Biology subjects

Ma, B.

Publications and source records attributed to Ma, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

The Bacteriocin Sublancin Restores Vancomycin efficacy against vancomycin-resistant enterococci in vitro and in vivo

Vancomycin-resistant enterococci (VRE) is one of the serious threat to global public health, with the diminishing effectiveness of antibiotics. There is an urgent need for novel strategies to control this multidrug-resistant bacterial infections. Here, our findings demonstrate that sublancin, a bacteriocin produced by Bacillus subtilis, exhibits intrinsic antibacterial activity and, more importantly, potentiates vancomycin, therapy restoring its efficacy against VRE. Using a series of in vitro assays, including fractional inhibitory concentration index, time-killing analysis, and resistance development assays, we show that sublancin significantly enhances the bactericidal effectiveness of vancomycin. In vivo, the sublancin-vancomycin combination therapy markedly reduced bacterial loads, improved svrvival rates in a Galleria mellonella model and enhanced bacterial clearance rates in a mouse model. Mechanistic studies using RT-PCR revealed that sublancin down-regulates the expression of the vanA resistance gene cluster. All in all, these findings make vancomycin and this antibiotic peptide combination as a promising candidatese to enhance vancomycin efficacy and overcome VRE infections, potentially through inteference with resistance gene expression.

pharmacology and toxicology↗

bioRxiv2026

Enhancing Pan-cancer Spatial Transcriptomics atSingle-cell Resolution with stPainter

Subcellular spatial transcriptomics technologies offer unprecedented views of tissue architecture but are fundamentally constrained by sparse gene panels and limited detection sensitivity. Current computational enhancement strategies typically rely on tissue-matched single-cell RNA sequencing (scRNA-seq) references and necessitate computationally intensive retraining for each dataset, impeding their scalability and clinical applicability. Here, we present STPAINTER, a conditional generative model that leverages a massive pretraining pan-cancer scRNA-seq atlas to universally enhance spatial transcriptomics data. Built upon a latent diffusion architecture with stochastic differential equation-guided generation, STPAINTER learns a universal manifold of cellular states to reconstruct genome-wide expression profiles from sparse spatial measurements. Uniquely, our pretraining paradigm enables zero-shot generalization and empowers downstream tasks by providing imputed transcriptomes and informative latent variables to enhance resolution at both the gene and cluster levels. Applied STPAINTER upon 6 spatial transcriptomics datasets of different cancer types, we demonstrate that our model empowers high-fidelity downstream analyses, including fine-grained subpopulation clustering and pathway enrichment. Furthermore, cross-validation with spatially resolved proteomics (CODEX) confirms the biological veracity of the imputed cellular landscapes. STPAINTER provides a robust, scalable framework for decoding complex tumor microenvironments without the need for auxiliary sequencing data.

bioinformatics↗

bioRxiv2025

Wnt-presenting materials sustain H3K14-acetylation in human skeletal stem cells for tissue engineering and bone repair

Engineering functional tissues for transplantation requires insight into epigenetic mechanisms that regulate stem cell fate. We have developed the Wnt-induced osteogenic tissue model (WIOTM), a platform that recapitulates human osteogenesis, and identified acetylation of histone H3 at lysine 14 (H3K14ac) as a critical epigenetic regulator in human skeletal stem cells (hSSCs). In WIOTM, localized Wnt signals drive asymmetric cell division (ACD), yielding a proximal hSSC with high H3K14ac and a distal daughter with reduced H3K14ac that migrates into the 3D collagen matrix and initiates osteogenic differentiation. Disrupting H3K14ac in hSSCs abrogates ACD and WIOTM formation. To test whether hSSCs maintain H3K14ac in vivo, we formed the WIOTM on Wnt-functionalized polymer bandages and transplanted them into calvarial defects. The WIOTM contributed to bone repair, and human cells adjacent to the bandages retained high H3K14ac despite the injury environment. These findings establish WIOTM as both a mechanistic and translational platform for regenerative medicine.

