Biology subjects

Chen, P.

Publications and source records attributed to Chen, P..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Discovery and optimization of antimicrobial peptides from extreme environments on global scale

The escalating crisis of global antimicrobial resistance (AMR) necessitates the discovery of novel antibiotics. Antimicrobial peptides (AMPs), particularly those from under-explored extreme environments, represent a promising therapeutic class. Here, we introduce SEGMA (Structure-aware Extremophile Genome Mining for Antimicrobial peptides), a computational framework that integrates structure information to systematically mine AMPs from extremophile genomes on a global scale. By analyzing 60,461 extremophile metagenome-assembled genomes (MAGs) from diverse habitats, SEGMA identified 3,298 novel AMPs (termed "extremocins"), which exhibit unique amino acid profiles and physicochemical properties. Leveraging a beam search-guided optimization strategy, we further enhanced selected extremocins to achieve broad-spectrum antimicrobial activity. Experimental validation confirmed potent in vitro efficacy against clinically relevant pathogens. This study underscores the value of structure-aware mining and extremophile microbiomes in expanding the antibiotic arsenal against AMR. HighlightsO_LISEGMA, a structure-aware deep learning framework, mines 3,298 novel antimicrobial peptides (extremocins) from 60,461 extremophile genomes on global scale. C_LIO_LIExtremocins exhibit unique sequence features, and expand known antibiotic space, few of which shows homology to existing AMP databases. C_LIO_LIA beam search-guided optimization strategy enhanced selected extremocins to achieve broad-spectrum activity against clinically relevant pathogens. C_LIO_LIExperimental validation confirmed that candidate extremocins exhibit potent in vitro and in vivo antimicrobial activity, highlighting their therapeutic potential. C_LI

bioinformatics↗

bioRxiv2025

A Deep Learning Framework for Quantifying Dynamic Self-Organization in Myxococcus xanthus

Under starvation, Myxococcus xanthus bacteria initiate a multicellular developmental program in which cells move to form fruiting bodies and differentiate into distinct cell types. Many genes affecting this process have been identified, and it is assumed that perturbing genes within the same pathway induces similar changes in the phenotype, although those changes may be subtle or obscured by pleiotropic effects. However, these pathways cannot be systematically mapped, as there are no systematic methods for quantifying phenotype similarity. Here, we applied deep learning techniques to quantify the phenotype patterns and self-organization dynamics of 292 genetically distinct strains. By integrating ResNet and StyleGAN2 to construct a Variational AutoEncoder (VAE) and utilizing a Siamese network for phenotypic similarity metrics, we efficiently encoded high-resolution microscopy images into 13-dimensional feature vectors, capturing phenotypic variability in aggregation patterns across time and strains. Human evaluation confirmed that our models reconstructions were visually indistinguishable from real images and closely aligned with input phenotypes. Importantly, the feature space is interpretable: individual dimensions correlate with biological features such as aggregate number and size, and extrapolation along these dimensions produces predictable morphological changes. Remarkably, our model revealed that developmental phenotypes are predictable from the earliest stages before visible aggregate formation begins. This predictability held across both genetic and environmental sources of variation, suggesting fundamental constraints on developmental trajectories and indicating that subtle phenotypic variations carry important information. These results demonstrate how machine learning can reveal hidden structure in complex multicellular dynamics and provide scalable methods for phenotypic analysis without manual annotation.

systems biology↗

bioRxiv2025

Rete Ovarii Epithelial Cells as an Unappreciated Cell of Origin for Pelvic and Ovarian High-Grade Serous Carcinoma

