nucleolar stress gene signature for quantitative scoring across multi-omics contexts

The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, which has been implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological alterations or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) that is applicable across bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signalling, whereas these responses are attenuated in oxaliplatin-resistant cells. In combination with a ribosome biogenesis activity score (RiboSis), NuS captures related yet distinct dimensions of nucleolar function and stratifies tumors into functional states associated with distinct clinical outcomes. Furthermore, NuS-based analysis of perturbational transcriptomes enables prioritization of compounds with putative nucleolar stress-inducing activity. Collectively, this study establishes a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.

cell biology↗

bioRxiv2026

Transition metal-triggered immunity via an Arabidopsis NLR pair

Plants are challenged by multiple biotic (e.g. pathogens) and abiotic (e.g. heavy metals) stressors. Some transition metals can enhance plants defense against pathogens, but the mechanism remains unclear. Here, we demonstrate that an Arabidopsis head-to-head gene pair of intracellular nucleotide-binding leucine-rich repeat (NLR) receptors, both expressed in the endodermis of roots, antagonistically control transition metal-triggered immunity. One NLR, STM2 binds transition metal ions, such as Cd2+, Cu2+ and Zn2+, with its LRR domain to enhance its NAD+ hydrolytic activity and immune responses via the EDS1/PAD4/ADR1 module, triggering enhanced resistance to bacterial wilt Ralstonia solanacearum. The other NLR, STM1 suppresses STM2 to protect plants from transition metal-triggered immunity and growth inhibition in the presence of excess metals. STM1 also dampens resistance to the pathogen. Our study defines an NLR activated by transition metals and reveals a trade-off between susceptibility to pathogens and sensitivity to transition metals that are pervasive in soil.

plant biology↗

bioRxiv2026

Lipoengineering of Biomolecular Condensates Controls Material Properties and Multiphase Hierarchy to Guide Organoid Morphogenesis

Cells use post-translational modifications (PTMs) to reconfigure biomolecular condensates across length scales, space, and time.1,2 While charged PTMs are well-known electrostatic switches,3,4 how ubiquitous neutral PTMs shape condensate plasticity and hierarchy remains unclear. Here, we establish a set of design principles for using site-specific lipidation, a class of neutral hydrophobic PTMs, to rationally control properties and interactions of engineered biomolecular condensates. Through systematic analysis of over 80 lipidated synthetic intrinsically disordered proteins (IDPs), we uncovered two distinct axes of control. First, the interplay between the lipid and the local three-residue sequence of its attachment site acts as a programmable switch for cohesion--the homotypic interactions that define the material state of the condensed phase-- directing assemblies toward dynamic liquids, arrested gels, or ordered fibrillar solids. Second, the lipid, together with the global properties of the IDP scaffold, tunes adhesion--the heterotypic interactions that govern condensate miscibility and hierarchical organization. We harnessed these principles to rationally engineer complex, multi-phase architectures and create hybrid hydrogels with programmed microstructure and material properties that guide the morphogenesis of functional intestinal organoids. These findings establish a new framework for lipoengineering advanced biomaterials and provide a blueprint for dissecting structure-property relationships across diverse classes of PTMs.

bioengineering↗

bioRxiv2026

Plekha7 promotes retina organization and inhibits inflammation and photoreceptor loss

Plekha7 associates with p120 catenin and localizes at apical cell-cell junctions where it has been implicated in junction stabilization. However, its in vivo function and underlying mechanisms of action remain unclear. Here, we show that constitutive Plekha7 loss in mice disrupts retinal organization, reduces retinal thickness, and induces RPE multinucleation, microglia infiltration, and photoreceptor loss. Plekha7 deficiency reduces the accumulation of cadherin-catenin complexes at apical junctions without altering overall cadherin levels, indicating a defect in junctional maintenance. Mechanistically, PLEKHA7 regulates cadherin trafficking by limiting levels of endocytosed E-cadherin, thereby maintaining junctional cadherin pools. Notably, these effects are largely independent of p120 catenin. In addition, further Plekha7 roles in the regulation of centrosome, cilia, microtubule dynamics, and cytokinesis, likely contribute to the phenotypic changes induced by Plekha7 knockout. These findings establish Plekha7 as a key regulator of cadherin trafficking and epithelial organization with relevance to retinal disease.

