Biology subjects

Ni, X.

Publications and source records attributed to Ni, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Benchmarking single-cell foundation models for aging biology

Single cell foundation models (scFMs) provide representations of cellular states, but their utility across biological questions in aging research remains unclear. We established a benchmark of cellular representations for aging research, evaluating ten general-purpose scFMs, three aging-specific models and conventional methods across five biological questions using more than 2.5 million single cell transcriptomes. Using frozen pretrained representations, Geneformer performed best among scFMs for chronological age prediction and age pseudotime concordance, although 2,000 highly variable genes achieved higher mean performance. Several scFMs captured positive molecular age shifts across three disease contexts, consistent with reported aging-associated changes. SCimilarity performed well for rare cellular state identification across out-of-distribution datasets, exceeding aging specific models and conventional baselines. At the gene level, scGPT showed the highest recovery of reference TF target interactions, including aging-related regulatory hubs. Overall, scFMs supported diverse aging analyses, but performance depended on the biological question, highlighting their utility for rare cellular state identification and regulatory analysis.

bioinformatics↗

bioRxiv2026

AI-Guided Multi-Objective Engineering of Glucoamylase Enables Acidification-Free Starch Saccharification

Glucoamylase is essential for industrial starch saccharification, but the limited thermostability and near-neutral pH tolerance of fungal glucoamylases necessitate cooling and acidification of liquefied starch. Here, we developed an artificial intelligence-guided strategy to simultaneously improve the thermostability, pH tolerance, and catalytic activity of glucoamylase from Penicillium oxalicum (PoGA). Two property-specific machine-learning models, CASPE-T and CASPE-A, identified substitutions associated with thermostability and pH tolerance, respectively. Experimental screening identified beneficial substitutions in 11 of 21 CASPE-T and 12 of 22 CASPE-A candidates. Folding-energy-guided recombination integrated the two traits while maintaining structural compatibility. The optimal variant, PoGA T513E/Q305N, exhibited 2.21-fold higher specific activity than the wild type, with half-life extended from 22.3 to 57.9 min at 60 degrees C and from 16.6 to 64.7 min at pH 8.0. Molecular dynamics simulations attributed these improvements to reinforcement of high-occupancy hydrogen-bonding networks, suppression of conformational fluctuations in the linker and carbohydrate-binding module, enhanced long-range dynamic coordination, and preservation of a compact catalytic architecture. At 60 degrees C and pH 6.5 without acidification, PoGA T513E/Q305N produced 219.9 g/L glucose and achieved 89.1% starch conversion, 31.4% higher than the wild type. This work provides an efficient framework for multi-objective enzyme engineering and sustainable starch biorefining.

synthetic biology↗

bioRxiv2026

Pervasive Backdoor Vulnerabilities in Genomic Foundation Models

Genomic foundation models are increasingly used to interpret and design DNA sequences, yet their susceptibility to training-data manipulation remains poorly understood. Here we systematically evaluate backdoor poisoning across three model families, seven parameter scales ranging from 50 million to 7 billion, and 18 genomic classification tasks. We introduce two complementary 48-nucleotide triggers: a composition-matched synthetic sequence and a biologically grounded trigger derived from transposon terminal inverted repeats. Poisoning 5% of the training data induced high attack success rates across all tested models, with model-level median values ranging from 91.4% to 100%. Increasing parameter scale did not consistently improve resistance, whereas poisoning rate and trigger length had stronger effects on attack efficacy. Performance on unmodified sequences was generally preserved, with 79.4% of model - task - trigger configurations changing by no more than two percentage points, although larger task-specific losses occurred. We further developed a two-stage defense that combines single-nucleotide mutation-sensitivity screening with reference-database validation. Across 28 evaluated configurations, the method achieved 100% precision and a median recall of 92.95%, while localizing the trigger in nearly all detected poisoned sequences. These findings establish training-data poisoning as a pervasive and difficult-to-detect vulnerability in genomic foundation models and motivate stronger data-provenance controls, adversarial evaluation and post-training security auditing.