Over the past two decades, converging clinicopathologic, molecular, and evolutionary evidence has established that pelvic and ovarian high-grade serous carcinoma (HGSC) originates predominantly from tubal-type epithelia rather than the ovarian surface epithelium. Consequently, Fallopian tube secretory epithelial cells are widely recognized as the principal cell of origin for HGSC. However, the female reproductive tract contains additional tubular epithelial networks whose potential contributions to HGSC pathogenesis remain unexplored. Here, we identify the rete ovarii (RO), a complex network of intra- and extra-ovarian tubules located within the ovarian hilus and mesovarium, as an alternative candidate tissue of origin for HGSC. We demonstrate that genetic and genomic alterations in rete ovarii epithelial cells (ROECs) can drive their malignant transformation, giving rise to tumors that closely recapitulate the histologic and molecular characteristics of human HGSC. Spatially resolved single-cell transcriptomic analyses of tumors derived from Brca/Trp53/Pten-deficient ROECs (BTP-RO) reveal distinct invasive and immunosuppressive molecular programs. These findings establish ROECs as a previously unrecognized cell of origin for HGSC, expanding the landscape of potential precursor populations beyond the Fallopian tube. The RO-based HGSC model provides a powerful framework for developing origin-informed prevention strategies, early detection approaches, and targeted therapeutics.

cancer biology↗

bioRxiv2025

Virus-like particle capture reveals coordination of actin remodeling during Shigella flexneri entry by host proteins

Shigella spp. are intracellular bacterial pathogens that enter the host via plasma membrane insertion of a type 3 secretion system (T3SS) translocon, which triggers signaling cascades that include modulation of cytoskeletal dynamics, resulting in bacterial uptake. To better understand translocon insertion-induced host processes, we adapted a method to capture in virus-like particles (VLP) host proteins that are recruited to the cytosolic face of natively delivered S. flexneri translocons. Proteomic analyses reveal enrichment of 14-3-3{zeta}, a signaling protein, and CAP2, a regulator of actin turnover. 14-3-3{zeta} and CAP2 are necessary for host entry by T3SS pathogens. 14-3-3{zeta} dimers function as molecular scaffolds in the formation of bacterial-associated membrane ruffles. Concurrently, CAP2 localizes to membrane ruffles and cooperates with 14-3-3{zeta} to enable the formation of membrane ruffles that function efficiently in bacterial uptake. The findings define a coordinated role for 14-3-3{zeta} and CAP2 in cytoskeletal dynamics during T3SS pathogen infection.

microbiology↗

bioRxiv2025

Noncanonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy

We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent noncanonical amino acid Anap. By integrating genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags and enabling physiologically relevant visualization of protein pathobiology.

cell biology↗

bioRxiv2025

Phosphatidylcholine Metabolism Controls Alveolar Progenitor Renewal and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease marked by alveolar type 2 (AT2) stem cell dysfunction and excessive matrix deposition, with no effective treatments. Recent advances have recognized that AT2 cells act as stem cells, in addition to their role in the production of pulmonary surfactants in the distal alveolar space. We and others have reported a failure of AT2 regeneration and a loss of AT2 cells in IPF. We recently further reported that there is a defect in lipid metabolism in IPF AT2 cells and we discovered a selective loss of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in AT2 cells from IPF, as well as in AT2 cells from bleomycin-injured mice. Pharmacological and genetic experiments confirm that LPCAT1 is required for AT2 cell renewal in 3D organoid assays. AT2 cell-specific Lpcat1 deletion resulted in reduced AT2 renewal, spontaneous lung fibrosis, and heightened susceptibility to bleomycin-induced fibrosis in mice in vivo. Expression-based high-content drug screening with an LPCAT1 knock-in cell line identified several drug families that upregulated LPCAT1 expression. We further confirmed that anti-malarial artesunate and PLA2 inhibitor ONO-RS-082 increased LPCAT1 mRNA expression, promoted AT2 renewal, and attenuated bleomycin-induced lung fibrosis in mice in vivo. Our findings establish LPCAT1 as a critical regulator of AT2 renewal and lipid metabolism in IPF, suggesting that reactivation of LPCAT1 could offer a novel therapeutic strategy for restoring alveolar progenitor function and mitigating lung fibrosis.

