Biology subjects

Jiang, Y.

Publications and source records attributed to Jiang, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

Pyruvate kinase activates SARM1 to exacerbate axonal degeneration in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, characterized by progressive axonal degeneration. However, the molecular link between hyperglycemia and axon injury remains unclear. Here, we identify pyruvate kinase M (PKM) as a direct metabolic activator of the NADase SARM1 under high-glucose conditions. Proteomic and biochemical analyses reveal that PKM binds the TIR domain of SARM1 via its C-terminal region, allosterically enhancing NADase activity independently of PKMs glycolytic role. In dorsal root ganglion (DRG) neurons, hyperglycemia strengthens the PKM-SARM1 interaction, driving NAD depletion, axonal fragmentation, and sensory dysfunction. Genetic depletion of PKM protects against streptozotocin-induced neuropathy, preserving nerve fiber density, restoring NAD levels, and alleviating mechanical allodynia. Most notably, we developed Pep-SP1, a competitive inhibitory peptide derived from residues 645-655 of the SARM1 TIR domain, which selectively disrupts the PKM-SARM1 interaction without impairing PKM metabolism or SARM1 catalytic activity. Systemic delivery of Pep-SP1 attenuates axonal degeneration and improves sensory outcomes in diabetic mice. By targeting a disease-potentiating interface, we expand therapeutic strategies beyond catalytic and allosteric inhibition, offering a mechanistically distinct avenue for axon protection with broad relevance to metabolic and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Notch as a Driver of Lineage Plasticity and Therapeutic Target in Enzalutamide-Resistant Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, in castration-resistant prostate cancer (CRPC) remains a significant clinical challenge, often driven by mechanisms including lineage plasticity. The precise molecular mechanisms driving this process, particularly downstream effectors, remain incompletely understood. Given its established roles in cell fate and stemness, alongside its complex functions in prostate cancer, the Notch signaling pathway presented a compelling focus for study. This study investigates the role of Notch signaling in mediating lineage plasticity and therapeutic resistance in CRPC. Employing transcriptomic analysis and functional assays, we identified Notch activity is elevated across prostate cancer progression resistance. Notably, both CRISPR-mediated knockout and targeted inhibition of Notch reversed enzalutamide resistance in vitro. Collectively, this study delineates dynamic alterations in Notch signaling activity during prostate cancer progression and establishes its function as a crucial and druggable driver of therapy resistance. These findings underscore Notch signaling as a promising therapeutic target to counteract resistance to AR-targeted therapies in advanced prostate cancer.

cancer biology↗

bioRxiv2025

Sequential Amino Acid Mutagenesis-Driven De Novo Evolution of Adenine Deaminases Enables Efficient In Vivo Base Editing in Primate

Base editing allows for the precise modification of genetic information, providing new avenues for treating diseases1. The adenine base editor ABE8e is currently the most efficient and widely used tool for adenine base editing. ABE8e was developed through multiple rounds of directed evolution of Escherichia coli tRNA adenine deaminase, including phage-assisted continuous evolution (PACE)2,3. While PACE is highly effective, it is a complex system that poses challenges for implementation4. Despite its high efficiency, ABE8e is associated with limitations such as relatively higher bystander editing effects and elevated off-target activity5, which need to be addressed to further enhance its precision and safety. Here, we developed a novel method for the de novo discovery of evolved ABE components, particularly adenine deaminases. This process involves identifying candidate proteins through AI-based structural prediction and clustering, followed by the enhancement of deaminase editing activity through screening libraries created by sequential amino acid saturation mutagenesis. This evolutionary strategy simplifies the approach by employing saturation mutagenesis libraries tailored to specific segments, thereby enabling exploration of an expanded sequence space and increasing the likelihood of discovering adenine deaminases with superior capabilities. The newly developed hpABE5.20 here demonstrates a more refined editing window, reduced DNA off-target effects that are both sgRNA-dependent and -independent, and minimized RNA off-target activity, while maintaining robust editing efficiency relative to ABE8e. Furthermore, hpABE5.20 has been successfully applied for precise and effective therapeutic adenine base editing in cellular disease models, humanized mice, and non-human primates.