cell biology↗

bioRxiv2025

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by limited therapeutic options for advanced disease. Immunotherapy, in particular, has had dismal success rates in the PDAC due to a tumor microenvironment (TME) that contributes to immune exclusion and poor drug delivery. Many cytokines necessary for Natural Killer (NK) and T cell chemotaxis, activation, and cytotoxicity are absent in the PDAC TME. Despite their early success, cytokine therapies have largely failed in the treatment of solid tumors as a result of the lack of efficacy of single cytokine administration and toxicities from systemic delivery. To overcome these limitations, we designed multiplexed mRNA cocktails encoding diverse interleukins, chemokines, and interferons for intratumoral delivery. Administration of a cytokine-encoding mRNA mixture into mice with orthotopically transplanted PDAC tumors achieved robust yet transient cytokine expression locally in the PDAC TME, leading to NK cell and CD8+ T cell immunity and reduced tumor growth and fibrosis in multiple mouse models. Combining cytokine mRNAs with those encoding tumor-associated antigens further activated CD8+ T cell-mediated tumor control and enhanced survival after just a single dose in PDAC-bearing mice. Remarkably, lipid-based nanoparticle (NP) encapsulation of an all-in-one cytokine and antigen mRNA cocktail allowed safe systemic administration and local delivery of these immunogenic signals to autochthonous PDAC tumors in genetically engineered mouse models, culminating in complete tumor responses in 50% of animals. These results suggest that multiplexed mRNA approaches to delivering cytokine signals and antigens generally absent in the TME could pave the way for an effective immunotherapy for PDAC.

cancer biology↗

bioRxiv2025

Loss of tight junction protein claudin 18 uncovers alveolar epithelial stem cell plasticity and emergence of non-fibrogenic transitional progenitors

Persistence of senescent alveolar transitional progenitors following lung injury is implicated in the pathogenesis of fibrosis. We identified transitional cells in uninjured Cldn18 knockout (KO) mouse lungs distinct from previously reported damage-associated transitional progenitors (DATPs) with a less fibrogenic transcriptomic profile. Cldn18 KO mice are protected from bleomycin-induced fibrosis, with early restoration of cellular homeostasis. Lineage tracing implicates accelerated differentiation as a mechanism for protection from fibrosis, leading us to name these cells regeneration-associated transitional progenitors (RATPs). Multiome confirms that RATPs and DATPs are epigenetically distinct, with RATPs comprised of RATP2s and RATP1s based on epigenomic proximity to AT2s and AT1s, respectively, and suggests dynamic regulatory remodeling during AT2-to-AT1 differentiation, with NKX2.1 and AP-1 active in early transitions and TEAD factors in later stages. These results reveal an unexpected role for Cldn18 in regulation of AEC plasticity, while identification of RATPs challenges the notion that persistence of transitional alveolar cells is invariably pathologic.

cell biology↗

bioRxiv2025

Programming Microbe-Computer Interaction for Customized Life-Nonlife and Cross-Life Communication

This extension of human-computer interaction (HCI) paradigm to the non-intelligent microbe-computer interaction (MCI) is attractive for building generalized life-nonlife communication. Main challenges lie in how to construct biohybrid interface within individual MCI unit and thereafter program cross-life communication based on these MCI units. Here, we propose the design and construction of opto-interfaced MCI unit composed of engineered microbes and computer terminals, for enabling quantifiable transduction between microbial signals and digital signals. These units were able to serve as biohybrid sensors, actuators and transceivers, supporting biomonitoring, bio-actuation and microbe-centric bidirectional operations. Based on these functional units, we established programmable cross-life communication architectures capable of unicast, multicast, and logic-gate-driven communication with temporal dynamic control. The architectures were validated in biomedical scenarios including tumor hypoxia biomarking, epidermal heavy metal detoxification, and colitis intervention, demonstrating robust performance in closed-loop diagnostic-therapeutic applications. Additionally, we integrated MCI with an unmanned surface vessel for environmental monitoring, highlighting its cross-domain potential. Collectively, we provide a scalable strategy for building customized life-nonlife and cross-life communication, which is expected as an important complement to internet of things (IoT).