cell biology↗

bioRxiv2025

GUANACO: A Unified Web-Based Platform for Single-Cell Multi-Omics Data Visualization

While single-cell multi-omics has advanced our understanding of cellular heterogeneity, the complexity of these datasets remains a barrier for non-computational users. Here, we introduce GUANACO, a Dash-based Python package for interactive, code-free visualization of single-cell RNA-seq and ATAC-seq data. GUANACO integrates matrix- and genome-track views, supporting flexible cell/gene selection, statistical testing, and transcription factor binding site exploration. Its user-friendly interface offers colorblind-friendly palettes, intuitive controls, and options for generating publication-ready figures. With a low memory requirement and cost-effective deployment, GUANACO facilitates seamless sharing and reproducible research, empowering researchers to explore, interpret, and communicate single-cell insights without extra coding.

bioinformatics↗

bioRxiv2025

Transfer RNA modifications during rhizome development in Oryza longistaminata

The rhizome organ endows many clonal plants with the ability to reproduce under stressful climates. Such rhizome-mediated perenniality also underlies the recent success of perennial rice breeding. Despite the importance of this organ, its developmental regulation is poorly understood. Here, using Oryza longistaminata, an emerging model for rhizome biology, we explored the involvement of tRNA modification in rhizome development. Through comparative profiling of modified nucleotides in rhizome samples at different developmental stages and/or subjected to various treatments, we identified a number of key rhizome-related tRNA modifications and revealed that, akin to the observations in many non-plant organisms, tRNA modifications are associated with hormonal signalling to regulate rhizomes responses to environmental cues. Furthermore, genome-wide analysis of tRNA-modifying genes was performed to facilitate future functional studies. These results and analyses not only deepen our understanding of rhizome development but also underscore the regulatory roles of tRNA modification in plant organ development.

plant biology↗

bioRxiv2025

The role of FRUITFULL controlling cell cycle during early flower development revealed by time series snRNA-seq experiments.

BACKGROUNDStarting from pools of undifferentiated cells, plants generate new organs post-embryonically in response to external and endogenous signals. This requires a dynamic coordination of cell division with cellular growth and differentiation regulatory programs. However, little is known how this coordination is achieved at the molecular level during flower development. RESULTSWe used time-series single-nucleus RNA sequencing (snRNA-seq) experiments of synchronized Arabidopsis thaliana flower developmental stages to characterize the transcriptome dynamics and the connections between cell cycle and developmental regulatory programs during early flower development. The results show a bifurcation between transcriptional trajectories corresponding to cell cycle progression and floral development. We identify the regulation of the cell cycle inhibitor KIP-RELATED PROTEIN 2 (KRP2) by FRUITFULL (FUL) as a key regulatory point on this bifurcation point, and validate the importance of this regulation in vivo. CONCLUSIONSOur work illustrates how time-series snRNA-seq experiments can be used to identify bifurcation points between regulatory programs and to identify candidate regulators on these bifurcations. In particular, we identify the regulation of KRP2 by FUL as an important regulatory point to balance cell division and developmental differentiation in plants.

plant biology↗

bioRxiv2025

Multiscale 3D whole joint cellular and molecular mapping dissects the relationship between structure and pain

Understanding musculoskeletal joints from a 3D multiscale perspective, from molecular to anatomical levels, is essential for resolving the confounding relationships between structure and pain, elucidating the intricate mechanisms regulating joint health and diseases, and developing new treatment strategies. Here, we introduce a musculoskeletal joint immunostaining and clearing (MUSIC) method specifically designed to overcome key challenges of immunostaining and optical clearing of intact joints. Coupled with large-field light sheet microscopy, our approach enables 3D high-resolution, microscale neurovascular mapping within the context of whole-joint anatomy without the need for image coregistration across various joints, including temporomandibular joints, knees, and spines, and multiple species, including mouse, rat, and pig. Our findings reveal 3D heterogeneous distributions of neurovascular networks and previously uncharacterized neurovascular pathways within joints. Using the proteoglycan 4 knockout (Prg4-/-) mouse model of joint degeneration, we identified significant alterations in joint-wide neurovascular architecture, highlighting neurovascular changes along degenerative processes. Furthermore, in a traumatic joint injury mouse model, we observed long-lasting pain behavior and a time-course 3D neurovascular remodeling preceding detectable joint morphological change, bridging microscale alterations with potential pain mechanisms. This platform offers a powerful tool for multiscale 3D analysis, enabling new insights into joint pathophysiology and intricate interplay among joint tissues.