cell biology↗

bioRxiv2026

Phase separation behavior of TDP-43 governs its protein interactome and regulation of altern

TDP-43 is a nuclear RNA-binding protein that regulates RNA metabolism, including alternative splicing. Its aggregation is a major pathological hallmark of several neurodegenerative diseases. TDP-43 undergoes phase separation (PS) and this condensation behavior may be linked to aggregate formation. Whether and how PS governs TDP-43 RNA regulatory functions remains poorly understood. Here we utilized rationally designed mutations in the TDP-43 low complexity domain to tune TDP-43 PS, yielding a panel of TDP-43 variants with reduced propensity to form condensates (PS-deficient), and a panel forming irreversible, undynamic condensates (solid-like) in vitro and in cells. Two complementary interactomics approaches identified PS-dependent interactions between TDP-43 and key RNA regulatory factors, including splicing regulators and the RNA helicase UPF1, which show increased interactions with solid-like variants. Our results highlight that TDP-43 PS regulates RNA and protein homeostasis by modulating a subset of TDP-43-dependent alternative splicing events and by reshaping interactions with RNA regulatory factors.

biochemistry↗

bioRxiv2026

Forensic Identification of Confiscated Helmeted Hornbill (Rhinoplax vigil) Casques and Implications for Individual Quantification in Wildlife Crimes

In wildlife forensic practice, species identification and estimation of the Minimum Number of Individuals (MNI) for highly processed specimens have long relied on weight-based conversion methods, which may result in underestimation of the number of individuals involved in a case. Focusing on 41 confiscated casque products of the helmeted hornbill (Rhinoplax vigil), including 32 newly added Tianjin samples, this study combines macroscopic morphological examination with mitochondrial DNA barcoding (16S rRNA, COI, and Cytb) to explore a more robust approach for individual quantification. The results demonstrate that the conventional "weight-based" approach overlooks critical biological information contained in anatomical structures and cannot accurately reflect the actual number of individuals involved. Based on this, we propose an anatomy-based criterion centered on the principle of structural uniqueness: specimens retaining biologically unique beak or casque structures should be directly assigned to a single individual, whereas weight-based estimation should only be applied when original anatomical features are entirely absent. In addition, based on morphometric calibration using a larger sample size (n = 40), we propose updating the reference benchmark for estimating the number of individuals in heavily processed solid casque products from 86 g to 65 g. This approach improves the scientific rigor and accuracy of forensic identification and provides reliable technical support for the conviction, sentencing, and law enforcement of wildlife trafficking cases involving helmeted hornbill and other endangered species.

zoology↗

bioRxiv2026

Separable Brain Maturation Patterns Mediate Exposome Influences on Cognitive Development: A Longitudinal Study

Adolescent cognitive ability develops within a complex landscape of environmental exposures, yet the patterns of brain maturation through which these exposures relate to cognitive development remain poorly understood. Resolving this requires an integrated longitudinal view of the multidimensional exposome, multimodal brain change, and cognitive growth. Here, we examined whether brain maturation mediates the relationship between the exposome and cognitive development in a large longitudinal cohort of 1,112 adolescents, using 4,882 multimodal brain features and 112 exposome variables spanning six domains. Brain maturation patterns associated with cognitive development showed moderate yet consistent spatial correspondence with those associated with the exposome, with the family environment domain showing the strongest correspondence. We identified four latent brain patterns associated with distinct components of the exposome-cognition relationship. Collectively, these results indicate that distinct exposome domains relate to cognitive development through distinct brain maturation pathways, which also exhibit different molecular annotation profiles.

neuroscience↗

bioRxiv2026

A confined gene drive for population modification in the malaria vector Anopheles stephensi

Gene drives are genetic elements that bias their own inheritance to spread desired traits in target populations, enabling population modification or suppression. Although homing-based drives can propagate efficiently, their potential for uncontrolled spread may present a challenge for field deployment. Thus, confined drive systems are needed. Here, we developed a confined modification drive, called Toxin-Antidote Recessive Embryo (TARE) drive, in the globally important malaria vector Anopheles stephensi. This drive works by cleaving and disrupting wild-type alleles in the germline or early embryo from maternally deposited Cas9. Disrupted alleles are recessive lethal, thus increasing the drive in a frequency-dependent manner. Inheritance bias was moderate in crosses between drive heterozygote mosquitoes, possibly due to low gRNA activity and thus moderate germline cleavage rates. Single-release cage trials confirmed the TARE drives ability to spread, although the drive ultimately declined due to fitness costs and resistance alleles associated with repetitive elements. Nonetheless our modelling analysis indicate that this TARE system could achieve population spread if the resistance issue is addressed. These findings demonstrate a functional prototype TARE drive in Anopheles stephensi and highlight key parameters governing its performance. Minor design optimizations could substantially improve efficiency and integrity, enabling rapid but confined population modification.