bioengineering↗

bioRxiv2025

Tissue-Specific Iron Levels Modulate Lipid Peroxidation and the FLASH Radiotherapy Effect

Iron is vital to living cells, playing a key role in cellular respiration, DNA synthesis, and various metabolic functions. Importantly, cancer cells have a higher dependency on iron compared to normal cells to support their rapid growth and survival. Due to this fact, tumors are more vulnerable to ferroptosis, an iron-dependent form of regulated cell death. Radiation therapy (RT), a standard treatment for many cancer patients, is known to induce ferroptosis. Ultra-high dose rate FLASH RT offers an improved therapeutic window by minimizing damage to normal tissues while preserving tumor control. However, the precise biological mechanisms behind the protective effects of FLASH RT on normal tissues remain unclear. In this study, we propose that variations in lipid peroxidation and ferroptosis, driven by intrinsic differences in iron levels between normal and cancerous tissues, contribute to this effect. Our findings show that FLASH RT increases lipid peroxidation and induces ferroptosis in tumor cells but does not significantly elevate lipid peroxidation and ferroptosis in normal tissues compared to conventional RT. To determine whether raising iron levels in normal tissues could abrogate the protective effects of FLASH, mice were fed a high-iron diet before RT. A high-iron diet before and after RT reversed the protective effect of FLASH, resulting in increased intestinal damage and lipid peroxidation. This suggests that baseline iron levels and iron-driven lipid peroxidation are critical factors in mediating the protective outcomes of FLASH RT. Overall, our study sheds light on the role of iron in modulating RT responses and provides new mechanistic insights into how FLASH RT influences normal and cancerous tissues.

cancer biology↗

bioRxiv2025

Targeting the selectivity filter to drastically alter the activity and substrate spectrum of a promiscuous metal transporter

d-Block metal transporters play a crucial role in maintaining the homeostasis of life-essential trace elements and are attractive targets for protein engineering aimed to selectively enriching or excluding metals in living organisms. However, systematic efforts to engineer these transporters have been hindered by limited understanding of their transport mechanism and substrate specificity. In this study, we applied a focused-screen approach to human ZIP8, a promiscuous d-block divalent metal transporter, by systematically changing three key residues that form the selectivity filter at the entrance of the transport pathway. Screening a library of 48 constructs using an ICP-MS-based transport assay, we identified variants with significantly altered transport activities and/or substrate preferences. The E343D variant exhibited dramatically enhanced activity for all tested metal substrates, a shift in substrate preference, and an expanded substrate spectrum including the non-substrate metals VO2+ and Cu2+. Additionally, we identified lead ion (Pb2+) as a substrate of wild-type ZIP8. These findings suggest that the ZIP fold is highly adaptable and amenable for transporting a wide range of metals with diverse physicochemical properties, making it a promising scaffold to generate novel metal transporters for applications.

biochemistry↗

bioRxiv2025

Powerful one-dimensional scan to detect heterotic QTL

To meet the growing global demand for food, increasing yields through heterosis in agriculture is crucial. A deep understanding of the genetic basis of heterosis has led to the development of a quantitative genetic framework that incorporates both dominance and epistatic effects. However, incorporating all pairwise epistatic interactions is computationally challenging due to the large sequencing depth and population sizes needed to uncover the genes behind complex traits. In this study, we developed hQTL-ODS, a one-dimensional scanning method that directly assesses the net contribution of each locus to heterosis. Simulations show that hQTL-ODS reduces computational time while offering higher power and lower false-positive rate. We applied this method to a population of 5,234 wheat hybrids with whole-genome sequenced profile, revealing key epistatic hubs that play a critical role in determining heterosis. Our findings offered valuable insights for improving breeding strategies to enhance crop yields.

genetics↗

bioRxiv2025

Beyond Natural Antibodies: Scaffold-Based Generation of Novel Anti-3CLpro Nanobody Nb01