bioengineering↗

bioRxiv2025

Walking Selectively Modulates Behaviorally Relevant Auditory Responses According to Stride Cycle Phase

Perception in natural environments unfolds while the body is in motion, yet how locomotion shapes cortical computations for fine-grained and dynamic scene analysis remains unclear. Here, we combined over-ground walking with mobile EEG and a transitional click-train paradigm to test how natural locomotion influences auditory processing in humans. Participants listened to two-segment click trains in which a subtle inter-click-interval (ICI) change signaled a pitch shift and performed a task-engaged change-detection task while either sitting or walking; an independent cohort also completed a passive-listening version. Walking elevated behavioral detection thresholds and slowed responses, indicating reduced sensitivity to fine temporal changes. Neurally, locomotion produced a response-component-specific attenuation: activity time-locked to the ICI transition--the change response previously linked to temporally integrative updating of an ongoing auditory object--was strongly reduced, whereas the offset response was largely preserved and onset responses were only modestly affected. Critically, this modulation persisted during passive listening and was selectively amplified near the perceptual threshold during task-engaged detection, revealing an interaction between motor state and cognitive demand. Thus, natural locomotion does not uniformly degrade hearing; instead, it preferentially down-weights a behaviorally critical, temporally demanding stage of auditory processing, offering a framework for understanding how motor-cognitive state shapes auditory scene analysis in the moving brain.

neuroscience↗

bioRxiv2025

Controlling treatment toxicity in ovarian cancer to prime the patient for tumor extinction therapy

High-grade serous ovarian cancer (HGSOC) remains a major clinical challenge. In particular among those patients with homologous recombination (HR)-proficient tumors (>50%), most eventually succumb to their disease due to high recurrence rates, acquired resistance, and cumulative toxicity. This report summarizes work from the 12th IMO Workshop in which we explored an alternative "extinction therapy" strategy for frontline treatment of HGSOC. Inspired by ecological principles, this multi-strike approach aims to eradicate tumors not through a singular "magic bullet" but through a series of therapies after standard frontline treatment when the tumor is still, and perhaps most, vulnerable. We present a framework leveraging mathematical modeling (MM) to develop personalized multi-strike protocols for HGSOC. Key contributions include: 1) An "IMOme" score using liquid biopsy data to assess patient-specific hematopoietic toxicity risk, guiding the timing and selection of subsequent therapies, 2) MM strategies to design effective lowdose combinations of targeted agents to achieve synthetic lethality while managing toxicity, and 3) A MM framework to analyze the interplay between chemotherapy, gut microbiome toxicity, and immunotherapy, demonstrating how mitigating microbiome damage could enhance immune response. Overall, the computational approaches presented herein aim to support the design of personalized, multi-strike regimens in the frontline setting that proactively target tumor extinction while managing toxicity, ultimately seeking to deliver cures for patients with HGSOC.