bioinformatics↗

bioRxiv2026

3D Passive Cavitation Mapping (3D-PCM) with a Large-aperture Planar Array

Urinary stone disease is a common urological condition with increasing incidence, particularly in developed countries. Laser lithotripsy (LL) has become a preferred minimally invasive treatment due to its high precision and low tissue damage. Recent studies suggest that cavitation plays a critical role in stone damage during LL, and three-dimensional passive cavitation mapping (3D-PCM) has emerged as a promising tool for detecting these events. However, clinical translation of 3D-PCM remains challenging due to limitations in imaging depth, field of view (FOV), and procedural compatibility. Here, we present a large-FOV dual-modality imaging system (3D-PCM and B-mode ultrasound) based on a large-aperture planar ultrasound array. Through array optimization and model-based reconstruction, our system achieves an expanded FOV of [~]40 x 40 mm2 at a clinically relevant imaging depth of [~]110 mm, while maintaining high spatial resolution of [~]0.6 mm laterally and [~]0.4 mm axially. In vivo experiments in a porcine model demonstrate that the reconstructed cavitation distribution correlates well with stone damage. Our technology has the potential to provide real-time treatment feedback during LL without disrupting the standard workflow.

bioengineering↗

bioRxiv2026

ArchaicSeeker 3.0: A deep-learning framework for scalable, haplotype-resolved inference of archaic introgression

Archaic introgression has left a significant mark on human genetic diversity, but reliably identifying introgressed segments remains a major challenge, especially with complex demographic histories and limited sample sizes. Existing methods often rely on demographic assumptions or cohort-specific parameter fitting, which compromises robustness and scalability. We introduce ArchaicSeeker 3.0 (AS3), a deep-learning framework designed for haplotype-resolved detection of archaic introgression. AS3 integrates a tract-scale sequence model with an overlap-aware reassembly approach and boundary refinement, enabling accurate, boundary-coherent reconstruction of introgressed segments across diverse genomic contexts. By leveraging a simulation-trained model, AS3 avoids inference-time recalibration, offering stable performance across unrepresented demographic scenarios and small cohorts. In extensive simulations, AS3 outperforms existing methods in precision, recall, and F1 score, while providing more continuous segments with accurate boundary localization. It demonstrates robustness in small-target regimes and varying marker densities. Applied to 3,453 genomes from 209 populations, AS3 shows strong concordance with existing introgression callers and identifies additional introgressed regions, including high-frequency AS3-specific introgressed segments supported by locus-level haplotype and phylogenetic analyses. AS3 provides a scalable, robust solution for detecting archaic introgression from single individuals to large biobank datasets, marking a significant advancement in the field of local ancestry inference and opening new possibilities for the study of human evolutionary genetics. ArchaicSeeker 3.0 is available at https://github.com/Shuhua-Group/ArchaicSeeker3.0.

bioinformatics↗

bioRxiv2026

A Critical Sites-Driven and Light-weighted Protein Engineering Platform

Protein large language models (PLMs) provide a novel computational paradigm for the deep mining of sequence co-evolutionary information, significantly accelerating the generation of functional proteins for biotechnological and medical applications. However, the misalignment between zero-shot predicted evolutionary fitness and industrial application requirements leads to a limited success rate in acquiring beneficial mutations, while the high training cost presents another drawback of large models. Here, we developed CASPE (Critical Amino acids Streamline Protein Evolution), a lightweight protein engineering platform for the precise localization and adaptation of critical residues, consisting of the CAS (Critical amino acid sites) and APCNet (Amino acid Point Cloud Classification Network). CAS utilizes gradient activation mapping and multi-layer attention matrices to directly extract key information determining target properties from PLMs and transform it into explicit site importance indicators, without relying on additional structural information or prior knowledge. Working in tandem with APCNet, CASPE establishes a workflow encompassing the entire trajectory from site localization to residue prediction. CASPE achieved remarkable hit rates in identifying beneficial variants for thermostability (31.3-60%) and pH tolerance (40-80%), further uncovering the potential mechanisms of action at these key target sites. Directed evolution of phytase further validated the generalizability of CASPE. CASPET-Phytase achieved a 33.3% success rate in obtaining beneficial mutants, which was significantly better than FoldX (6.7%) and ESM2-t33 (13.3%). CASPE guides enzyme evolution towards precise, site-targeted optimization, providing an efficient computational framework for developing industrial enzymes.

bioengineering↗

bioRxiv2026

Spatio-temporal mapping of immune cell dynamics during human sequential lymph node metastasis