genetics↗

bioRxiv2026

Chromosomal rearrangements 1 and sequence similarity drivepreferential allosyndetic introgression from a wild relative into wheat

Recombination in polyploid genomes is generally constrained to homologous or homoeologous chromosomes; however, how chromosomal rearrangements influence recombination between chromosomes remains unclear. Here, we demonstrate that large-scale chromosomal rearrangements in the wild relatives of wheat are associated with recombination involving non-homoeologous chromosomes or arms during alien gene introgression under conditions that permit homoeologous recombination mediated by ph1b. Using a wheat chromosome 6A monosomic-induced 6AS*6CL Robertsonian translocation combined with ph1b-mediated recombination, we generated 17 independent recombinants carrying a new stem rust resistance gene, Sr69, from Aegilops caudata chromosome arm 6CL. Unexpectedly, 94.1% (16 of 17) of recombinants resulted from exchanges with wheat group-7 chromosomes rather than with the homoeologous group-6 chromosome. Comparative sequence- and marker-based analyses identified a 67-Mb rearranged interval on Ae. caudata 6CL that corresponds to telomeric regions of the long arms of wheat group-7 chromosomes. Sequence similarity within this interval was quantitatively associated with recombination frequency, with higher similarity corresponding to more frequent translocations. Physical and optical mapping showed that recombination within the rearranged interval generated compensating 7A/6C, 7B/6C, and 7D/6C translocations, whereas recombination outside this region produced non-compensating 6A/6C exchanges. An independent case involving the powdery mildew resistance gene Pm7C showed a similar correspondence between a rearranged 7CL region and preferential introgression into wheat 7DS. Together, these results indicate that ph1b-mediated recombination involving structurally altered chromosomes is driven by local chromosomal structure and sequence similarity rather than strict homoeologous group identity. This provides a mechanistic basis for harnessing untapped beneficial genes from structurally rearranged alien genomes. Significance StatementAlien gene introgression is a powerful strategy for wheat improvement, typically relying on ph1b-mediated recombination between homoeologous chromosomes. The genomic basis and outcomes of introgression from structurally rearranged alien chromosomes remain unclear. Here, we show that ph1b-induced recombination can efficiently target wheat-allosyntenic blocks in rearranged alien genomes, preferentially transferring genes from structurally altered alien segments into their syntenic regions on wheat chromosomes of different homoeologous groups. Crossover formation is governed by extended sequence similarity within corresponding intervals rather than strict collinearity across entire homoeologous chromosomes. As many wild species exhibit extensive genome rearrangement, these findings and methodologies expand access to underexploited genetic diversity embedded within highly rearranged wild genomes for wheat improvement.

genetics↗

bioRxiv2026

How much information is there for inferring species trees?

AO_SCPLOWBSTRACTC_SCPLOWAs modern phylogenomics datasets become increasingly large, it is useful to develop recommendations for how to subsample datasets for best species tree inference. Here we apply a new measure of phylogenetic information content that estimates the reduction in tree space occupied by a posterior sample of inferred trees relative to a prior sample in order to assess the effects of gene tree parameters on species tree estimation. We find that, consistent with earlier studies, when data are informative, more data result in better species tree inference. However, when data are uninformative, subsampling a dataset to include only the most informative loci may produce a better species tree sample. We perform analyses on a variety of simulated and empirical datasets.

