Biology subjects

Zou, L.

Publications and source records attributed to Zou, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Aberrations in stromal signaling, muscle contractility and epithelial architecture underlie poor embryo-implantation outcomes after murine ovarian stimulation

Ovarian stimulation is widely used in assisted reproductive technologies, yet its effects on uterine architecture and embryo implantation remain poorly understood. Using a mouse model, we show that ovarian stimulation or superovulation disrupts pre-implantation luminal epithelial folding and induces aberrant smooth muscle structure and contractile function. These structural defects result in embryo trapping within aberrant longitudinal folds, impaired implantation chamber formation, misalignment of the embryo-uterine axis, and subsequent embryo loss. These ovarian stimulation effects were reversible after rest and restoration of normal estrus cycling. Transcriptomic analysis suggests widespread disruption in the stroma and immune compartments of the stimulated uteri. Pathway analysis revealed significant disruption of stromal extracellular matrix and enhanced probability of stroma-immune communication via collagen signaling. Platelet derived growth factor receptor A (PDGFRA) expression was elevated in both the stroma and smooth muscle of the stimulated uteri. Short-term pharmacological inhibition of PDGFRA in the stimulated uteri prior to implantation fully restored epithelial fold transition and implantation chamber formation and partially restored smooth muscle architecture and contractility. Importantly, PDGFRA protein was also elevated in endometrial biopsies from women undergoing ovarian stimulation when compared to natural cycle biopsies. Together, this study establishes muscle contractions and stromal and smooth muscle PDGFRA signaling as novel non-cell autonomous regulators of uterine epithelial architecture critical for embryo implantation.

Developmental Biology↗

bioRxiv2026

Detergent-Free Nuclear-Cytoplasmic Fractionation Enables Spatially Resolved PELSA for Enhanced Nuclear Drug Target Identification

Accurate identification of drug target proteins remain major challenges in proteomics-based target discovery, particularly for low-abundance nuclear proteins that are difficult to detect because of the complexity of whole-cell lysates. Here, we developed a detergent-free nuclear-cytoplasmic fractionation strategy compatible with peptide-centric local stability analysis (PELSA), which markedly improves detection of nuclear drug targets. Using K562 cells, we demonstrated that mild detergent-free fractionation enables high-fidelity nuclear-cytoplasmic separation with minimal cross-contamination. When coupled with PELSA, this workflow significantly increases the number of detected nuclear targets relative to whole-cell analysis. Benchmarking with well-characterized nuclear drugs, including the histone deacetylase inhibitor panobinostat and the RNA polymerase II inhibitor -amanitin, our results showed improved identification of canonical nuclear targets. Broad profiling of staurosporine target further revealed expanded kinase target coverage by combining the results of nuclear and cytoplasmic fraction, with the CLK family kinases detected exclusively in the nuclear fractions. Additionally, we showed that PELSA can also be performed on intact nucleus level. Collectively, these findings establish detergent-free nuclear-cytoplasmic fractionation-PELSA as a robust and scalable strategy for spatially resolved drug target identification, improving sensitivity for nuclear and low-abundance proteins.

biochemistry↗

bioRxiv2026

A SIRT5-induced metabolic switch underlies chemoresistance and ATR checkpoint dependence in triple-negative breast cancer

Chemoresistance is the leading cause of poor prognosis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain unknown. To reveal metabolic drivers of de novo chemoresistance in TNBC, we analyzed pretreatment primary tumor biopsies, employing quantitative proteomics and metabolomics. Chemoresistant TNBCs exhibit hallmarks of oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism linked to overexpression of the mitochondrial sirtuin, SIRT5. Through gain- and loss-of-function studies and stable isotope tracing, we demonstrate that SIRT5 induces a coordinated metabolic switch that redirects glycolysis to the pentose phosphate pathway, thereby augmenting nucleotide pools, while enhancing glutaminolysis to support OXPHOS. Mechanistically, SIRT5 enhances conversion of 6-phospho-D-gluconate to ribulose-5-phosphate through demalonylation of 6-phosphogluconate dehydrogenase (6-PGD), and coordinately activates oncogenic c-MYC to promote glutamine utilization and dependence. Concurrently, SIRT5-induced nucleotide deregulation induces replication stress and hypersensitivity to ATR checkpoint activation, and ATR inhibition synergistically reverses chemoresistance in TNBC. Thus, elevated SIRT5 orchestrates a coordinated metabolic switch to expand nucleotide pools and drive chemoresistance, while producing ATR checkpoint dependence that represents a metabolic vulnerability of SIRT5-overexpressing TNBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/716852v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1c7a27corg.highwire.dtl.DTLVardef@17cb22borg.highwire.dtl.DTLVardef@1956670org.highwire.dtl.DTLVardef@1786dee_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Gray matter Volume Modulates the Effect of Acute Physical Activity on Reading Comprehension and Cognitive Load in Adolescents. The Cogni-Action Project