Regional lymph node (LN) metastasis critically influences distant metastatic progression, anti-tumour immunity, and patient prognosis. While tumour-induced immune modulation in tumour-draining LNs (TDLNs) has been extensively studied using murine models, the systematic reconstruction of the immune system from primary tumours through TDLNs and subsequent lymph nodes in human cancer progression remains understudied. Here, we utilised integrated multi-omics approaches, including imaging mass cytometry, single-cell RNA sequencing, Visium and Xenium spatial transcriptomics, and multi-colour immunofluorescence to systematically characterise immune cell dynamics across 147 paired primary tumours, sentinel TDLNs (S-TDLNs), and secondary axillary LNs (ALNs) obtained from 50 treatment-naive triple-negative breast cancer patients with different progression statuses. Our comprehensive profiling revealed critical immune alterations, such as decreased type-2 conventional dendritic cells (cDC2), naive T cells, and B cells, along with an increase in immunosuppressive macrophages. Developing a novel single-cell transformer model, we identified substantial alterations in various immune cell populations, notably MARCO+ macrophages, which strongly correlated with breast cancer patient survival outcomes. Spatial analysis combined with our newly integrated cell-cell interaction platform revealed diminished immune cell communication and impaired priming interactions among dendritic cells, B cells, and T cells within metastatic lymph nodes and primary tumour sites. In an independent neoadjuvant immunotherapy cohort of 36 TNBC patients with 52 lymph node samples, we found preservation of CD1c cDC2 in lymph nodes predicted pathological complete response and longer event-free survival, highlighting cDC2 as a potential biomarker and therapeutic target. Collectively, this systematic mapping of immune landscape alterations during human sequential LN metastasis provides essential insights for understanding cancer metastasis mechanisms and paves the way for innovative immunotherapeutic strategies.

immunology↗

bioRxiv2025

Creating an energy efficient central metabolism for boosting biosynthesis without compromising cell growth of yeast

Long-term natural evolution selects glycolysis as the major metabolic mode for rapid cell growth, which however lacks sufficient NADPH supply to dive the biosynthesis of reduced chemicals such as free fatty acids (FFAs). Engineering energy economical pathway for chemical overproduction always compromises cellular fitness due to the rigidity of cellular metabolism. Here, we successfully replaced glycolysis metabolism with an optimized pentose phosphate pathway (PPP) in an industrial yeast Ogataea polymorpha, for the first time, which enabled a higher energy generation efficiency than glycolysis and a balanced supply of ATP and NADPH. More importantly, we discovered a global carbon metabolism regulator CMR that drives metabolic flux toward glycolysis for energy generation, and its disruption relieved the tight regulation of metabolic flux distribution and significantly enhanced the efficiency of cellular energy generation, which significantly boosted the FFA production by 63% in a FFA overproducing chassis. The final engineered yeast produced FFAs at a titer of 41.7 g/L, the highest titer reported by microbial fermentation. Our work provides valuable insights into the metabolic regulation mechanisms and a feasible approach for constructing energy efficient metabolism for chemical overproduction.

synthetic biology↗

bioRxiv2025

A Syngeneic Immunocompetent Mouse Model of Gallbladder Cancer Reveals Tumorigenesis and Therapeutic Response

PurposeGallbladder cancer (GBC) is a rare but highly lethal malignancy with one of the poorest prognoses among cancers of the digestive system cancers. However, current experimental models of GBC face critical limitations, particularly their dependence on immunodeficient hosts, which precludes the investigation of the tumor microenvironment. We aimed to establish a novel syngeneic immunocompetent mouse model that recapitulates human GBC and enables the investigation of tumor-immune interactions. Experimental DesignWe engineered a murine cell line (mGBC1-ZH) from normal mouse gallbladder organoids expressing Kras and Trp53 (encoding mouse p53) mutations. Tumorigenic potential of mGBC1-ZH was evaluated by subcutaneous and orthotopic implantation. RNA-Seq and WES was used to demonstrate its characterization and similarity with human GBC. Immunohistochemistry, CCK8, and transwell assays wereused to investigate the role of CXCL5 in GBC. Therapeutic responses to standard first-line chemotherapeutic agents was evaluated in the syngeneic GBC model. ResultsThis model supports both subcutaneous and orthotopic tumor growth in immunocompetent C57BL/6J hosts while preserving hallmark features of human GBC, including biliary epithelial differentiation (CK7+/CK19+), aggressive histopathology, and an immunosuppressive "cold" tumor microenvironment. Genomic characterization revealed recurrent chromosomal instability and copy number alterations mirroring human GBC. Comprehensive transcriptomic profiling revealed profound gene expression changes during the model development, and resembled transcriptional features between mGBC1-ZH and human GBC cell lines and samples. CXCL5 was found to be upregulated in human GBC, and promote proliferation, metastasis, and neutrophils infiltration of GBC in the syngeneic mouse model. Functional validation of the syngeneic GBC model demonstrated therapeutic responsiveness to frontline chemotherapeutics gemcitabine and cisplatin with significant in vivo tumor regression. ConclusionsIn summary, we establised a novel syngeneic GBC mouse model, overcoming the limitations of traditional models by enabling studies in immunocompetent hosts. This model provides valuable insights into the molecular evolution from normal gallbladder cells to transformed cancer cells and establishes a robust platform for both mechanistic studies and therapeutic development.