evolutionary biology↗

bioRxiv2026

Claw4Science: A Dataset and Platform for the OpenClaw Scientific Agent Ecosystem

Large language models have enabled a new class of scientific software in the form of AI agents that can execute research workflows across bioinformatics, drug discovery, and related domains. Among these systems, OpenClaw introduced a skill-based design that allows workflows to be expressed as structured Markdown files, lowering the barrier to contribution and enabling rapid ecosystem growth. However, this growth has led to fragmentation. Projects are distributed across independent repositories, skills vary widely in quality, naming is inconsistent, and there is no unified way to discover or compare available tools. In this work, we construct the first curated dataset of the OpenClaw scientific ecosystem. The dataset includes 91 projects organized by functional role and 2,230 skills spanning 34 scientific categories. Based on this dataset, we perform a systematic analysis of the structure, distribution, and emerging patterns of scientific agent development. To make this ecosystem accessible in practice, we further build Claw4Science, a public platform at https://claw4science.org, which is built on top of our dataset. The platform organizes projects and aggregates distributed skill repositories into a unified interface, with a focus on bioinformatics and scientific workflows, providing a practical entry point for navigating the ecosystem. Our results show that the OpenClaw ecosystem reflects a shift from isolated systems to a more modular and shareable model of scientific computation. At the same time, challenges in evaluation, reproducibility, and governance remain open. We argue that our dataset provides a foundation for future benchmark development and standardized infrastructure for scientific AI agents.

bioinformatics↗

bioRxiv2026

Population genomics reveal genetic variants associated with lunar-regulated spawning time in grass puffer

High and low tides occur twice a day (every [~]12.4 hours), with the largest tidal ranges during spring tides around new and full moons (every [~]14.765 days). Although lunar cycles shape diverse animal phenotypes, particularly the reproduction of coastal animals, the genetic basis of lunar-related rhythms remains unclear. Since phenotypic variation is a valuable resource for elucidating such mechanisms, we examined geographic variation in the lunar-regulated mass spawning of the grass puffer (Takifugu alboplumbeus) along the Japanese coast. Western populations spawned during the first half of the spring tides, whereas eastern populations spawned during the second half. Furthermore, the spawning was restricted to a narrow daily time window that occurred earlier in the western populations than in the eastern ones. Assuming that spawning is regulated by circadian gating, this geographic shift in the daily spawning window could account for the population difference in semilunar spawning timing. Consistent with this hypothesis, the free-running circadian period ({tau}), which can affect the phase of the gating window, was shorter in the western populations. Mathematical modeling recapitulated the observed geographic difference in the spawning time window based on variation in {tau}. To identify candidate genes responsible for these differences, we conducted population genomics analysis and identified proline-rich transmembrane protein 1-like (prrt1l) as a candidate. Expression of prrt1l was observed in the circadian pacemaker suprachiasmatic nucleus, and triple CRISPR F0 knockout of prrt1l shortened the free-running period in larvae. These findings suggest a potential mechanism underlying the geographic variation in lunar-synchronized spawning behavior. HighlightsO_LIThe geographic variation exists in the lunar-regulated spawning of the grass puffer, with differences in spawning dates and times between western and eastern Japan. C_LIO_LIThe free-running period of western populations is shorter than that of eastern populations, which is consistent with their earlier spawning timing. C_LIO_LIPopulation genomics analysis identified prrt1l as a candidate gene harboring population-specific missense mutations, the knockout of which shortens the free-running period. C_LI

evolutionary biology↗

bioRxiv2026

Intercellular communication is a heritable dimension of human tissue architecture

Methods that map genetic risk to cells do not directly test whether spatially organized ligand-receptor (LR) gene annotations carry conditional heritability association. Here we introduce EdgeMap, which scores each gene by the spatial activity of its LR contexts in spatial transcriptomics data, maps these scores alongside cell-intrinsic annotations to SNP-level LD scores, and tests both jointly against GWAS summary statistics. Across 17 traits and five human tissues, edge z-scores are systematically higher in biologically matched tissues: all 15 traits with both matched and unmatched tissue classes show this ordering (median{Delta} z = 1.51; sign P = 3.1 x 10-5), and 11 of 13 nominal-positive associations concentrate in the biologically matched set (P = 1 x 10-4). The pattern survives broad LR-gene-class and cell-type composition controls. Donor-level cross-section summaries, independent GWAS replication for LDL and CAD, and cell-segmented Visium HD liver data provide convergent support. A secondary analysis prioritizes constituent genes within active LR contexts; sixteen of 31 prioritized genes are absent from standard gene-level methods. These results establish spatially weighted LR-gene annotations as a complementary layer for interpreting complex-trait genetic architecture.

genetics↗