In the post-pandemic era, continuous mutations and persistent infections of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pose a significant threat to global health, making the normalization of preventive measures imperative. Due to its high conservation, the 3CLpro is relatively stable across all these variants without significant changes, suggesting that drugs targeting this enzyme could be effective against all variant viruses. And compared to traditional antibodies, nanobodies show significant advantages against SARS-CoV-2 and its variants. Traditional antibodies often lose their inhibitory activity due to viral mutation. Nanobodies are characterised by their small size, high stability, high affinity for antigen binding, and high water solubility, which enable them to capture viruses quickly and effectively address the continuous mutations and persistent infections of SARS-CoV-2. In this research, we devised a strategy to produce nanobodies by utilizing a fragment-generating large language model, resulting in the identification of a nanobody named Nb01. Nb01 exhibits potent and broad-spectrum neutralizing activity against numerous SARS-CoV-2 variants. The nanobody Nb01, directed against the SARS-CoV-2 3CLpro, demonstrated efficacy against the majority of prevalent SARS-CoV-2 variants. Notably, it has a higher affinity than the current best performing nanobodies (S43, bn03, R14, and 3-2A2-4) for most of the variants, including the Alpha (27.5%), Gamma (29.7%), Omicron BA.2 (32.2%), BA.4/5 (81.2%), BF.7 (64.2%) and XBB (5.5%) variants. For other variants, Nb01 displayed affinities that were on par with these benchmark nanobodies. In summary, the exceptional specificity, low toxicity, robust stability, and extensive spectrum of Nb01 indicate its potential to be developed as a nanobody therapeutic for the management of SARS-CoV-2 infections and its diverse variants.

bioinformatics↗

bioRxiv2025

Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice

Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimers disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5xFAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.

neuroscience↗

bioRxiv2025

Pan-cancer Analysis Identified Ectopic RUNX1T1 Associated with Lineage Plasticity

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression, allowing cancer cells to rapidly alter their identity and evade targeted therapies. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the lack of pan-cancer gene markers quantifying lineage plasticity has limited its utility as a predictive biomarker. Homeobox (HOX) genes encode a family of transcription factors that play critical roles in embryonic development and tissue identity by establishing distinct expression patterns, known as HOX codes, in specific cell lineages. Through comprehensive bioinformatic analysis of multi-omics data--including expression profiles of 39 HOX genes from over 80,000 RNA sequencing samples across 114 cancer types--we first demonstrated that HOX codes effectively represent the lineages of cancer cells. We then identified multiple lineage-plastic cancer subtypes by applying the calculated HOX codes. Specifically, we identified lineage-plastic tumor subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), which exhibit altered HOX codes compared to non-plastic subtypes. Downstream differential expression analysis revealed significantly elevated RUNX1T1 levels across all three lineage-plastic cancer types, which was further validated through bulk and single-cell RNA sequencing data derived from preclinical and clinical samples. Together, our findings provide a novel strategy for characterizing lineage plasticity in pan-cancer cells and suggest ectopic RUNX1T1 expression as a pan-cancer marker and critical mediator of lineage plasticity.

cancer biology↗

bioRxiv2025

Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of Treponema pallidum outer membrane proteins

Knowledge of Treponema pallidum subspecies pallidum (TPA) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols-, three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Lastly, we noted that BamA and FadL candidate ECL vaccinogens previously shown to elicit antibodies that kill treponemes during in vitro cultivation are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing selection of vaccine targets. IMPORTANCESyphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA. Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.