cancer biology↗

bioRxiv2025

Endothelial Kallikrein-Related Peptidase 8 Promotes Diabetic Nephropathy through a LIFR dependent mechanism

BackgroundDiabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus; however, the exact pathways in endothelial cells (ECs) linked to DN progress remain unclear. Tissue kallikrein-related peptidases (KLKs) participate in pathophysiological processes in ECs. We aimed to explore the roles of endothelial KLKs in DN and define the underlying mechanisms. Methods and resultsKLK8 was the most highly upregulated member of KLKs in renal tissues in streptozotocin (STZ)-induced diabetic mice and cultured glomerular ECs (GECs) upon high glucose (HG) treatment. Both global (Klk8-/-) and endothelial Klk8 knockout (Klk8{Delta}EC) mice displayed improved albuminuria, mesangial matrix expansion and glomerulosclerosis caused by STZ compared to Klk8f/f mice. Single-cell RNA seq (scRNA-seq) showed that many pathways associated with DN in ECs, mesangial cells (MCs) and tubule cells were reversed in Klk8{Delta}EC mice. Endothelial-to-mesenchymal transition (EndMT) was extensively improved in Klk8{Delta}EC mice, and by KLK8 siRNA in cultured GECs upon HG. Using proteome and other biochemical approaches, we revealed that KLK8 cleaved syndecan-4(SDC4), which contributed to loss of glycocalyx integrity in GECs in cultured cells and animal diabetic models. Furthermore, scRNA-seq showed that Lifr was one of the key genes linked to the disease progressed in ECs and MCs and regulated by endothelial Klk8. LIFR signaling contributed to HG-induced GEC dysfunction and MC activation, which was associated with endothelial Klk8. Knockdown of Lifr by lentivirus-Lifr shRNA ameliorated hallmark features of DN and improved EndMT and Sdc4 expression glomeruli of diabetic mice. LIFR was upregulated in GECs and MCs in DN patients. Circulatory levels of LIF, KLK8 and soluble SDC4 were increased in patients with DN, and KLK8 level was positively correlated with LIF, soluble SDC4 and creatinine levels. ConclusionEndothelial KLK8 promotes GECs dysfunction and abnormal crosstalk with MCs through a LIFR-dependent signaling in DN, which immediately highlights therapeutic targets for DN. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/662673v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@dae3b1org.highwire.dtl.DTLVardef@9aab24org.highwire.dtl.DTLVardef@59eaa5org.highwire.dtl.DTLVardef@13c138a_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

Construction of recombinant Bacillus subtilis spores surface-displaying PRRSV ORF1b, GP5, M, and N proteins in tandem and evaluation of their immunogenicity in mice

Porcine reproductive and respiratory syndrome virus (PRRSV), a single-stranded RNA virus, is a highly contagious pathogen that causes severe reproductive and respiratory disorders in pigs, leading to significant economic losses in the swine industry worldwide. However, current commercial vaccines provide only limited protection against circulating PRRSV strains, highlighting the urgent need for novel vaccine strategies. B. Bacillus subtilis, a well-characterized probiotic, has emerged as a promising platform for mucosal vaccine delivery due to its safety profile and ability to induce robust immune responses. In this study, we screened B cell and T cell linear epitopes from PRRSV-ORF1b, GP5, M, and N proteins to construct a recombinant tandem antigen (ER), which was displayed on the surface of B. subtilis 168 spores. The resulting recombinant strain, designated B. subtilis BE, was evaluated for immunogenicity in mice via oral administration. The results showed that Oral immunization with B. subtilis BE significantly elevated antigen-specific secretory IgA levels in intestinal contents and IgG levels in serum, indicating potent mucosal and systemic humoral responses. Moreover, B. subtilis BE induced measurable neutralizing antibody titers and enhanced cellular immunity, as evidenced by increased frequencies of CD3+ and CD8+ T cells in mesenteric lymph nodes and upregulation of IFN-, TNF-, and IFN-{gamma} expression in intestinal tissues. Collectively, these findings demonstrate that B. subtilis BE elicits both humoral and cellular immune responses and may serve as a novel oral vaccine candidate against PRRSV, offering a promising alternative for controlling the ongoing epidemic.