synthetic biology↗

bioRxiv2025

Bispecific Targeting of CHI3L1 and PD-1/PD-L1 Axis as a Novel Therapeutic Strategy for Idiopathic Pulmonary Fibrosis

CHI3L1, a chitinase-like protein, plays a key role in the pathogenesis of pulmonary fibrosis, though the precise mechanisms remain unclear. This study explores how CHI3L1 regulates profibrotic macrophage activation and invasive myofibroblast differentiation and their interactions. In vitro, CHI3L1 induced profibrotic M2 macrophage activation and differentiation marked by increased expression of CD163, CD206, and PD-L1. CHI3L1 also enhanced TGF-{beta}1 effects on lung fibroblasts including myofibroblast transformation, migration and tissue invasion. Mechanistically, CHI3L1 increased TGF-{beta}1-stimulation of Smad, Akt and Erk signaling and PD-L1 played a significant role in TGF-{beta}1/CHI3L1-stimulated myofibroblast transformation. Coculture experiment further confirmed the ability of CHI3L1 to induce profibrotic macrophage activation that enhanced myofibroblast transformation mediated via a CD44-PD-L1 axis. Following in vivo bleomycin challenge, CHI3L1 transgenic mice exhibited significantly higher levels of PD-L1+ M2 macrophages, PD-L1+/PDGFR+ fibroblasts and increased numbers of PD-1+ and CD45+/PD-1+ cells compared to wild-type controls. Notably, combined treatment with anti-CHI3L1 and anti-PD-1 antibodies, or a bispecific anti-CHI3L1-anti-PD-1 antibody, resulted in greater inhibition of bleomycin-induced fibrosis than either antibody alone. These findings suggest that there is a stimulatory interaction between CHI3L1 and the PD-1/PD-L1 axis in promoting profibrotic macrophage activation and invasive fibroblast differentiation. The results also highlight the potential of bispecific targeting of CHI3L1 and the PD-1/PD-L1 pathway as an effective therapeutic approach for pulmonary fibrosis.

immunology↗

bioRxiv2025

MYC-Driven Activation of USP39 Enhances SRSF1 Stability and Promotes PDAC Progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor SRSF1 plays a key oncogenic role in PDAC, where its tightly regulated expression constrains KRAS-driven signaling under normal conditions, while its upregulation promotes tumorigenesis. SRSF1 expression is regulated in part by proteostasis. However, the precise mechanisms remain unclear. Here, we identify USP39 as a deubiquitinase that interacts with SRSF1 in an RNA-independent manner and stabilizes it by reducing ubiquitination. USP39 expression is elevated in PDAC tumors and precancerous lesions, and correlates with poor patient survival. USP39 knockdown suppresses PDAC cell proliferation and migration, effects that are partially rescued by SRSF1 overexpression. Mechanistically, we show that MYC directly activates USP39 transcription via E-box motifs within its exon 1b promoter, linking MYC-driven transcriptional regulation to post- translational stabilization of SRSF1. Together, these findings define a MYC-USP39-SRSF1 regulatory axis that integrates transcriptional and post-translational mechanisms in PDAC and highlight USP39 as a potential therapeutic target.

cancer biology↗

bioRxiv2025

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation at the parental-to-zygote transition in mammals is poorly understood. To address this, we developed a CENP-A-mScarlet knock-in mouse model, which revealed sex-specific dynamics: mature sperm retains 10% of the CENP-A levels present in MII-oocytes. However, in zygotes prior to the first mitosis, this difference is resolved, using maternally inherited cytoplasmic-CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization domains impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity. Highlights[bullet] CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans. [bullet]CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A. [bullet]Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner. [bullet]CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization. Key TermsCentromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse

genetics↗

bioRxiv2025

KRAS withdrawal in Cholangiocarcinoma leads to immune infiltration and tumor regression