microbiology↗

bioRxiv2025

Assessing plant phenological changes based on drivers of spring phenology

Understanding plant phenological responses to climate warming is crucial for predicting changes in plant communities and ecosystems but challenging when relying on sensitivity analysis that is not based on drivers of spring phenology. In this article, we present a new measure phenological lag to quantify the overall effect of phenological constraints including insufficient winter chilling, photoperiod, and environmental stresses, based on observed response and that expected from species-specific changes in spring temperatures, i.e., changes in spring forcing (degree days) from warming and average temperature at budburst with the warmer climate. We applied this new analytical framework to a global dataset with 980 species and 1527 responses to synthesize observed changes in spring budburst (leafing or flowering) and investigate the mechanisms of differential phenological responses reported previously. We found longer phenological lags with experimental studies and native plants in flowering, likely due to more stressful environments associated with warmer and drier climate. Less forcing changes were mainly responsible for the smaller responses in leafing and flowering in boreal region (compared to temperate region) and in grass leafing (compared to trees and shrubs). Higher budburst temperatures also contributed to the smaller responses in flowering for experimental studies and with herbs and grasses. The effects of altitude, latitude, MAT, and average spring temperature change were minor (all combined <2.5% variations), while those of photoperiod and long-term precipitation were not significant in influencing spring phenology. Our method helps to determine mechanisms responsible for changes in spring phenology and differences in plant phenological responses.

ecology↗

bioRxiv2025

RBMX2: A Pivotal Regulator Linking Mycobacterium bovis Infection to Epithelial-Mesenchymal Transition and Lung Cancer Progression

Tuberculosis (TB) is a complex disease that arises from the dynamic interplay among the pathogen, host, and environmental factors. In 2022, TB affected approximately 10.6 million people worldwide, resulting in 1.3 million deaths. In regions with a high burden of zoonotic TB, Mycobacterium bovis (M. bovis) accounts for nearly 10% of human TB cases. The immune evasion strategies and latent nature of Mycobacterium tuberculosis (M. tb) pose significant challenges to understanding the host immune response to TB infection. In this study, we identify RNA-binding motif protein X-linked 2 (RBMX2) as a novel host factor that may facilitate M. bovis infection. However, the molecular mechanisms and functional roles of RBMX2 during M. bovis infection remain poorly understood. Our findings show that RBMX2 is significantly upregulated across multiple cell types following infection, including embryonic bovine lung (EBL) cells, bovine macrophage (BoMac) cells, bovine pulmonary alveolar primary cells, and human alveolar epithelial cells (A549). Using a combination of global transcriptomic sequencing, proteomic profiling, cell adhesion assays, ChIP-PCR, and Western blotting, we demonstrate that RBMX2 suppresses cell adhesion and tight junction formation in EBL cells while promoting M. bovis adhesion and invasion through activation of the p65 signaling pathway. Importantly, integrated analyses of transcriptomic, proteomic, and metabolomic data reveal that RBMX2 plays a key role in regulating epithelial-mesenchymal transition (EMT), a cellular process closely associated with cancer progression. To further explore the potential link between RBMX2 and cancer, we analyzed the TIMER2.0 database and found elevated RBMX2 expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared to normal lung tissues. These findings were corroborated by immunofluorescence staining. Using an M. bovis-infected BoMac-induced EBL-EMT model, we show that RBMX2 promotes EMT through activation of the p65/MMP-9 pathway following infection. Additionally, we validated the EMT process in human lung epithelial cancer cells (H1299), further supporting the involvement of RBMX2 in this transition. Collectively, our study identifies RBMX2 as a novel host factor that may enhance M. bovis infection and drive infection-induced EMT. These findings provide new insights into the molecular mechanisms underlying TB pathogenesis and suggest that RBMX2 could serve as a potential target for the development of TB vaccines and therapeutic strategies against TB-associated lung cancer.

microbiology↗

bioRxiv2025

distQTL: Distribution Quantitative Trait Loci Identification by Population-Scale Single-Cell Data