immunology↗

bioRxiv2025

Discovery of orally bioavailable Zika and West Nile Virus antiviral compounds targeting the NS2B-NS3 protease

Flaviviruses are a class of pathogenic viruses with pandemic potential that are typically transmitted via infected arthropods. In addition, Zika virus is sexually transmissible and causes congenital malformations if infection occurs during pregnancy. Although over 1.5 million people were infected during the 2015-2016 Zika outbreak, to date, there are no clinical-stage vaccines or antivirals. Herein, we report the discovery of potent inhibitors of the Zika virus NS2B-NS3 protease that also show activity against the West Nile virus NS2B-NS3 protease. Starting from a crystallographic fragment screen, we employed a pharmacophore approach coupled with high-throughput library chemistry to elaborate fragments in the active site. Potent, metabolically stable, non-covalent, non-peptidomimetic inhibitors were identified with antiviral activity in vitro. The lead compound was progressed to a three-day Zika virus challenge study in AG129 mice, where it displayed significant viral RNA load reduction in both mouse plasma and spleen.

microbiology↗

bioRxiv2025

CK2 directly controls CARD9 protein homeostasis

CARD9 is an attractive target for therapeutic intervention because the human genetic data provides strong evidence for the causal role of CARD9 in both protection and susceptibility to autoimmune disease. Expression quantitative trait loci (eQTLs) link higher CARD9 expression to increased disease risk and lower CARD9 expression to protection. Additionally, a rare allele variant leading to a C-terminal truncation of CARD9 (CARD9{Delta}11) and subsequent loss-of-function is also protective for inflammatory bowel disease (IBD). The mechanism of CARD9-driven inflammation through scaffold assembly with BCL10 and MALT1 (CBM complex) suggests a durable inflammatory signal driven by increasing levels of CARD9. Therefore, CARD9 depletion is a desired therapeutic strategy for drug discovery, yet a difficult one due to the nature of CARD9 as an adaptor protein target and the limited number of chemical tools available to engage it. Here, we uncover through a protein homeostasis screen that casein kinase 2 (CK2/CSNK2) inhibition leads to cellular CARD9 depletion. Following up with arrayed CRISPR screening, we identify key casein kinase isoforms/subunits responsible for CARD9 depletion. We find that CK2 directly binds to CARD9 and phosphorylates S424/S425 as well as S483/S484. Orthosteric CK2 inhibition prevents CK2 binding to CARD9 and leads to CARD9 destabilization. We show that the interaction between CK2 and CARD9{Delta}11 is significantly attenuated and not sensitive to CK2-mediated protein stabilization. The CK2-driven CARD9 depletion mechanism is preserved outside of immortalized cell lines and conserved between primary, differentiated mouse and human dendritic cells. Finally, we demonstrate therapeutic proof of concept in vivo using CK2 inhibition to deplete CARD9 in murine whole blood, peritoneum, and colon. Our study expands the scope of cellular consequences dealt by kinase inhibition, offers an unconventional approach for engaging a therapeutically intractable target, and identifies a novel mechanism that could contribute to disease protection conferred by the CARD9{Delta}11 allele.

immunology↗

bioRxiv2025

Looking for the optimal pathway to stimulate hippocampus in human participants using transcranial ultrasound stimulation (TUS): a simulation study

At present, very limited methods can directly modulate the neural activities in deep brain structures in human participants. Low-intensity transcranial ultrasound stimulation (TUS), as an emerging and advanced modality of non-invasive brain stimulation (NIBS), has great potential for focally stimulating the subcortical structures that are related to sleep, emotion and the functions of motor of cognition. Due to the focality, the integration of various methods, including magnetic resonance imaging and possible pathways, is important to perform TUS intervention for precise targeting and dosing. Based on structural MRI scans, we constructed a simulation model of low-intensity TUS, with a particular focus on the optimal pathways of targeting hippocampus in human participants. Finally, we outlooked the future perspectives of TUS in clinical applications in neurological and psychiatric fields.