BackgroundPhysical activity has been associated with better reading comprehension and reduces cognitive load (CL), but the role of brain volume in modulating this relationship remains unclear. Therefore, this study aims to determine whether the gray matter volume in key regions modulates the effects of different physical activity modalities on reading comprehension and associated CL. MethodsThirteen male adolescents (12-13 years). Adolescents with MRI data participated in a randomized cross-over trial comparing three conditions: 1) sedentary behavior (SC, emulating a school class), 2) moderate-intensity continuous training (MICT), and 3) cooperative high-intensity interval training (C-HIIT), with physical activity conditions duration adjusted to match SC energy expenditure. Gray matter volumes were measured in the bilateral hippocampus, left pars opercularis, and the brainstem. CL was assessed via pupil dilation during reading using eye-tracking. Reading comprehension was measured through seven-question multiple-choice tests with expert-validated items. ResultsC-HIIT demonstrated superior effects on both CL and reading comprehension compared to MICT and SC, with significant brain volume modulation effects across all examined regions. Brain volume interactions with physical activity modalities systematically modified the pattern of cognitive responses, with C-HIIT consistently benefiting from these modulations, whereas the effects of MICT were generally attenuated. ConclusionThis study suggests that selecting the appropriate physical activity modality may be relevant for cognitive outcomes during reading in adolescents. C-HIIT yielded lower CL and better reading comprehension, and these effects were not explained by brain volume alone but by its interaction with exercise modality.

neuroscience↗

bioRxiv2026

The genome of an aneuploid cultivar facilitates elucidating the genetic bases of trait polymorphisms in Phalaenopsis orchids

As an important ornamental crop, Phalaenopsis orchids exhibit extraordinary trait diversity with unclear genetic bases. Here, we present a haplotype-resolved, chromosome-level genome for an aneuploid cultivar Santiago. We reveal pervasive variation in the number and sequence among homoeologous genes. When serving as a reference, this genome facilitates the genetic understanding of trait variation in a hybrid population that is highly representative in trait polymorphisms. Specifically, nucleotide polymorphisms in a potential long-distance enhancer and the consequential expression variation of PsAGL6-2, presence/absence of PsMYB12 and b-type homoeologous gene of PsMYB2 determine lip morphology variation, presence/absence of venation-associated stripes and background pink color, respectively. Diverse functions of PsMYBx1 in repressing anthocyanin accumulation across different cultivars further enhances the color patterning diversity in Phalaenopsis. Our study provides a practical framework for using a highly heterogeneous, haplotype-resolved genome to decode phenotypic diversity and has the potential to promote marker-assisted breeding in Phalaenopsis.

genomics↗

bioRxiv2025

Structural basis for TORC2 activation

The Target of Rapamycin Complex 2 (TORC2) is a central node in signaling feedback loops serving to maintain biophysical homeostasis of the plasma membrane (PM). How TORC2 is regulated by mechanical perturbation of the PM is not well understood. To address this, we determined the cryo-electron microscopy structure of endogenous yeast TORC2 to up to 2.2 [A] resolution. Our model refines the position and interactions of TORC2-specific subunits, providing a structural basis for the differential assembly of Tor2 into TORC2. Furthermore, we observe the insertion of the pleckstrin-homology domain of the Avo1 subunit into the Tor2 active site, providing a regulatory mechanism by phosphoinositides. Structure-guided functional experiments reveal a potential TORC2 membrane binding surface and a positively charged pocket in the Avo3 subunit that is necessary for TORC2 activation. Collectively, our data suggest that signaling phosphoinositides activate TORC2 by membrane-induced structural rearrangements via concerted action of conserved regulatory subunits.

biochemistry↗

bioRxiv2025

APALORD: An R-based tool for differential alternative polyadenylation analysis of long-read RNA-seq data