Mapping expression quantitative trait loci (eQTLs) is a powerful method to study how genetic variation influences gene expression. Traditional bulk eQTL methods rely on averaged gene expression across a possibly heterogeneous mixture of cells, which can obscure underlying regulatory heterogeneity. Single-cell eQTL methods circumvent the averaging artifacts, providing an immense opportunity to interrogate transcriptional regulation at a much finer resolution. Recent developments in metric space regression methods allow the use of full empirical distributions as response objects instead of simple summary statistics such as mean. Here, we leverage Frechet regression to identify distribution QTLs (distQTLs) using population-scale single-cell RNA sequencing data. We apply distQTL to the OneK1K cohort, consisting of scRNA-seq data of peripheral blood mononuclear cells from 982 donors, and compare results to various eQTL approaches based on summary statistics and mixed effects modeling. We demonstrate the superior performance of distQTL across different gene expression contexts compared to other methods and benchmark our results against findings from the Genotype-Tissue Expression Project. Finally, we orthogonally validate calls from distQTL using cell-type-specific epigenomic profiles.

genomics↗

bioRxiv2025

A global P-Process map to avoid P-value abuse

P-abuse is serious in difference identification analysis of data. How to avoid P-abuse is a huge challenge. Here, we evolve P-value (a single value) to P-Process (a global landscape of P-values under different sample size) to help researchers correctly recognize and use p-value. We observed -ln(P-Process) after rotation has very similar morphology with Wiener Process (or Brownian motion). Based on this property, for any sample size, we estimated the 95% fluctuation range of P-value and further estimated how many samples (N95()) could make sure 95% of P-values less than the given significant level . Tests proved that the estimation obtains a good performance with only a small number of samples in each group. For broader accessibility, a free web-service, P-Process Map, is available online to show the whole landscape of P-Process. At the end of the article, we explained 10 of the most typical P-abuse problems which can be easily voided by using P-Process. This "rethinking" of P-value from a higher position, which is profoundly different from the way we have seen this for the past century, would yield a new era - 2P era in which hypothesis testing is strongly required to evolve from P-value to P-Process.

bioinformatics↗

bioRxiv2025

Single-Cell Multiomic Analysis of Circadian Rhythmicity in Mouse Liver

Circadian rhythms are remarkably widespread across most organisms, regulating hormonal, metabolic, physiological, and behavioral oscillations through molecular clocks that orchestrate the rhythmic expression of thousands of genes. Here, we generate single-nucleus RNA and ATAC multiomics data to simultaneously characterize gene expression and chromatin accessibility of mouse liver cells across the 24-hour day. We interrogate multimodal circadian rhythmicity in both discretized cell types and transient sub-lobule cell states, capturing space-time omics profiles. We delve beyond mean cyclic patterns to characterize stochastic transcriptional bursting and infer spatiotemporal gene regulatory networks that control circadian rhythmicity and liver physiology. Our findings apply to existing single-cell data of mouse and Drosophila brains and are validated by time-series single-molecule fluorescence in situ hybridization and vast amounts of orthogonal omics data. Altogether, our study constructs a comprehensive map of the time-series transcriptomic and epigenomic landscapes that elucidate the function and mechanism of the liver peripheral clocks.

bioinformatics↗

bioRxiv2025

It runs in the family: Discovery of enzymes in the oleuropein pathway in Olive (Olea europaea) by comparative transcriptomics