cancer biology↗

bioRxiv2025

Taurine is a Natural Host Cytoadhesion Inhibitor in Asymptomatic Malaria Cases

The prolonged dry season in malaria-endemic regions of sub-Saharan Africa can be divided into periods of high and low transmission. The majority of symptomatic malaria cases are restricted to the short high transmission period that follows the rainy season. Shortly after, persistent asymptomatic malaria cases are more prevalent throughout the prolonged low transmission period. It is still unclear whether host metabolic alterations play a role in asymptomatic infections during seasonal malaria. In this study, we analyzed the blood plasma metabolome (n=199) of individuals in The Gambia, West Africa, capturing data from both high and low malaria transmission periods. Plasma samples from individuals (n=16) were collected monthly throughout the low transmission season, enabling a longitudinal analysis of metabolic alternations over six months. Our findings reveal that significant changes in host plasma metabolite composition are associated with seasonality and malaria pathogenicity. Notably, we observed elevated levels of taurine in asymptomatic malaria infections, especially during periods of low transmission. In vitro, this naturally occurring host molecule inhibits the cytoadhesion of malaria-infected red blood cells (iRBCs), which is key to malaria disease severity and mortality. Exogenous taurine can significantly reduce or reverse binding of iRBCs to the common adhesion receptor CD36 and the endothelial protein C receptor (EPCR), the later being associated with cerebral malaria. This study uncovers a mechanism by which elevated taurine plasma levels in asymptomatic infections could reduce cytoadhesion and lead to increased splenic clearance, thereby strengthening host resistance to symptomatic infections. In the absence of health strategies targeting dry season parasite reservoirs, our findings highlight taurine as a potential prophylactic or therapeutic agent to reduce symptomatic malaria in sub-Saharan Africa. One Sentence SummaryMetabolomics uncovers taurine as a natural host inhibitor of Plasmodium falciparum cytoadhesion in asymptomatic malaria carriers, offering new insights for disease control.

microbiology↗

bioRxiv2025

Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell homeostasis in idiopathic pulmonary fibrosis and reverses pulmonary fibrosis in mice

Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.

cell biology↗

bioRxiv2025

Multi-omics analyses reveal the effect of DNA methylation on iridoid glycosides biosynthesis in Rehmannia glutinosa

Rehmannia glutinosa roots produce a group of lipophilic bioactive components known as iridoid glycosides. However, the molecular mechanisms by which DNA methylation regulates the biosynthesis of iridoid glycosides in R. glutinosa remain unknown. Herein, the development of R. glutinosa roots and the content of iridoid glycosides in the Wenxian region were significantly higher than those in Xinxiang. Low methylation level contributed to the accumulation of iridoid glycosides and the expression of related enzyme genes. Demethylation promoted both roots growth and development, as well as the accumulation of iridoid glycosides. Up-regulated RgALDH13, RgHDR1, RgG10H4, RgDXR1, RgG10H3, and RgUPD1, along with transcription factors (TFs), form the regulatory network for the biosynthesis of iridoid glycosides. Furthermore, the primary active region of the RgG10H4 promoter is located in the -164 bp region, where the RgMYB2 protein specifically binds to the TAACCA motif in the RgG10H4 promoter. Collectively, low levels of DNA methylation enhance the expression of core genes, followed by inducing the accumulation of iridoid glycosides, which suggests that RgMYB2-RgG10H4 plays a positive role in this process. These findings will contribute to a deeper understanding of the role of DNA methylation in the accumulation of iridoid glycosides. HighlightLow levels of DNA methylation contribute to the accumulation of iridoid glycosides and the expression of key enzyme genes in R. glutinosa.

molecular biology↗

bioRxiv2025

Electroacupuncture promotes post-stroke motor recovery through miR-124-3p-mediated regulation of NRG1/ErbB4 signaling pathway

