Biology subjects

Liu, L.

Publications and source records attributed to Liu, L..

At least 127 records · Page 7Linked to original sources

bioRxiv2026

Improving Growth Predictions in Aquaculture through an Improved Bioenergetics Model Incorporating Feed Composition and Nutrient Digestibility for Largemouth Bass (Micropterus salmoides)

Bioenergetics models serve as mechanistic tools to predict growth by linking energy intake, metabolic expenditure, and nutrient partitioning. However, traditional models rely primarily on gross energy (GE) intake, thereby oversimplifying the effects of feed composition and nutrient availability on fish growth. This work therefore proposed a refined bioenergetics model incorporating nutrient-specific digestibility coefficients (ADCs) and feed composition and tested using a compiled dataset (n=235; 165 for calibration and 70 for independent validation) and a field experimental dataset of largemouth bass (Micropterus salmoides). We first optimized parameters of a gross energy intake-based bioenergetics model, increasing R2 from 0.62 to 0.96 and thereby providing a calibrated foundation for subsequent refined model. The refined model demonstrated superior predictive performance on the compiled dataset (R2 = 0.97) with RMSE = 19.86 g and MAE = 10.31 g), representing reductions of 4.13% in RMSE and 19.98% in MAE and a 1.03% increase in R2 compared with the optimized GE-based model. In the field experiment, the refined model achieved high predictive accuracy (R2 = 0.98 and 0.97), whereas the optimized GE-based model showed poor performance (R2 = 0.33 and 0.06 respectively). This study is, to our knowledge, the first bioenergetics framework for largemouth bass that decomposes feed composition and nutrient-specific ADCs to compute macronutrient-resolved digestible energy, enabling formulation-aware growth prediction and nutrient-oriented optimization.

bioengineering↗

bioRxiv2026

Unleashed condensation by recurrent mutations of an epigenetic regulator promotes cancer

The pathological mechanisms and significance for the prevalent hotspot mutations in disordered protein regions are poorly understood. ASXL1 is an obligate co-factor for BAP1 in H2AK119 deubiquitination. ASXL1 mutations are very frequent in myeloid malignancies, and are mostly C-terminal truncating mutations concentrated in a specific disordered region of ASXL1. ASXL1 truncations are gain-of-function mutations that promote myeloid malignancies, but the underlying mechanisms remain poorly understood. Here we show that the frequently truncated mutants of ASXL1 possess an intrinsic property of forming phase-separated biomolecular condensates, and this property is normally suppressed by the frequently deleted regions. A disease-mutant of the endogenous ASXL1 in leukemia cells forms dynamic nuclear co-condensates with other endogenous factors important for gene activation. The ASXL1 disease-mutants can greatly enhance H2A deubiquitination activity of BAP1 in cells and in vitro reconstituted system, enhance myeloid leukemia cell growth, and promote leukemogenesis in a mouse transplant model by turning on myeloid leukemogenic transcriptional programs. However, substitution of residues important for condensation disrupted or impaired all these abilities, suggesting that the condensation property is crucially important for the ASXL1 mutants in promoting cancer. Moreover, we discover that the conserved negative charges in the highly disordered and frequently deleted region on ASXL1 suppress the condensation of the wild type ASXL1. Charge-neutralizing mutations in this region restores condensation of the full-length ASXL1, and are sufficient to turn ASXL1 into a leukemogenic protein. Biochemical, biophysical, and simulation analyses suggest the intramolecular interactions normally mask the N-terminal region in engaging intermolecular interactions required for phase separation, and disease truncations escape from the regulatory interactions and unleash the phase separation property to form nuclear hubs to promote expression of tumorigenic gene programs. Finally, by showing a striking correlation of the mutation frequencies with the condensation properties and leukemogenesis activity for a series of human patient mutations, we suggest that dysregulation of condensation is a central mechanism for ASXL1 mutations in promoting myeloid malignancies. This suggests that dysregulation of condensation may be a key mechanism for some of the prevalent hotspot disease mutations in the disordered proteomes.