Olive (Olea europaea L.) is one of the most important crop trees, with olive oil being a key ingredient of the Mediterranean diet. Oleuropein, an oleoside-type secoiridoid, is the major determinant of flavor and quality of olive oil. Iridoid biosynthesis has been elucidated in Catharanthus roseus, which produces secologanin-type secoiridoids, but iridoid biosynthesis in other species remains unresolved. In this work, we sequenced RNA from olive fruit mesocarp of six commercial olive cultivars with varying oleuropein content, during maturation and ripening. Using this data we discovered three polyphenol oxidases with oleuropein synthase (OS) activity, a novel oleoside-11-methyl ester glucosyl transferase (OMEGT) synthesizing a potential intermediate in the route, and a 7-epi-loganic acid O-methyltransferase (7eLAMT). Interestingly, integrating transcriptomics data from 15 plant species from three iridoid-producing plant orders (Lamiales, Gentianales, and Cornales), and tissue expression panels from Jasminum sambac and Fraxinus excelsior, we discovered two 2-oxoglutarate dependent dioxygenases (named 7eLAS) that synthesize 7-epi-loganic acid; in contrast C. roseus 7-deoxy-loganic acid hydroxylase (7DLH), a known bottleneck in MIA production, is a cytochrome p450. This comparative co-expression method, which combines guilt by association and comparative transcriptomics approaches, can successfully leverage big datasets for untargeted discovery of enzymes. Key FindingsO_LIExpression of genes involved in iridoid biosynthesis, from the early MEP pathway to the last step of oleuropein biosynthesis, decreases during olive fruit maturation. C_LIO_LIWe discovered an oxoglutarate dependent dioxygenase, 7-epi-loganic acid synthase (7eLAS), catalyzing the stereoselective oxidation of 7-deoxy-loganic acid to 7-epi-loganic acid, in a reaction analogous to C. roseus 7-deoxy-loganic acid hydroxylase (7DLH), a cytochrome p450. C_LIO_LIWe report a 7-epi-loganic acid O-methyltransferase (7eLAMT) orthologous to Catharanthus roseus loganic acid O-methyltransferase and found a novel oleoside-11-methyl ester glucosyl transferase (OMEGT) synthesizing 7-{beta}-1-D-glucopyranosyl-oleoside-11-methyl ester, a potential intermediate in the oleuropein biosynthesis route. C_LIO_LIWe discovered three olive polyphenol oxidases that have oleuropein synthase (OS) activity, catalyzing the conversion of ligstroside to oleuropein. C_LI

biochemistry↗

bioRxiv2025

Tissue-specific mutagenesis from endogenous guanine damageis suppressed by Polκ and DNA repair

Knowledge of mutational patterns has expanded significantly, but a persistent challenge is to link these complex patterns to the underlying molecular mechanism or source of DNA damage, especially when that damage is endogenous and not driven by environmental mutagens. Technological advances now allow us to catalogue mutation across tissues or even closely related cell types, but the results are largely descriptive until we identify the endogenous sources of mutation and how they differ across tissues. Here, we combine mouse genetics, advanced sequencing, biochemistry and mass spectrometry to provide a detailed mechanistic understanding of endogenous mutagenesis. We reveal that endogenous guanine adducts are significant drivers of tissue-specific mutagenesis, while the interwoven actions of DNA polymerase Pol{kappa} and DNA repair mechanisms are pivotal in mitigating mutagenesis. For the first time, we use untargeted DNA adductomics to characterize new sources of endogenous DNA damage. Our novel approach to understanding endogenous mutational landscapes reveals previously unseen mutational processes and points to vast potential for new discoveries.

molecular biology↗

bioRxiv2025

Peptidergic top-down control of metabolic state-dependent behavioral decisions in a conflicting sensory context

Animals make economically beneficial behavioral decisions by integrating the external sensory environment with their internal state. The metabolic state, i.e. hunger, can shift priorities, prompting risk-taking and reducing responses to danger during foraging activities. How behavioral changes are processed in the nervous system to generate flexible responses based on needs and risks remains largely unclear. Here, we demonstrate in Drosophila larvae that the corticotropin releasing hormone (CRH) homolog diuretic hormone 44 (Dh44) and its producing neurons exert metabolic top-down control of behavioral choice in a conflicting sensory context. The metabolic state via Dh44 signaling mediates the transition from avoiding to tolerating aversive light conditions in the presence of food. In vivo imaging of neuropeptide release revealed that Dh44 regulates the acute release of Insulin-like peptide 7 (Ilp7) specifically in a conflicting context, thereby inducing light tolerance. Optogenetic activation of specific subsets of Dh44 or Ilp7 producing neurons during starvation is sufficient to shift behavior from light tolerance to avoidance by regulating light avoidance circuit responses. This top-down feedforward peptidergic circuit may represent a general mechanism that helps organisms to balance risk-taking with metabolic needs by allowing flexible adjustment of behavior in a conflicting multisensory environment.

neuroscience↗