Alternative polyadenylation (APA) is a critical co/post-transcriptional process that enhances RNA isoform diversity, regulating mRNA stability, localization and translation in a spatiotemporal manner. Over the past decade, long-read (LR) RNA sequencing techniques have advanced rapidly, producing datasets that could offer insights into APA mechanisms. Here we introduce APALORD (Alternative Polyadenylation Analysis of LOng-ReaDs), an R-based analysis tool for APA analysis of LR RNA-seq data. Leveraging precise 3 end information from 3-primed LR RNA-seq data, APALORD identifies polyadenylation sites (PASs) and quantifies PAS usage (PAU) at individual sites for each sample. It conducts APA analysis at the gene level (using Kolmogorov-Smirnov test) and at the level of individual PAS (using DEXSeq) across sample conditions. APALORD was applied to direct RNA-seq data from human embryonic stem cells (hESCs) and hESC-derived neurons. PASs were identified with high accuracy and a transcriptome-wide 3UTR lengthening trend was found, consistent with previous studies. APALORD analysis of PacBio cDNA data from human tissues confirmed a 3UTR lengthening trend in cortex compared to liver. R2C2 libraries generated on the Nanopore platform were analyzed with APALORD and it revealed APA change associated with polysome fractions in human neural progenitor cells. In summary, APALORD offers a comprehensive framework for differential APA analysis using LR RNA-Seq data, empowering researchers to investigate 3 end dynamics across diverse biological contexts.

bioinformatics↗

bioRxiv2025

Functional loss of CHS2 confers high levels resistance to Bacillus thuringiensis Vip3Aa, but with significant fitness costs in five lepidopteran species

Bacillus thuringiensis (Bt) crops, engineered to produce insecticidal proteins such as Vip3Aa and Cry toxins, have revolutionized pest management by providing a sustainable alternative to chemical pesticides. However, the development of resistance to these toxins has driven the investigation of underlying mechanisms to better understand how pests evade toxicity and to develop more effective resistance management strategies. Recently, a laboratory-selected Spodoptera frugiperda strain exhibited a high level of resistance to Vip3Aa (resistance ratio: 5562-fold), with the mutation of the chitin synthase gene, SfCHS2, identified as a key factor. In this study, we extend these findings to additional lepidopteran species, including Spodoptera exigua and Agrotis ipsilon. Our results show that CHS2 knockout strains lack the peritrophic matrix (PM), while the resistant Sfru_R3 strain retains its PM. Knockout of this gene resulted in high levels resistance to Vip3Aa. These findings further validate the role of the CHS2 gene in Vip3Aa resistance and highlight its potential as a target for resistance management in lepidopteran pests. This study advances our understanding of the molecular mechanisms behind resistance to Vip3Aa and supports the development of strategies to delay resistance in Bt crop management.

genetics↗

bioRxiv2025

Deep learning guided discovery of antibacterial polymeric nanoparticles

Drug-resistant bacterial infections pose a serious threat to global health, driving the development of novel antibacterial strategies beyond classic antibiotics. Self-assembled polymeric nanoparticles (SANPs) have emerged as promising candidates due to their unique structural properties, which enhance membrane interaction, drug loading, and therapeutic accumulation. The structural diversity and tunable properties of SANPs provide a flexible design platform for antibacterial applications. However, navigating the vast chemical space of SANPs remains a significant challenge due to the complex structure-activity relationships. To address this, we developed PolyCLOVER, a deep learning-guided framework for the efficient discovery of antibacterial SANPs. The framework integrates multi-stage self-supervised learning, active learning, and high-throughput experimentation to iteratively guide the discovery of SANPs with potent antibacterial activity and low toxicity. Through this framework, we identified three potent SANPs within a combinatorial library of [~]100,000 poly({beta}-amino ester)s, with minimum inhibitory concentrations of 4 g/mL and 8 g/mL against clinically multidrug-resistant S. aureus and A. baumannii, respectively. Moreover, they can also act as antibiotic carriers, restoring the sensitivity of pathogens to penicillin G. In vivo studies demonstrated their therapeutic efficacy both as monotherapies and in combination therapies with antibiotics. These results demonstrate PolyCLOVER as a powerful framework for discovering multi-functional SANPs to combat antibiotic resistance.