biochemistry↗

bioRxiv2026

Antibody Responses Against Coronaviruses in the Wuhan Population

Prolonged circulation of SARS-CoV-2 may broaden population-level neutralizing antibody responses to diverse coronaviruses; however, the extent of this breadth remains unclear. To address this gap, we assessed serum neutralizing activity in 869 individuals from Wuhan, China, including 78 pre-pandemic samples collected in 2017 and 791 post-pandemic samples obtained in 2025. Specifically, using pseudovirus neutralization assays, sera were tested against a panel of coronaviruses, including circulating SARS-CoV-2 Omicron subvariants XFG and NB.1.8.1. Neutralization was measured at a fixed dilution for all samples and by determination of 50% inhibitory dilution (ID50) for selected sera. In parallel, antigenic cartography and genetic distance analyses were applied to relate functional antigenic relationships to spike protein divergence. Our results showed that, compared with pre-pandemic sera, post-pandemic sera exhibited enhanced neutralizing activity against multiple sarbecoviruses and the merbecovirus MjHKU4r-CoV-1, with mean inhibition increases ranging from 1.7% to 76.5% at a 1:20 dilution. Notably, the largest increases from 51.8% to 76.5% were observed against clade 1b sarbecoviruses. In contrast, neutralizing activity against human alphacoronaviruses and MERS-CoV showed no meaningful enhancement. Moreover, neutralizing titers in post-pandemic sera were strongly correlated across sarbecoviruses, particularly among clade 1b viruses. Antigenic mapping further revealed that several zoonotic sarbecoviruses were antigenically closer to ancestral SARS-CoV-2 than contemporary Omicron subvariants, despite substantially greater genetic divergence. Taken together, these findings demonstrate that cumulative SARS-CoV-2 exposure promotes broadly cross-neutralizing antibody responses within the sarbecovirus subgenus and provide a quantitative framework to inform the rational design of pan-sarbecovirus vaccines and antibody-based countermeasures for future coronavirus preparedness.

microbiology↗

bioRxiv2026

Individual Brain Structure Deviations and its Gene Expression Signatures in Early-Onset Schizophrenia

BackgroundSchizophrenia is a highly heritable mental disorder associated with widespread anatomical alterations during neurodevelopment. Converging evidence suggests transcriptomic architecture underlying brain abnormalities in schizophrenia, while how individualized brain morphological deviations relate to gene expression levels remains unclear. MethodsTo investigate individual-level brain deviations and its transcriptomic signatures in schizophrenia, this study collected T1-weighted MRI data from 95 early-onset schizophrenia (EOS) patients and 99 typically developing (TD) controls. Normative modeling was used to measure individual deviations in cortical thickness and subcortical volume. Partial least squares regression was calculated to capture covarying patterns between structural deviations and whole-brain gene expression levels. Clustering analysis was performed on latent brain-gene covarying components, and the results were further functionally decoded through gene enrichment analyses. ResultsGroup-level comparisons suggested patients with EOS showed consistently decreased z-scores of cortical thickness in the frontal and temporal lobe regions, while increased inter-individual variability in the lingual gyrus. Clustering analysis of z-scores with transcriptomic signatures identified two distinct brain-gene covarying subtypes. Subtype 1 showed thickening cingulate gyrus, thinning occipital pole, and atrophic subcortical nuclei. Subtype 2 exhibited widespread cortical thinning across the frontal, parietal, temporal, and limbic regions, but enlarged subcortical nuclei. Genes underlying two subtypes were both enriched for neurodevelopmental diseases. However, subtype 1 was associated with synaptic transmission, and subtype 2 was related to cytoskeletal and neuronal connectivity. ConclusionThis study reveals individual-level anatomical deviations and transcriptomic heterogeneity in early-onset schizophrenia. The findings provide an individualized brain-gene coupling framework for understanding pathophysiology of schizophrenia during brain development.

molecular biology↗

bioRxiv2026

Inflammation in schizophrenia: Peripheral interleukin-6 levels-related disease-specific functional activity abnormalities

