Biology subjects

Zeng, S.

Publications and source records attributed to Zeng, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatial multi-omics analysis reveals vimentin-high macrophages-endothelial cells niche shapes CAFs heterogeneity in colorectal cancer metastasis

The spatial architecture of the tumor microenvironment (TME) is pivotal in the progression of colorectal cancer (CRC) liver metastasis. By applying high-plex spatial multi-omic mapping and neighborhood analysis to a discovery cohort of colorectal cancer primary tumor (PT) and paired liver metastases (LM), we identified a specialized vimentin-high macrophages-endothelial cells niche that orchestrates cancer-associated fibroblast (CAF) phenotypes. Mechanistically, in primary tumors, vimentin-high macrophages secrete INHBA to activate the ACVR2/TGF-{beta} axis in endothelial cells, driving CAFs toward a myCAF phenotype. Conversely, in liver metastases, these macrophages secrete CXCL9 to trigger the PI3K-Akt/NF-[kcy]B/CXCL12 cascade in endothelial cells, directing CAFs toward an iCAF state. Clinically, high niche activity predicts poor survival. Divergent endothelial signaling in primary versus metastatic lesions exposes site-specific stromal vulnerabilities for therapeutic targeting, with architectural features discernible from routine histopathology. These findings reveal a site-specific regulatory mechanism of the macrophage-endothelial niche, offering a novel and clinically significant biomarker for CRC prognosis.

cancer biology↗

bioRxiv2026

Assessing the Reliability of LLM-Generated Phenotype-Genotype Associations Through External Validation

BackgroundPhenotype-genotype associations underpin precision medicine by enabling disease prevention, early diagnosis, risk stratification, therapeutic target discovery, and personalized treatment. However, the rapid growth of scientific evidence has made manual curation of these associations increasingly labor-intensive, time-consuming, and incomplete. Large Language Models (LLMs) offer a potential path to scalable genomic generation and synthesis of this knowledge, but their ability to accurately identify phenotype-genotype associations and the extent to which these outputs are supported by established genomic knowledge bases remain unclear. Materials and MethodsFour LLMs, Claude Sonnet 4.6, DeepSeek V4 Flash, Gemini 3 Flash Preview, and GPT-5.5, were benchmarked on six zero-shot task categories covering forward and reverse phenotype-gene and phenotype-SNP generation. A total of 4,196 associations were identified from curated inputs and evaluated through a multistage external verification pipeline comprising phenotype normalization, ontology mapping, genomic identifier validation against Ensembl, and evidence verification using both the GWAS Catalog and OMIM. Associations were assigned a fused evidence level of strong, moderate, weak, or none. ResultsOverall, 74.19% of generated associations were matched to at least one external genomic knowledge base; 9.15% received strong support and 54.46% moderate support. Phenotype-gene associations were more verifiable than phenotype-SNP associations (strong or moderate: 67.19% vs 54.06%). Among existing associations, Claude Sonnet 4.6 achieved the highest overall strong or moderate rate (69.2%), followed by GPT-5.5 (65.1%), DeepSeek V4 Flash (61.7%), and Gemini 3 Flash Preview (56.9%). ConclusionLLMs can support scalable generation of candidate phenotype-genotype associations. Performance varied substantially by relation type and was lower for SNP-level and rare disease associations, highlighting both the limitations of current genomic resources and the need for rigorous validation pipelines.

bioinformatics↗

bioRxiv2026

A Principled Statistical Framework for Analyzing Spatial Patterns in Spatially Resolved Multi-Omics

Emerging spatial multi-omics technologies enable the profiling of molecular variation within its tissue context, yet existing methods for identifying spatially variable features lack principled approaches to experimental design and cross-sample inference. Here, we present STORM, a principled Statistical TOol for spatially Resolved Multi-omics, for rigorously analyzing spatial patterns in spatial multi-omics research. STORM incorporates a robust and efficient nonparametric test that quantifies local deviations in molecular feature measurements to detect spatial dependence across transcriptomic and proteomic data. It further estimates an interpretable spatial effect size, supports power calculations for both spatial locations and biological replicates, and enables formal group-level comparisons. In several simulated and experimental spatial multi-omics case studies, STORM demonstrates reliable performance in detecting spatial structures while offering quantitative support for study design decisions. Overall, STORM provides a principled statistical framework that unifies spatial hypothesis testing, effect size estimation, power analysis, and experimental design for spatial multi-omics data.

bioinformatics↗

bioRxiv2026

Incorporation of single-neuron projectome-based connectivity motifs enhances the cortex-specific performance of artificial neural networks