microbiology↗

bioRxiv2025

Dynamic Pathway of Guanidine-III Riboswitch Folding Revealed by Single-Molecule FRET: Mg2+-Assisted Preorganization and Ligand-Induced Kinetic Trapping

Riboswitches are structured RNA elements that regulate gene expression by sensing and binding small molecules. The guanidine-III riboswitch, a critical bacterial regulator responding to guanidine toxicity, undergoes precise conformational changes that remain poorly characterized at a dynamic, mechanistic level. In this study, we employed single-molecule Forster Resonance Energy Transfer (smFRET) coupled with molecular dynamics (MD) simulations to delineate how the guanidine-III riboswitch transitions among distinct conformational states. We identify three principal states [-] an extended (E-state), a compacted prefolded intermediate (P-state), and a folded pseudoknot structure (F-state) [-] with rapid interconversion in the absence of ligand. Magnesium ions significantly stabilize intermediate states via a cooperative, preorganization mechanism, enhancing ligand binding efficiency. Binding of guanidine drastically suppresses the reverse transitions, kinetically trapping the riboswitch into its active folded state primarily through a conformational selection mechanism, with additional contributions from induced-fit dynamics. This work illuminates the unique dynamic pathway by which the guanidine-III riboswitch integrates ionic and ligand cues, ensuring precise gene regulatory responses in bacteria.

biophysics↗

bioRxiv2025

circASbase：A Comprehensive Database of Alternative Splicing Events in circRNAs

Despite extensive studies highlight the critical roles of alternative splicing in generating mature circRNA isoforms and enhancing their function diversity, a significant gap remains in the availability of dedicated databases for circRNA alternative splicing events. To bridge this gap, we developed circASbase, a pioneering and comprehensive database that catalogues 452,129 alternative splicing events in 884,047 full-length circRNAs from 581 samples across 13 species, and provides rich annotations to facilitate understanding the splicing regulation of circRNAs. Our findings reveal substantial differences between circRNAs and linear transcripts regarding the distribution and occurrence of alternative splicing events, highlighting the unique regulatory landscape of circRNAs. These unique splicing events result in functional differences of circRNAs by affecting IRES sites, m6A sites, ORFs, protein features, miRNA targets, and more. In summary, circASbase not only covers the urgent need of the research community for data repositories, but also represents a significant advancement in our understanding of circRNA biology. With its user-friendly interfaces and web-based visualization tools, circASbase is poised to become an indispensable resource for researchers exploring the regulatory mechanisms and functional roles of alternative splicing events in circRNAs. This database will continuously drive new insights and discoveries in the field, setting the stage for further advancements in circRNA research. circASbase is available at http://reprod.njmu.edu.cn/cgi-bin/circASbase/

bioinformatics↗

bioRxiv2025

BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance

Extrachromosomal circular DNA (ecDNA) are commonly produced within the nucleus to drive genome dynamics and heterogeneity, enabling cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes mediate ecDNA production. Following DNA fragmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively catalyzes ecDNA production in Drosophila and mammals, with patient tumor ecDNA harboring junctions marked by LIG4 activity. Notably, disrupting LIG4 or BRCA1-A in cancer cells impairs ecDNA-mediated adaptation, hindering resistance to both chemotherapy and targeted therapies. Together, our study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers new therapeutic targets to block ecDNA-mediated adaptation for cancer treatment.

cancer biology↗

bioRxiv2024

Accumulation of Dietary and Non-Enzymatic Oxysterols in Preeclamptic Placentas: Insights into Cholesterol Dynamics in Pregnancy Complications

Oxysterols--oxidized derivatives of cholesterol--play key roles in regulating lipid metabolism, oxidative stress, and immune signaling. Despite their biological importance, their presence and function in human placental tissue remain poorly understood, particularly in pregnancy complications such as preeclampsia. Preeclampsia is a hypertensive disorder of pregnancy associated with oxidative stress and altered lipid homeostasis. This study profiled both dietary and non-enzymatic oxysterols in third-trimester human placentas from healthy term pregnancies and those complicated with preeclampsia, delivered at term or preterm and term. Findings indicate significantly higher oxysterol levels in preeclamptic placentas, particularly for 7-ketcholesterol (7-Keto) and 5,6{beta}-cholestanetriol, (Triol) regardless of gestational age. 5{beta},6{beta}-epoxycholesterol (OCallaghan, Woods, & OBrien, 2001) was higher in term preeclampsia, while total cholesterol levels were significantly lower in preeclamptic placentas. Correlation analyses revealed distinct associations between oxysterols, cholesterol, and total fat content, indicating unique oxidative signatures in preeclamptic pregnancies. These findings contribute to a growing body of evidence suggesting that altered oxysterol profiles may reflect oxidative stress and placental dysfunction. While causality cannot be inferred, oxysterol profiling may hold potential as a complementary biomarker strategy for identifying pregnancies at risk of adverse outcomes.