BackgroundPeripheral inflammation is implicated in the pathophysiology of schizophrenia, but how inflammatory signals map onto the large-scale brain organization remains incompletely understood. MethodsWe applied a supervised multimodal fusion approach guided by interleukin-6 (IL-6) to gray matter volume (GMV) and resting-state regional homogeneity (ReHo) from a population-based discovery cohort in the UK Biobank. Brain components related to IL-6 were identified and then projected onto an independent schizophrenia cohort to examine their relevance to the disease. Imaging-transcriptomic analyses using the Allen Human Brain Atlas characterize the molecular substrates underlying the disease-relevant pattern. ResultsTwo ReHo components were significantly associated with plasma IL-6, while no GMV components showed robust IL-6 correlations. One of the components (ReHo IC4) exhibited a conserved functional pattern characterized by enhanced visual synchrony and reduced synchrony in the medial prefrontal cortex. This pattern remained unchanged in both the healthy controls and patients. In contrast, another component (ReHo IC8) showed increased synchrony in the default mode network and reduced synchrony in sensorimotor networks, and its loadings were significantly elevated in patients with schizophrenia. Imaging-transcriptomic analysis revealed the molecular architecture of this disease-amplified pattern. The default mode region was enriched in synaptic signaling pathways, while the sensorimotor region was linked to mitochondrial bioenergetic processes; both patterns significantly enriched with gene sets related to schizophrenia. ConclusionsThis study identified an IL-6-associated functional brain pattern that is amplified in schizophrenia, linking peripheral inflammation to disease-specific network dysregulation. The findings provide a systems-level framework for understanding how peripheral inflammation interacts with large-scale brain network activities in schizophrenia.

neuroscience↗

bioRxiv2026

PERK retains a predominantly monomeric state under ER stress conditions

The unfolded protein response (UPR) is a central adaptive mechanism that safeguards protein homeostasis in the endoplasmic reticulum (ER). In the heart, UPR signaling contributes to cellular remodeling and survival across a range of pathological contexts, including ischemia, pressure overload, and cardiometabolic stress. Among the three canonical UPR branches, the PKR-like ER kinase (PERK) pathway plays a critical role in modulating translational control and redox balance during stress adaptation. Despite its functional importance, the molecular dynamics of PERK activation and assembly remain incompletely understood. Here, we investigate the oligomerization behavior of PERK in living cells using advanced fluorescence microscopy. We identify a concentration-dependent mechanism of PERK self-association, as well as a distinct population of oligomeric PERK whose assembly state remains stable upon ER stress induction. These findings challenge the traditional view of stress-induced oligomerization as a prerequisite for PERK activation and suggest the existence of non-canonical modes of PERK assembly with potential regulatory significance.

cell biology↗

bioRxiv2026

Formation of homolog pairing-induced domains in early Drosophila embryo genome

Somatic homolog pairing is a defining feature of the diploid genome organization in Drosophila and underlies its transvection-based gene regulation. Here, to understand the physical effect of homolog pairing on the resulting three-dimensional (3D) organization, we employ the heterogeneous loop model and reconstruct 3D structures of the Drosophila embryo genome based on its haplotype-resolved Hi-C data. The resulting structures reveal robust end-to-end juxtaposition between homologous chromosomes amid substantial cell-to-cell variability. On sub-megabase scales, tight pairing between homologous loci at domain boundaries give rise to significant coincidence between cis and trans-homolog domain boundaries in the Hi-C map, while interior regions remain loosely associated. To uncover the physical origin of this organization, we compare the contact maps resulting from the polymer models implementing specific and non-specific button-mediated pairing mechanisms with Hi-C, finding that the intra-chromosomal contacts constrained by specifically paired inter-chromosomal buttons give rise to pairing-induced domains (PIDs). Our study suggests specific adhesive interactions as a central organizing principle of the diploid genome in Drosophila embryos. SignificanceSomatic homolog pairing distinguishes Drosophila from most eukaryotes; yet how the homolog pairing organizes Drosophila genome has remained elusive due to the lack of explicit model. By analyzing 3D structures reconstructed from haplotype-resolved Hi-C data, we clarify that specific homolog-recognizing buttons should generate pairing-induced domains that simultaneously organize cis and trans-homolog contacts. Our study provides a physical explanation on how a single molecular mechanism can simultaneously coordinate homolog pairing and architecture of chromatin domain in the diploid genome.

biophysics↗

bioRxiv2026

TREM2 agonist antibody rebuilds the resident synovial macrophage lining barrier in rheumatoid arthritis