Background and AimsCholangiocarcinoma (CCA) is a liver cancer with poor survival rates. Current treatments, including targeted therapies for specific mutations, are limited and benefit only a small subset of patients. KRAS mutations are found in 15-40% of CCA, representing a new potential treatment target. Whether KRAS inhibition leads to CCA tumor regression is unknown partly due to the lack of conditional animal models. Approach and ResultsWe engineered a conditional KrasG12D-driven CCA mouse model by co-delivering plasmids encoding the Sleeping Beauty transposase with a luciferase reporter, a transposon-borne inducible KrasG12D transgene and Cas9 and Trp53 guide RNA into mouse liver by hydrodynamic tail-vein injection. In vivo bioluminescent imaging showed that KrasG12D withdrawal resulted in 99% tumor regression by day 7. KrasG12D withdrawal resulted in infiltration of activated CD8+ T cells by IHC and IF staining. Single cell RNA-Seq result also validated the enrichment of activated CD8+ T cells subpopulation in KrasG12D-withdrawn tumor. RNA-Seq suggested that KrasG12D withdrawal stimulated transforming growth factor beta pathway and induced senescence. We used cytokine array to characterize the secretion of pro-inflammatory factors, including IL-15 and Ccl17, upon KrasG12D withdrawal. Lentiviral overexpression of murine CCL17 delayed CCA tumor progression in a xenograft model, and overexpression of murine IL-15 resulted in tumor regression in a transplant model. Flow cytometry analysis revealed that IL-15 and CCL17 recruited and activated CD8+ T cells in CCA tumor. Expression of IL-15 resulted in blockade of tumor progression in our TKP CCA model. ConclusionsKrasG12D withdrawal results in rapid tumor regression, highlighting the importance of oncogenic Kras in CCA tumor maintenance. KrasG12D withdrawal induces p53-independent senescence, secretion of pro-inflammatory factors, and immune surveillance by activated CD8+ T cells. We identified two secreted factors IL-15 and CCL17 that could recruit and activate T cells and control CCA tumor progression. This study underscores KRAS inhibition as a potential therapeutic approach for CCA.

cancer biology↗

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2025

Kasugamycin inhibits melanoma lung metastasis and regulates CHI3L1-driven M2-like tumor-associated macrophage differentiation

CHI3L1, a chitinase-like protein, is a potent immune modulator involved in various diseases, including lung cancer. While recent studies have demonstrated that kasugamycin (KSM) is a pan-chitinase inhibitor with strong anti-fibrotic activity, its effects on specific chitinase-like proteins remain undefined. This study shows that KSM effectively abrogates CHI3L1-stimulated cellular signaling and bioactivities. In a B16/F10 melanoma lung metastasis model, where CHI3L1 plays a critical role, KSM treatment significantly reduced melanoma lung metastasis dose-dependently. The anti-tumor effect of KSM was found to be CHI3L1-specific, as CHI3L1 overexpression enhanced melanoma lung colony formation, which was effectively blocked by KSM. In melanoma-challenged lungs, KSM treatment significantly reduced the elevation of M2 macrophages expressing CD206, CD163, and PD-L1. In studies using human monocytic THP-1 cells, CHI3L1 promoted M2 macrophage differentiation, which KSM significantly suppressed. Bulk RNA sequencing of differentiated macrophages revealed that CHI3L1 highly induced the expression of epidermal growth factor receptor (EGFR), and this induction was counter-regulated by KSM, and CHI3L1-driven M2 macrophage activation was reduced with EGFR blocker treatment. These findings reveal a novel anti-tumor mechanism of KSM, which inhibits M2-like tumor-associated macrophage differentiation, potentially through the CHI3L1-EGFR axis.

immunology↗

bioRxiv2025

Sarcoidosis resolvers and progressors demonstrate distinct systemic metabolomic profiles