physiology↗

bioRxiv2024

Efficient laminar-distributed interactions and orientation selectivity in the mouse V1 cortical column

The emergence of orientation selectivity in the visual cortex is a well-known phenomenon in neuroscience, but the details of such emergence and the role of different cortical layers and cell types, particularly in rodents which lack a topographical organization of orientation-selectivity (OS) properties, are less clear. To tackle this question, we use an existing biologically detailed model of the mouse V1 cortical column, which is constrained by existing connectivity data across cortical layers and between pyramidal, PV, SST and VIP cell types. Using this model as a basis, we implemented activity-dependent structural plasticity induced by stimulation with orientated drifting gratings, leading to a good match of tuning properties of pyramidal cells with experimentally observed OS laminar distribution, their evoked firing rate and tuning width. We then employed a mean-field model to uncover the role of co-tuned subnetworks in laminar signal propagation and explain the effects of intra- and inter-laminar coupling distributions. Our plasticity-induced modified model and mean-field model were able to explain both the excitatory enhancement through co-tuned subnetworks and inter-laminar disynaptic inhibition. Overall, our work highlights the importance of the clustering of neural selectivity features for effective excitatory transmission in cortical circuits.

neuroscience↗

bioRxiv2024

Tachykinin1-expressing neurons in the parasubthalamic nucleus control active avoidance learning

Active avoidance is a type of instrumental behavior that requires an organism actively to engage in specific actions to avoid or escape from a potentially aversive stimulus and is crucial for the survival and well-being of organisms. It requires a widely distributed, hard-wired neural circuits spanning multiple brain regions, including the amygdala and thalamus. However, less is known about whether and how the hypothalamus encodes and controls active avoidance learning. Here we identify a previously unknown role for the parasubthalamic nucleus (PSTN), located in the lateral subdivision of the posterior hypothalamus, in the encoding and control of active avoidance learning. Fiber photometry calcium imaging shows that the activity of tachykinin1-expressing PSTN (PSTNTac1) neurons progressively increases during this learning. Cell-type specific ablation and optogenetic inhibition of PSTNTac1 neurons attenuates active avoidance learning, whereas optogenetic activation of these cells promotes this learning via a negative motivational drive. Moreover, the PSTN mediates this learning differentially through its downstream targets. Together, this study identifies the PSTN as a new member of the neural networks involved in active avoidance learning and offers us potential implications for therapeutic interventions targeting anxiety disorders and other conditions involving maladaptive avoidance learning.

neuroscience↗

bioRxiv2024

Biocontrol efficiency and mechanism of novel Streptomyces luomodiensis SCA4-21 against banana Fusarium wilt