The organizational principles of natural neural networks could inspire the new architecture design of artificial neural networks (ANNs). Analysis of single-neuron connectomes of mouse brains revealed distinct profiles of three-node connectivity motifs in various cortical areas and hippocampal formation. A connectome-informed neural network algorithm ("CINA") was developed to incorporate natural connectivity motifs into ANN algorithms represented by recurrent neural network (RNN) and transformer-based large language model (LLM). We found that incorporation of the average profile of cortical motifs improved the RNNs performance in noise-resistant categorization and motor learning benchmark tasks, as compared with RNNs with random connectivity. Notably, incorporating cortex-specific motifs further elevated the RNNs performance in tasks related to the cortical function, and this effect was enhanced by artificially increasing the bias in the motif profile. Similar experimental results were verified on an LLM using Motif-Transformer for natural language question answering and brain-signal decoding tasks. Graph-theoretic analyses showed that incorporating natural motifs drove the emergence of modular and small-world properties in ANNs. Together, we demonstrated not only connectome-inspired optimization of ANN architecture but also functional significance of specific motif profiles in various cortices.

neuroscience↗

bioRxiv2026

A distinct adolescent profile for activity and dopamine release in the nucleus accumbens during Pavlovian conditioning

Across species, adolescence is a time of heightened reward sensitivity and enhanced impulsivity and risk-taking. In adults, these behavioral features are linked with a tendency to approach and interact with reward-associated cues - a behavior known as sign tracking - which is thought to reflect the transfer of incentive salience from reward to cue. Counterintuitively, adolescents are less likely to exhibit sign tracking, compared with adults, and more likely to exhibit goal tracking, or approach to the site of reward. To investigate a possible neural basis for this age difference, we recorded the activity of individual neurons in the nucleus accumbens (NAc) of male and female rats during Pavlovian conditioning in adolescence and adulthood. In a separate group, we used a fluorescent indicator (GRABDA) to measure dopamine release at the same ages. We found that cue-evoked NAc activity increased over the course of training in adolescents and then further in adulthood. The majority of adolescents were goal trackers or intermediates, for whom reward-evoked activity peaked during adolescence and declines in adulthood, correlating with increased prevalence and intensity of sign tracking. Meanwhile, cue-evoked dopamine release was markedly higher in sign trackers than in goal trackers at all time points. These results suggest that the progression from adolescence to adulthood may be accompanied by changes in the engagement of the mesolimbic dopamine system and/or the responsivity of NAc neural signaling to dopamine, contributing to limited sensitivity to reward cues, coupled with heightened sensitivity to primary rewards, in adolescent animals. Significance StatementAdolescence is a time of enhanced reward sensitivity, impulsivity, and risk-taking, making adolescents vulnerable to drug use and other risky behaviors. In adults, attraction to reward-associated cues - which can be modeled in animals using a behavior called sign tracking - plays an important role in risky behaviors. Surprisingly, we find that adolescents exhibit less sign tracking compared with adults. Here, we investigate the neural circuits underlying this age difference by monitoring neural activity and dopamine release in the nucleus accumbens (NAc), a key brain area for reward-seeking behavior, in the same animals as adolescents and as adults. We find that the majority of adolescents show a reduced neural sensitivity to reward cues, but a heightened neural response to the reward itself.

neuroscience↗

bioRxiv2026

The effects of breeding timing, clutch size, and nesting strategy on reproductive success in the crested ibis (Nipponia nippon)

O_LIStudying the reproduction process, which is a key determinant of individual and population fitness in endangered species, is challenging but urgently needed. The crested ibis (Nipponia nippon), a flagship endangered species recovering from an extreme population bottleneck, provides a valuable opportunity to examine how life-history strategies shape reproductive success and inform future conservation practices. C_LIO_LIWe monitored 176 breeding pairs of crested ibis over three consecutive breeding seasons and investigated the effects of three key life-history traits, namely breeding timing, clutch size, and nesting strategy (solitary versus colonial), on reproductive success (hatching and fledging success). C_LIO_LIOur analysis found that both hatching and fledging success declined significantly as breeding initiated later, and a positive association between clutch size and reproductive success in this species. These patterns were robust and repeatable across three years. Unlike other closely related species in this family, sibling competition is generally non-lethal, leading to large clutch sizes fledged in this endangered species. We consider this pattern to be a main reason underlying the rapid population recovery observed in the crested ibis. On the other hand, nesting strategy (colonial vs. solitary breeding) had no detectable effect on reproductive success. This pattern indicates the crested ibis can adopt different breeding strategies across habitats, highlighting its capacity to flexibly adjust breeding behavior in response to local environmental conditions. C_LIO_LIOur results provide an integrative assessment of how key life-history traits shape reproductive outcomes in a wild population of the crested ibis, serving as a foundation for evaluating its current status of population recovery and refining future conservation strategies for endangered avian species sharing similar life-history characteristics. C_LI