Sarcoidosis is an idiopathic syndrome with striking disparities in clinical outcome. We have previously identified immune distinctions between sarcoidosis clinical cohorts that either resolve or progress. A significantly higher percentage of Programmed Death 1 (PD-1)+Th17 cells was present in sarcoidosis and IPF subjects experiencing disease progression. Metabolites, or bioactive compounds, have been shown to interact with immune cells, such as Th17 cells by regulating cellular processes such as proliferation, signaling and differentiation. Metabolomic analysis was conducted on two subject cohorts: Sarcoidosis (n=19) and healthy controls (n=23). Sarcoidosis subjects were further subdivided by clinical outcome and prior to therapeutic initiation: disease progression or clinical resolution. Metabolites are considered significant if they had a fold change greater than two and a p-value is <0.05 in pairwise 2-sample t-tests. Multiple group comparison was performed using ANOVA and Tukeys honestly significance difference post hoc tests to identify statistically different pairwise differences. Progressors exhibit significantly elevated serum levels of trimethylamine N-oxide (TMAO) and taurine, with reduced glycerate, alanine, and proline concentrations (Figure 1A-C). TMAO is elevated in sarcoidosis progressors relative to resolvers. Taurine levels are also significantly elevated in progressors, comparing to resolvers. The significant reductions in glycerate, alanine, and proline in progressors compared to resolvers, along with elevated TMAO, point to disruptions in core metabolic pathways, including glycolysis, pyruvate metabolism, and collagen synthesis, that underlie bioenergetic dysfunction, altered amino acid utilization, and impaired tissue repair. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/642370v1_fig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@12b058corg.highwire.dtl.DTLVardef@1795b24org.highwire.dtl.DTLVardef@4e993dorg.highwire.dtl.DTLVardef@2e97da_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Comparison of metabolome clusters among sarcoidosis and healthy control cohorts. A) PLS-DA demonstrates clusters among sarcoidosis resolver, progressor, and controls, and B) only between resolver and progressor. Circles indicate 95% confidence region of each group. Distinct signatures exemplified using boxplots C). Metabolites with a fold change greater than two and a p-value is <0.05 in pairwise 2-sample t-tests are considered significant. Multiple group comparison were performed using ANOVA and Tukeys honestly significance difference post hoc tests to identify statistically different pairwise differences. *p<0.05, **p<0.01, ***p<0.001. C_FIG

systems biology↗

bioRxiv2025

Deciphering Ibogaines Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses

Ibogaine is the main psychoactive alkaloid produced by the iboga tree (Tabernanthe iboga) that has a unique therapeutic potential across multiple indications, including opioid dependence, substance use disorders, depression, anxiety, posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI). We systematically examined the effects of ibogaine, its main metabolite noribogaine, and a series of iboga analogs at monoamine neurotransmitter transporters, some which have been linked to the oneiric and therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with sub-micromolar potency in cell-based fluorimetry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. The iboga compounds also inhibit the plasma membrane monoamine transporters (MATs), prominently including the serotonin transporter (SERT), and a novel iboga target, the organic cation transporter 2 (OCT2). SERT transport inhibition was demonstrated in serotonin axons and soma in the brain and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine showed dual inhibition of VMAT2 and SERT with comparable potency, providing an explanatory model for the known neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the complexity of the iboga pharmacology, which we termed "matrix pharmacology". The matrix pharmacology concept is outlined and used to explain why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/641351v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@a1cacaorg.highwire.dtl.DTLVardef@8be27org.highwire.dtl.DTLVardef@1fc320forg.highwire.dtl.DTLVardef@3a8837_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Asymmetric Histone Inheritance Regulates Differential Transcription Re-initiation and Cell Fate Decisions in Mouse Olfactory Horizontal Basal Cells

The olfactory epithelium (OE) possesses an adult stem cell population, the horizontal basal cells (HBCs), to permit lifelong tissue regeneration. Here we show that HBCs exhibit asymmetric inheritance of histone H4 but not H2A-H2B during OE regeneration in mice. Primary HBC cultures further revealed asymmetric histone inheritance for H3 and H3.3. Upon mitotic exit, asymmetric histone inheritance correlates with asynchronous transcription re-initiation and differential enrichment of p63, a key transcription factor for HBC cell fate. Disruption of asymmetric histone inheritance abolished these asymmetric cellular features and attenuated OE regeneration and smell behavior recovery. Single-cell RNA sequencing of paired HBC daughters in culture further supported asymmetric multilineage cell fate priming. Together, these findings reveal asymmetric histone inheritance in a mammalian adult stem cell lineage and highlight its biological significance in neural tissue regeneration and animal behavior.