The soil-borne fungi Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) causes banana Fusarium wilt, which seriously threats global banana production. Biocontrol has been considered viable alternative method to manage banana Fusarium wilt. In previous study, we found that novel S. luomodiensis SCA4-21 exhibited antifungal activity. Here, we revealed that the extracts of strain SCA4-21 significantly inhibited the growth of Foc TR4 hyphae and spore germination, severely disrupting the ultrastructure of Foc TR4 hyphal cells and spore morphology. These extracts also exhibited broad-spectrum antifungal activity against eight other phytopathogenic fungi. Furthermore, we demonstrated that strain SCA4-21 produce 32 volatile organic compounds, including five antifungal compounds. In a pot experiment, we discovered that the inoculation of strain SCA4-21 significantly inhibited the infection of Foc TR4 in banana seedling corms, achieving a biocontrol efficiency of 59.3%, and promoted the growth of banana seedlings. Additionally, this inoculation significantly enhanced the abundances of beneficial bacterial genera Streptomyces, Bacillus, Sphingomonas, and Massilia, as well as fungal genera Mortierella, Purpureocillium, Gibellulopsis, and Xenomyrothecium, while significantly reduced the abundances of pathogenic bacteria genus Pantoea and fungal genus Fusarium, in the banana rhizosphere soil. Moreover, the inoculation of strain SCA4-21 significantly increased the enrichment of pathways such as carbohydrate metabolism, amino acid metabolism, and metabolism of terpenoids and polyketides. Therefore, we postulated that strain SCA4-21 may synergistically combat banana Fusarium wilt by producing antifungal compounds and enriching beneficial bacteria and fungi. Our findings present a promising biocontrol agent for the management of banana Fusarium wilt. IMPORTANCEBanana (Musa spp.) is one of the most popular fruit crops and the fourth largest food crop in developing countries within tropical and subtropical regions. However, the emergence and rapid spread of strain Foc TR4 seriously hinder the development of banana industry. Currently, there is no effective control measure available. Biological control holds potential due to its safety and effectiveness. Here, we found that the extracts of S. luomodiensis SCA4-21 exhibited significant inhibitory effects on the hyphal growth and spore germination of Foc TR4, as well as severe destructive effects on its cell morphology and ultrastructure, and broad-spectrum antifungal activity. We also discovered that the inoculation of strain SCA4-21 significantly inhibited the infection of Foc TR4 in banana seedling corms, reduced the incidence index of banana Fusarium wilt, promoted the growth of banana seedlings, and enhances beneficial microbes and metabolic pathways, suggesting that strain SCA4-21 is a promising biocontrol agent.

physiology↗

bioRxiv2024

The utility of single-cell RNA sequencing data in predicting plant metabolic pathway genes

It is an ever challenging task to make genome-wide predictions for plant metabolic pathway genes (MPGs) encoding enzymes that catalyze the biosynthesis of plant natural products. Here, starting from 1,129 benchmark MPGs that have experimental evidence in Arabidopsis thaliana, we investigate the utilities of single-cell RNA sequencing (scRNA-seq) data--a recently arisen omics data that has been used in several other fields--in predicting MPGs using five machine learning (ML) algorithms that support multi-label tasks. Compared with traditional bulk RNA-seq data, scRNA-seq data lead to different but comparable co-expression networks among MPGs within metabolic classes, and significantly higher prediction accuracy of MPGs into classes. Prediction accuracy for individual metabolic classes is not associated with the co-expression network tightness, but correlated with the number of MPGs within each class, indicating that including more benchmark genes in the future will improve the MPG prediction. Splitting the RNA-seq data into genetic background/condition or tissue-specific subsets can improve the gene co-expression network tightness and MPG prediction accuracy for some classes; scRNA-seq-based models still outperform bulk RNA-seq-based models for most classes when corresponding subsets are used. In addition, deep learning approaches outperform classical machine learning approaches; approaches implemented in an ensembled workflow AutoGluon tend to have severe overfitting issues potentially due to the relative scarcity of benchmark MPGs within classes. Our results demonstrate the superiority of scRNA-seq data over bulk RNA-seq data in predicting MPGs into metabolic classes, and propose that scRNA-seq data should be included in the future to advance the identification of plant MPGs.

plant biology↗

bioRxiv2024

Inhibition of Androgen Receptor Exposes Replication Stress Vulnerability in Prostate Cancer

Standard initial systemic treatment for patients with metastatic prostate cancer includes agents that target androgen receptor (AR) signaling. Despite an initial positive response to these AR pathway inhibitors (ARPIs), acquired resistance remains a significant challenge. We show that treatment of AR-positive prostate cancer cells with the frontline ARPI enzalutamide induces DNA replication stress. Such stress is exacerbated by suppression of translesion DNA synthesis (TLS), leading to aberrant accumulation of single-stranded DNA (ssDNA) gaps and persistent DNA damage biomarkers. We further demonstrate that the TLS inhibitor, JH-RE-06, markedly sensitizes AR-positive prostate cancer cells, but not AR-negative benign cells, to enzalutamide in vitro. Combination therapy with enzalutamide and JH-RE-06 significantly suppresses cancer growth in a syngeneic murine tumor model over vehicle control or individual treatment groups. These findings suggest that AR inhibition broadly triggers DNA replication stress in hormone-sensitive prostate cancer, thereby exposing a unique vulnerability that can be exploited by a TLS-disrupting adjuvant for targeted therapy.

cancer biology↗