zoology↗

bioRxiv2026

Gn1a rice promotes symbiotic fish growth via reprogramming soil microbiome

Rice-fish symbiotic ecosystems significantly contribute to world food supply. Mutation in rice (Oryza sativa) quantitative trait locus Gn1a, encoding a cytokinin oxidase/dehydrogenase (OsCKX2), leads to cytokinin accumulation in plant, which promotes tillering and panicle branching to achieved higher yield and also shows a selective effect on soil microbial composition. Given that the growth of aquatic animals can be shaped by their surrounding microbial communities, we asked whether adjusting rice cytokinin levels might synergistically boosts both rice yield and fish growth. Herein, we co-cultured common carp (Cyprinus carpio) with ckx2 rice plants to determine the effect of cytokinins on fish. Surprisingly, compared to wild-type plants, the ckx2 plants enhanced nearly 10% fish growth and improved fish antibacterial capacity against Aeromonas hydrophila and Edwardsiella tarda. In fact, the growth-promoting effect on fish requires mediation by the soil microbiota. Mechanistically, ckx2 plants secreted more cytokinins into soil to reprogram the microbial composition, which subsequently translocated to fish gut and modulated the keystone microbes in gut to facilitate short-chain fatty acid production and carbohydrate degradation. These findings provide the first evidence that rice-derived cytokinins exert a cross-kingdom growth-promoting effect on fish, providing a boosting dual-production strategy for advancing rice-fish symbiotic ecosystem.

plant biology↗

bioRxiv2025

A novel dephosphorylation peptide inhibits 17β-HSD1 enzyme activity in ovarian granulosa cells and breast cancer cells

Estradiol (E2), a pivotal mammalian reproductive hormone, is closely associated with estrogen-dependent diseases. 17{beta}-hydroxysteroid dehydrogenase type 1 (17{beta}-HSD1), a critical E2 synthesis enzyme, has been understudied for its post-translational regulation-despite its potential as a therapeutic target, no clinically approved inhibitors are currently available. In our investigation of porcine follicular atresia mechanisms, we identified five differentially phosphorylated residues in 17{beta}-HSD1. Using in vitro site-directed mutagenesis and transgenic mouse models carrying point mutations, we established that Ser30 and Ser274 are critical phosphorylation sites that robustly modulate 17{beta}-HSD1 enzymatic activity. We further demonstrated that activin A and insulin-like growth factor 1 (IGF-1) enhance 17{beta}-HSD1 activity by promoting its phosphorylation at these two sites. To target these regulatory residues, we designed and synthesized cell-penetrating peptides (CPPs) that specifically suppress 17{beta}-HSD1 phosphorylation. Functional assays conclusively demonstrated that these CPPs significantly suppressed 17{beta}-HSD1 activity in vitro. Notably, they also inhibited the proliferation, migration and invasion of MCF-7 cells, as well as tumor growth in a mouse model of breast cancer. Our study provides novel mechanistic insights into the regulation of 17{beta}-HSD1 and E2 synthesis, addressing a critical gap in steroid hormone biology. The identification of Ser30/Ser274 as functional phosphorylation sites and the development of CPP-based inhibitors offer both theoretical advances and translational potential, opening new avenues for the treatment of estrogen-dependent breast cancer.

cell biology↗

bioRxiv2025

mMap: a comprehensive and continuously updated species distribution database facilitating the understanding of mosquito diversity and distribution patterns

Mosquitoes, as vectors of deadly diseases like malaria and dengue, exhibit complex and dynamic global distribution patterns influenced by climate change and human activity. However, gaps in species-level data and biases in existing databases hinder accurate risk assessments. Here, we present mMap (v1.01), a comprehensive and curated mosquito distribution database integrating multi-source records from literature (36,242 entries across 1,809 studies), museum collections, and field reports in 6 languages. Systematic data harmonization and validation workflows address taxonomic and spatial uncertainties, enabling family-level analyses previously constrained by fragmented data. Our results reveal significant range expansions for 28 invasive species (e.g., Aedes albopictus in Europe) and corrections to historical distributions (e.g., Ae. vexans in 22 new countries). The interactive mMap platform (accessible at https://mos-map.vercel.app/) provides open-access tools for visualizing spatial-temporal trends, automated SDM forecasting, and expert-curated species profiles. By unifying dispersed data into a scalable framework, mMap advances research on mosquito biodiversity, invasion ecology, and disease risk mapping, offering a critical resource for global health strategies in an era of rapid environmental change.