Rheumatoid arthritis (RA) can be viewed as a disease of barrier failure, in which CX3CR1+/TREM2+ synovial tissue-resident macrophages that form the lining barrier over cartilage and bone become fragmented and disorganized. However, how to therapeutically rebuild this barrier--and how macrophage states transition during repair--remain unclear. We engineered TR-Ab19, a mouse-selective agonistic antibody against TREM2, as a precision tool to initiate and interrogate barrier repair in vivo. TR-Ab19 engages TREM2-linked downstream signaling and redirects synovial macrophages from Clec4d+ inflammatory/proliferative programs toward TREM2+CX3CR1+Aqp1+ barrier-like states, thereby rebuilding the lining barrier. Across collagen-induced arthritis (CIA) and serum-transfer arthritis (STA) models, TR-Ab19 reduces synovitis, preserves cartilage and bone microarchitecture, limits osteoclastogenesis, and attenuates systemic cytokines and B-cell abnormalities. Single-cell RNA-seq with trajectory and cell-cell communication analyses reveal a TREM2-dependent shift toward a barrier-dominant macrophage ecosystem. Together, these findings establish antibody-mediated reprogramming of resident synovial macrophages as a barrier-centered strategy for RA and provide a framework for instructing macrophage niches in chronic inflammation.

bioengineering↗

bioRxiv2026

Clonal morphology-guided combination therapies overcome heterogeneity-driven drug tolerance

Tumor heterogeneity plays a critical role in tumor relapse and the development of drug resistance. Current personalized strategies, based on genetic profiling or bulk tumor drug sensitivity testing, offer limited clinical value as they overlook clonal heterogeneity. Here, through establishing primary tumor cell cultures from multiple metastatic sites, we observed that tumor cells exhibit high morphological plasticity and readily form distinct clonal morphologies during monoclonal expansion. Moreover, these heterogeneous clones displayed distinct tumorigenic and histological traits in orthotopic models, which may imply their differing clinical relevance in tumor progression. We also found that clonal morphological heterogeneity was exhibited by both established cell lines and primary lines derived from chemically induced tumor models. Subsequently, we analyzed the drug sensitivity profiles of tumor clones and identified clone-specific sensitive drugs. Despite limited in vitro synergy in pairwise combinations, both in vitro and in vivo assays confirmed their potent, clone-selective inhibition, suggesting rational drug combinations can precisely target distinct clonal populations. Taken together, Collectively, our findings propose that a heterogeneity-informed drug selection paradigm, enabled by rapid clonal morphology analysis of patient-derived cells, can be used to prevent recurrence and overcome resistance. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/703021v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1db607dorg.highwire.dtl.DTLVardef@19bbcd4org.highwire.dtl.DTLVardef@18a3355org.highwire.dtl.DTLVardef@304794_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITumor cells develop distinct morphologies during clonal expansion. C_LIO_LIDistinct morphologies serve as simple markers of tumor heterogeneity. C_LIO_LIDistinct clonal morphology defines a unique drug-response profile. C_LIO_LIClone-selective drug combinations combat heterogeneity-driven resistance. C_LI

cancer biology↗

bioRxiv2026

IBDkb: an AI-enhanced integrative knowledge base for inflammatory bowel disease research and drug discovery

IBDkb (Inflammatory Bowel Disease Knowledge Base; https://www.biosino.org/ibdkb) is a freely accessible, integrated web-based platform that systematically curates and harmonizes multi-source data related to inflammatory bowel disease (IBD). To address the fragmentation and therapeutic gaps in existing specialized resources, IBDkb establishes a unified framework featuring advanced full-text search, interactive visualizations, cross-module knowledge graphs, and AI-powered utilities for real-time literature retrieval, trend analysis, text/PDF interpretation, and domain-specific conversational assistance. The platform currently integrates 98,453 research articles, 3,390 clinical trials, 200 investigational drugs, 200,606 bioactive compounds, 103 therapeutic targets, 77 experimental models, 12 pathogenesis summaries, and 15 treatment strategies. These integrated tools facilitate efficient exploration of complex associations among drugs, targets, trials, and mechanisms, thereby accelerating hypothesis generation and translational research in IBD. The platform is openly available without registration and supports data downloads. A case study on structure-aware drug comparison further demonstrates its utility in facilitating cross-disease drug repositioning hypotheses.