developmental biology↗

bioRxiv2025

VIRGO2: Unveiling the Functional and Ecological Complexity of the Vaginal Microbiome with an Enhanced Non-Redundant Gene Catalog

Despite the importance of the cervicovaginal microbiome, the mechanisms that govern its composition and drive its impact on host physiology remain poorly understood. This study expands our understanding of the function and ecology of the vaginal microbiome using VIRGO2, an enhanced non-redundant gene catalog comprising over 1.7 million well-annotated genes from body-site specific microbes and viruses. Analyses using VIRGO2 revealed novel insights, including the identification of previously uncharacterized vaginal bacteria, features of the vaginal mycobiome and phageome, and differential expression of bacterial carbohydrate catabolic genes. Constructed from over 2,500 metagenomes and 4,000 bacterial genomes, VIRGO2 broadens geographic representation and microbial diversity compared to its predecessor. This updated catalog enables more precise profiling of taxonomic and functional composition from metagenomic and metatranscriptomic datasets. VIRGO2 is a critical resource for integrative analyses of vaginal microbial communities and their interactions with host tissues, thereby enhancing our mechanistic understanding of vaginal health and disease.

microbiology↗

bioRxiv2025

Highly potent novel multi-armoured IL13Rα2 CAR-T subverts the immunosuppressive microenvironment of Glioblastoma

Glioblastoma remains one of the most challenging and lethal brain cancers, with limited treatment options. While CAR-T cells have shown promise in some patients, sustaining T-cell activity and overcoming the immunosuppressive tumour microenvironment remain significant hurdles. Here, we present an armoured CAR-T cell design to address these challenges and enhance persistence in GBM tumours. We developed a highly specific humanised single-domain antibody targeting IL13R2 and included it alongside four additional modular elements in a single retroviral vector for CAR-T generation. Our results demonstrate that this single-cassette CAR-T cell design possesses high resilience against TGF-{beta}-mediated immunosuppression, enhanced tumour-killing capacity through IL-12 secretion while maintaining a favourable safety profile, extended persistence in the host, and an additional layer of safety control through the incorporation of a suicide switch. Importantly, despite its complexity, the construct can still be manufactured efficiently. These advancements represent a significant step forward in addressing key challenges associated with CAR-T cell therapy in solid tumours.

cancer biology↗

bioRxiv2025

Food pairing independently associated with cardiometabolic traits beyond dietary patterns across western and eastern populations

Cardiometabolic health is closely linked to diet. Both specific food choices and dietary indices are commonly used to guide cardiometabolic protection strategies. However, the balance between foods may also significantly impact cardiometabolic health. Here, we explore the balance and imbalance in long-term dietary food intake to quantify food pairing patterns (FPs), providing insights beyond conventional dietary indices and single-food intake frequencies. Using data from our GGMP (n = 6,994) and the NHANES (n = 7,350) cohorts, we observed that long-term food pairing patterns are independent of single food intake frequency and dietary indices. We identified 1,759 and 306 cardiometabolic-related long-term food pairing patterns from two cohorts (FDR < 0.05), respectively. Notably, around 80% of these pairing foods not individually associated with cardiometabolic traits, and food pairing pattern associations with cardiometabolic traits at hyper food group level were consistent across Eastern and Western populations. Besides, mediation analysis revealed that 72.7% of long-term food pairing patterns affected cardiometabolic traits through 31 microbial genera, with Clostridiumsensustricto1 playing a predominant role. Moreover, multi-step mediation analysis found that microbes mediated the impact of long-term food pairing patterns on cardiometabolic traits primarily through their metabolic pathways, such as pyruvate fermentation to propanoate and ergothioneine biosynthesis pathways. Our data suggest that balance between dietary foods is broadly associated with cardiometabolic traits by modulating gut microbial functionalities, in contrast to the lower occurrence when considering individual foods in isolation. These results offer a novel perspective for designing personalized dietary strategies beyond present dietary indices to enhance cardiometabolic health.

microbiology↗