neuroscience↗

bioRxiv2024

Crystal structure of Fatty Acid Thioesterase A bound by 129 fragments provides diverse development opportunities

To alleviate the growing issue of herbicide resistance, diversification of the herbicide portfolio is necessary. A promising yet underutilised mode of action (MoA) are Fatty Acid Thioesterases (Fat), which terminate de novo fatty acid (FA) biosynthesis by releasing fatty acids from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility by determining the amount and length of FAs present. To find novel chemical matter targeting this MoA we have solved the crystal structure of Arabidopsis thaliana FatA to 1.5[A] and conducted a crystallographic fragment screen which identified 141 hits. Our fragments recapitulated interactions made by current herbicides, but also targeted novel regions, namely the active site and the dimer interface. Ten fragments demonstrated on-scale potency, two of those exploiting different interactions to known herbicides. The screen also revealed large conformational changes exploited by some fragments, including stabilisation of a loop and shifts in the ACP-binding lid domain. These changes alter the accessibility of the substrate binding site by reducing the size of the apparent substrate access channel. Finally, the fragments readily lend themselves to designing compounds that both merge motifs and allow catalogue-based SAR exploration. Elaboration of one of the fragments resulted in an improvement of affinity from [~]20 M to [~]90nM KD. Thus our data may facilitate accelerated early discovery of alternative inhibitors that are novel in both chemical scaffolds and modes of interaction.

biochemistry↗

bioRxiv2024

ISCO: Intelligent Framework for Accurate Segmentation and Comparative Analysis of Organoids

Organoids are self-organizing 3D cell clusters that closely mimic the structure and function of in vivo tissues and organs. Quantifying organoid morphology is critical for advancing our understanding of organ development, drug discovery, and toxicity assessment. Recent advances in microscopy have provided powerful tools to capture detailed morphological features of organoids, yet manual image analysis remains labor-intensive and time-consuming. In response, we present a comprehensive microscopy-based analysis pipeline that utilizes SegmentAnything 2.1 to accurately segment individual organoids. Additionally, we introduce a suite of morphological features--including perimeter, area, radius, non-smoothness, and non-circularity--that enable researchers to quantitatively and automatically analyze organoid structures. To further standardize organoid analysis across the field, Intelligent segmentation and comparison of organoids(ISCO), an intelligent AI-driven open-source algorithm, is developed with the aim of establishing a comprehensive toolset for organoid characterization.

bioengineering↗

bioRxiv2024

High-resolution imaging atlas reveals context-dependent role of pancreatic sympathetic innervation in diabetic mice

Gaining a better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in islets of adult WT and diabetic mice. Our data shows that more than [~]30% /{beta}-cells are innervated by sympathetic nerves in both WT and diabetic mice. Also, sympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. Besides, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db/db mice, but decreases in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our comprehension of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation. HighlightsPancreatic sympathetic innervation plays an important role in glucose homeostasis. In our study, we systematically investigate sympathetic innervation in the islets of WT and diabetic mice. O_LI45.9% -cells and 31.8% {beta}-cells are innervated by sympathetic nerves in 10-week-old WT mice. C_LIO_LISympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. C_LIO_LIUnlike the core-mantle structure observed in WT and DIO mice, -cells and {beta}-cells are intermixed in db/db mice. C_LIO_LIPancreatic sympathetic denervation elicits varied responses across diabetic models, where it improves glucose tolerance and insulin sensitivity in db/db mice, yet it increases insulin sensitivity but reduces glucose tolerance in DIO mice. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/623708v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@183be78org.highwire.dtl.DTLVardef@4dc76borg.highwire.dtl.DTLVardef@5f5ca0org.highwire.dtl.DTLVardef@ba3cc7_HPS_FORMAT_FIGEXP M_FIG Summary of morphological and physiological phenotypes in diabetic mice. All data are normalized to that of WT-10 mice. The numbers of "+" refer to their relative numbers. {uparrow} or {downarrow} refers to increase or decrease, ns refers to "not significant". "-" refers to the experiment has not been carried out. C_FIG

neuroscience↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