bioinformatics↗

bioRxiv2026

Disruption of the VEGFR3-HSPG2 induces lymphatic reflux dysfunction and sepsis

The lymphatic system plays a central role in fluid transport and immune regulation, yet its contribution to sepsis remains incompletely understood. Analysis of more than 500,000 individuals from the UK Biobank reveals that lymphatic system disorders and genetic variants in FLT4 (VEGFR3) are strongly associated with increased sepsis risk. Single-cell RNA sequencing further shows a marked reduction of VEGFR3^high lymphatic endothelial cells during sepsis. LEC-specific deletion of VEGFR3 impairs lymphatic reflux without disrupting vessel architecture, leading to barrier failure, systemic inflammation, bacterial dissemination, and sepsis. Mechanistically, VEGFR3 sustains lymphatic glycocalyx integrity by promoting SOX18-dependent HSPG2 transcription and heparan sulfate biosynthesis. Consistently, LEC-specific HSPG2 knockdown or pharmacological inhibition of SOX18 phenocopies VEGFR3 deficiency, whereas heparan sulfate supplementation alleviates sepsis-like pathology. Moreover, HSPG2 genetic variants are significantly associated with both lymphatic disorders and sepsis. Collectively, these findings identify lymphatic reflux dysfunction as a pathogenic determinant of sepsis and establish disruption of the VEGFR3-SOX18-HSPG2-heparan sulfate axis as an active driver of disease.

molecular biology↗

bioRxiv2026

NanoSimFormer: An end-to-end Transformer-based simulator for nanopore sequencing signal data

Nanopore sequencing has achieved a new standard of accuracy with the advent of R10.4.1 flow cell and high-performance Transformer-based basecalling models. However, existing signal simulators often fail to capture the complex, non-linear dynamics of nanopore current signals, relying on static pore models or lacking optimization objectives linked to basecalling, resulting in synthetic signals with substantially lower accuracy and fidelity than experimental data. To address this, we introduce NanoSimFormer, an end-to-end Transformer-based signal simulator that integrates basecaller guidance during training to generate high-fidelity nanopore signals explicitly optimized for accurate calling. Rigorous evaluation across diverse human, bacterial, and fungal R10.4.1 DNA sequencing datasets demonstrates that NanoSimFormer consistently outperformed competing methods (seq2squiggle and Squigulator), achieving median read accuracies exceeding 99% and Q-scores above 22.8, closely matching experimental baselines. NanoSimFormer faithfully recapitulated experimental variant calling performance on the human HG002 sample, achieving F1-scores of 0.9967 for SNPs and 0.8295 for small indels, and notably minimized false-positive errors in homopolymer and short tandem repeat (STR) regions where other simulators struggled. Furthermore, NanoSimFormer-derived reads enabled high-quality de novo bacterial assembly with consensus error rates below one mismatch per 100 kbp, comparable to experimental assemblies, and preserved fungal mock community structures with high correlation to experimental abundance profiles in metagenomic benchmarks. With tunable parameters for amplitude noise and event duration variance, NanoSimFormer enables the simulation of datasets spanning a wide range of data qualities. Together, these results establish NanoSimFormer as a robust tool for benchmarking and algorithm development in the latest nanopore sequencing era.

bioinformatics↗

bioRxiv2026

Single-cell and spatial transcriptomics unveils key regulators governing cell differentiation for Schistosoma sexual development

Schistosomiasis remains a major global health challenge, primarily due to the large number of egg production by sexually mature parasites. However, the cellular basis and regulatory programs governing sexual development and egg production are poorly characterized. Here, we constructed a dynamic single-cell atlas of Schistosoma japonicum (S. japonicum) covering key development stages of sexual maturation and egg production, and integrated it for the first time with spatial transcriptomics to map tissue-resolved cellular niches. Through bioinformatic analysis and experimental validation, we identified several critical cell populations and regulatory networks that drive parasite development and egg laying. By mapping de novo identified transcription factors (TFs) onto these atlases, we generated a comprehensive spatiotemporal expression profile of TFs and define the regulatory programs of several tissue-specific TFs including Zfp, Fbp3, and Lim. Integrated re-clustering further revealed and validated key regulators of germline stem-cell differentiation in S. japonicum. Finally, comparative analyses with S. mansoni single-cell datasets revealed both conserved and species-divergent cellular plasticity, providing unprecedented insights into their distinct biological traits. Collectively, our comprehensive study establishes a foundational resource for understanding schistosome biology, deciphers regulatory programs underlying cell differentiation and pathogenicity, and accelerates the identification of key molecules involved in sexual development against schistosomiasis.