ObjectiveElectroacupuncture has demonstrated beneficial effects in post-stroke motor dysfunction, yet the molecular mechanisms underlying its therapeutic efficacy remain incompletely understood. This study aims to investigate whether electroacupuncture promotes post-stroke motor function recovery by modulating the interaction between miR-124-3p and the NRG1/ErbB4 signaling pathway, specifically exploring whether miR-124-3p directly targets NRG1 to regulate neural plasticity in a focal cerebral ischemia rat model. MethodsThe ischemic stroke model was established by middle cerebral artery occlusion/reperfusion (MCAO/R) in adult rats. These rats were randomly divided into sham, model, electroacupuncture and model plus miR-124-3p inhibitor groups. The model group, electroacupuncture group and model plus miR-124-3p inhibitor group received EA intervention 24 h after modelling for 7 consecutive days. Behavioural function was assessed by Zea Longa score and mechanical pain rating. Hippocampal damage was detected by HE staining and neuronal apoptosis was observed by TUNEL staining. IL-1{beta} and IL-18 levels were measured by ELISA. PCR and Western blotting were used to detect the expression of miR-124-3p and inflammatory pathway proteins. The interaction between miR-124-3p and TLR4 was verified by dual-luciferase reporter assay. ResultsElectroacupuncture improved motor function in rat model of MCAO/R, as evidenced by improved Zea Longa scores and decreased mechanical withdrawal thresholds. Electroacupuncture significantly attenuated neuronal damage and also inhibited the inflammatory response by decreasing IL-18 and IL-1{beta} levels (P < 0.001). Notably, electroacupuncture upregulated miR-124-3p expression (P < 0.0001) and activated the NRG1/ErbB4 signaling pathway in the hippocampus. When miR-124-3p was inhibited, NRG1 protein expression decreased while GABA expression tended to increase. Dual-luciferase reporter assays confirmed that miR-124-3p directly targets the 3UTR of NRG1 mRNA and regulates its expression at the translational level. These findings suggest that electroacupuncture may alleviate neuronal and axonal damage by modulating miR-124-3p/NRG1/ErbB4 signalling and regulating GABA release. ConclusionElectroacupuncture can ameliorate motor dysfunction induced after brain I/R injury by targeting and modulating the NRG1-ErbB4 signaling pathway via miR-124-3p. These data are expected to provide new insights into the mechanisms of electroacupuncture for the prevention of potential targets for the recovery of motor dysfunction after stroke.

animal behavior and cognition↗

bioRxiv2025

Promoting social connectedness through multi-person neurofeedback

Humans are inherently driven to build meaningful relationships, but attempts to socially connect with others are not always successful. This study investigates whether social connectedness can be improved by intentionally regulating inter-brain coupling, a neural correlate of successful social interactions. Using a multi-person neurofeedback system (i.e., a multi-brain computer interface), we showed dyads real-time visualizations of the extent to which their brainwaves (EEG signals) were "in sync". Our results showed that, compared to a sham control group, dyads who received multi-brain neurofeedback exhibited an increase in inter-brain coupling, and, critically, that this increase was associated with a higher sense of social connectedness. A chain mediation analysis suggested that this experience of enhanced social connectedness may have been driven by a sense of joint control and shared intentionality. Together, our findings showcase the potential for regulating inter-brain coupling to optimize human social relationships and behaviors.

neuroscience↗

bioRxiv2025

A Conserved Mycobacterial Nucleomodulin Hijacks the Host COMPASS Complex to Reprogram Pro-Inflammatory Transcription and Promote Intracellular Survival

Nucleomodulins are a class of effector proteins secreted by bacterial pathogens that translocate into the host cell nucleus to modulate nuclear processes. However, their target proteins and underlying molecular mechanisms remain poorly understood in mycobacteria. Herein, we identified a conserved hypothetical protein Rv1075c, designated MgdE, as a nucleomodulin that enhances mycobacterial intracellular survival. MgdE undergoes nuclear translocation via two nuclear localization signals, KRIR108-111 and RLRRPR300-305, and interacts with ASH2L and WDR5, two subunits of the host histone methyltransferase COMPASS complex. This interaction suppresses histone H3 lysine 4 (H3K4) methylation-mediated transcription of pro-inflammatory genes, including IL6 and IL1B, thereby promoting mycobacterial survival in both macrophages and mice. Our study provides the first experimental evidence that a bacterial nucleomodulin facilitates intracellular survival by directly targeting the host COMPASS complex. These findings advance our understanding of mycobacterial pathogenesis by revealing a novel mechanism that contributes to its intracellular survival strategy.

microbiology↗