microbiology↗

bioRxiv2026

Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute Myocardial Infarction

Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immuocytochemistry and qPCR of isolated rat cardiac cells as well as immunohistochemistry and western blot of rat myocardium was performed for presence of GPR39. Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle prior to or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min prior to or 30 min after reperfusion. Readouts also included tissue pO2, hemodynamics, and wall thickening. In Groups 5 and 6 animals, drug was injected for measurement of plasma and tissue levels. Immunocytochemistry and qPCR of cells and immunohistochemistry and western blot of tissue revealed GPR39 expression in all cardiac cells analyzed as well as entire myocardial tissue. There was marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in Group 2 where INV was measured. In contrast, Group 4 animals failed to show reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue pO2 in VC108 compared to vehicle treated animals. Similar results were obtained for INV in only in Group 2 animals. In Group 3 animals direct cardiomyocyte effect of VC108 was seen in myocardium as evidenced by reduced necrosis and apoptosis. We conclude that VC108 is very effective in reducing INV and NRV in an AMI model when given before coronary occlusion or just prior to reperfusion (the latter being clinically more relevant) both in male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and VSMC relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation. New and NoteworthyGPR39 is the receptor for 15-HETE, which is a vasoconstrictor with direct cardiomyocyte detrimental effects. Pharmacological inhibition of GPR39 by a novel inhibitor, VC108, reduces coronary no reflow after acute myocardial infarction by relaxing contracted pericytes surrounding capillaries, whereby increasing oxygen delivery. GPR39 inhibition also reduces necrosis and ferroptosis by interrupting aberrant downstream signaling responsible for cell death. Hence, pharmacological inhibition of GPR39 by VC108 offers a novel treatment of acute myocardial infarction. Graphical AbstractProposed mechanism of action of VC108 when given prior to and during coronary occlusion based on our results. The drug inhibits the action of the vasoconstrictor, 15-HETE, on GPR39. This causes vasodilation by relaxing contracted pericytes and increasing capillary perfusion, resulting in increased tissue pO2 and reduction in no reflow (left side). When tissue pO2 is not associated with necrosis, GPR39 inhibition by VC108 directly affects cardiomyocytes by inhibiting downstream signaling of GPR39 present in cardiomyocytes that can lead to cell injury and death. Hence, less necrosis and apoptosis are noted in VC108 versus vehicle treated animals. Created in https://BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/699339v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1058995org.highwire.dtl.DTLVardef@8bc0ceorg.highwire.dtl.DTLVardef@11f44e0org.highwire.dtl.DTLVardef@1e2e337_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Control of grain dimensions via ALLENE OXIDE CYCLASE

Cereal grain is a global food staple. Grain formation starts with fertilization of the embryo sac which generates filial tissues, such as the embryo and endosperm, that grow embedded in the maternal ovule and surrounding ovary wall. Maternal tissues provide nutrition and protection but are progressively reduced and degraded, such that filial tissues dominate the mature grain. While we know some enzymatic players, regulation of this process in temperate cereals like wheat and barley, remains less understood. However, previous work suggested a role for the phytohormone Jasmonate (JA). To learn more, we edited the barley ALLENE OXIDASE CYCLASE (HvAOC) gene encoding a JA biosynthetic enzyme. Defective HvAOC alleles caused enhanced vegetative growth, faster flowering and larger, heavier grain - phenotypes rescued by MeJA treatment. HvAOC control of final grain parameters is parentally-derived, consistent with enriched HvAOC expression in maternal compared to filial tissues. Defective HvAOC function enlarged maternal tissues involved in nutrient transfer, correlating with larger endosperm and higher expression of genes linked to sucrose transport. This work provides the first genetic dissection of JA in barley and highlights a key role for HvAOC in the coordination between growth and death of maternal tissues with grain size and weight.

plant biology↗

bioRxiv2026

An Asynchronous Production Line of Meiotic Prophase I in the Mouse Fetal Ovary

The initiation of meiosis in the mammalian female germline has long been described as a synchronous event, occurring within a narrow developmental window. Here, we challenge this paradigm through a systematic, quantitative analysis of meiotic entry and progression in the mouse fetal ovary. Using dynamic expression profiling of key regulators Stra8, Sycp1, and Sycp3 alongside proliferation markers, we demonstrate that germ cells enter meiosis asynchronously and continuously between embryonic days E12.5 and E16.5. During this extended period, mitotic proliferation persists, indicating that germ cells are progressively recruited into the meiotic pathway rather than halting division simultaneously. Homologous chromosome synapsis, marked by Sycp1/Sycp3 co-localization, initiates at E14.5 and is completed prenatally by E18.5. Integrating these data into a continuous-time Markov chain model, we derive a "meiotic clock" that predicts fixed temporal intervals from meiotic entry to synapsis completion ([~]72 hours) and to meiotic arrest ([~]91 hours), regardless of entry time. This model provides a predictive framework for germ cell development and establishes that female meiotic initiation is a prolonged, asynchronous production line rather than a synchronized transition, reshaping our understanding of oogenesis and its regulatory logic. TEASERThe initiation of female meiosis in mice is redefined as an asynchronous, continuous production line from E12.5 to E16.5, supported by a predictive "meiotic clock" model with fixed temporal intervals for synapsis and arrest.

developmental biology↗

bioRxiv2026

Myeloid PINK1 represses mtDNA release and immune signaling that impacts neuronal pathology in patient-derived idiopathic PD models

Parkinsons disease (PD) is a neurodegenerative disorder marked by the development of cardinal motor deficits preceded by a protracted prodromal period of non-motor symptoms often involving the gastrointestinal (GI) tract. There is an emerging consensus that both the peripheral immune system and local neuroinflammation play key roles in the etiology of PD. We previously demonstrated a critical function for the Parkinsons related proteins PINK1 and Parkin as repressors of the innate to adaptive immune response in cultured cells and mouse models of infection. However, it remained unclear whether these processes were conserved in patient-derived models, and precisely how immune signaling may ultimately drive the death of dopaminergic neurons. Here we show that GI infection of PINK1 knockout (KO) mice triggered acute neurodegeneration which was evident early in the enteric nervous system. Treating wild type enteric or dopaminergic neurons with conditioned medium from immune-stimulated PINK1 KO macrophages was sufficient to promote neuronal disruption in both mouse and human neurons in vitro. Within immune-activated macrophages, we reveal that loss of PINK1 led to an enhanced release of mitochondrial DNA (mtDNA) within mitochondrial derived vesicles, leading to the activation of cGAS/STING pathways. These changes were seen in both mouse/human in vitro models and in PD patient-derived primary macrophages. Notably, pharmacological modulation using a PINK1 activator with high therapeutic potential attenuated pro-inflammatory profiles elicited by the mtDNA-dependent STING/NF-{kappa}B pathway in idiopathic patient-derived macrophages. Ultimately, our study lays the foundation for understanding PINK1-related peripheral macrophage mechanisms in idiopathic PD and provides a target for further development to treat the disease at early stages. Graphical abstractPINK1-related immune mechanisms of Parkinsons disease and associations with early neurodegenerative events. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/694713v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@6f6488org.highwire.dtl.DTLVardef@13139aaorg.highwire.dtl.DTLVardef@c0d4d1org.highwire.dtl.DTLVardef@1d41e25_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

TSTScope Unifies Single-Cell Multi-Omics to Identify Functional T Cell States Predictive of Immunotherapy Response

Immune checkpoint blockade (ICB) can produce durable responses in cancer, but reliable predictors of benefit are still lacking. CD8 tumor-specific T cells are essential for ICB efficacy, yet it remains unclear which functional states of these cells determine therapeutic success. To address this, we developed TSTScope, an interpretable deep learning framework that integrates single-cell transcriptomic and T-cell receptor sequencing data to generate unified representations of CD8 T-cell identity. By applying TSTScope to non-small cell lung cancer (NSCLC) datasets, we characterized the gene programs defining tumor specificity and computationally inferred a population of potential TSTs. Crucially, we demonstrate that clinical response is not a product of TST abundance, but is instead governed by their functional state. We derived the MPR score, a metric capturing this functional potential, which proved to be a robust predictor of treatment outcomes. In an independent validation cohort, the MPR score significantly outperformed established biomarkers. Collectively, TSTScope identifies a distinct functional state of tumor-specific T cells as a primary determinant of ICB efficacy, providing both a mechanistic framework and a potent tool for precision immunotherapy.

bioinformatics↗