ecology↗

bioRxiv2025

Fast Loading and Transformation of Large-Volume Bioimaging Data Consistently Approaching the I/O Peak Speed

High-resolution large-volume biological imaging techniques are now widely used in biological research, but inefficiencies in data processing and visualization persist due to bottlenecks in loading/saving pipelines and limitations of conventional pyramid formats. To address these issues, we have decoupled data loading process into reading from disk and in-memory decompression, while data saving has been separated into in-memory compression and writing to disk. This approach allows us to dedicate more CPU cores to decompression and compression tasks, optimizing resource allocation and maximizing disk I/O throughput. As a result, both loading and saving processes operate near the disks peak data transfer capacity. Further, we integrated a video stream-inspired format into the pyramid structure, allowing direct access to regions of interest (ROIs) without loading extraneous data into RAM, reducing memory overhead. Compared to the latest methods, our approach improves pyramid data transformation efficiency by at least 6x and dramatically accelerates downstream tasks like visualization and deep learning inference. TeaserNovel bioimaging data processing pipeline achieves near-peak I/O throughput via decoupled architecture and video-formatting.

bioinformatics↗

bioRxiv2025

Evaluate and simulate the reproduction and survival of a reintroduced population in an endangered bird species Crested ibis (Nipponia nippon)

O_LIReintroduction programs are critical for restoring endangered species. However, scientific assessments and management recommendations based on comprehensive vital rates across the entire life cycle remain limited for such programs. The Crested ibis (Nipponia nippon), once nearly extinct, has been the focus of intensive conservation efforts, including reintroduction into its historical range. Here, we systematically evaluate the success of a Crested ibis reintroduction population by integrating long-term field monitoring with population dynamic modeling. C_LIO_LIWe conducted a systematic, multi-year (2023-2025) demographic study of a reintroduced Crested ibis population in Dongzhai National Nature Reserve, China. From 2013 to 2023, a total of 133 captive Crested ibises were released in seven batches within the nature reserve. By 2025, the wild population had exceeded 500. Based on the combination of field monitoring (n = 176 pairs) and GPS telemetry (n = 74 GPS tags, the longest monitoring time lasting 4 years), we quantified reproductive output and mortality rates across six life stages: nest building, incubation, offspring provisioning, fledgling (< 1 year), sub-adult (1-2 years), and adult (> 2 years). C_LIO_LIThe results show that the average clutch size of this population is 3.24 {+/-} 0.08, and each pair of parent birds can rear 1.31 {+/-} 0.12 nestlings to fledging each year. We found that high mortality during the incubation (32.5%, n = 425 eggs), offspring provisioning (34.1%, n = 287 chicks), and fledgling stages (38.6%, n = 63 birds). Key causes included unfertilized eggs, predation, starvation, and human disturbance. On the other hand, the mortalities in the nest building (9.1%, n = 176 pairs), sub-adult (9.8%, n = 28 birds) and adult stage (21.3%, n = 15 birds) were relatively low. Stage-structured matrix model shows a positive population growth of this reintroduced population (growth rate {lambda} = 1.053), with the population expected to increase 13-fold over 50 years (6,858 individuals). Sensitivity analysis indicates that adult survival had the strongest influence on population growth. Correspondingly, we predict that by 2075, its distribution range will expand 13-fold in tandem with population growth, exceeding 51,000 km{superscript 2} and covering several surrounding cities. C_LIO_LIOur comprehensive monitoring, evaluation, and simulation across the full life-cycle confirm that the reintroduced population is successfully established and self-sustaining. This finding addresses a critical research gap: the lack of a scientific and systematic framework for assessing population reintroductions in endangered species. Furthermore, we identified key conservation practices to enhance population growth and stability, including predator control, supplemental feeding, the rescue of weak chicks, and reducing human disturbance through public engagement. To ensure long-term viability, we also recommend implementing genetic management to avoid inbreeding. The resulting framework provides a practical model for improving reintroduction success and promoting species recovery in other endangered species. C_LI

ecology↗

bioRxiv2025

Candling analysis of egg development in an endangered bird species Crested ibis (Nipponia nippon)

Identifying key factors influencing the survival of animals, particularly rare and endangered species is crucial to biodiversity conservation. In birds, hatching failure is pronounced in endangered species. Accurate assessment of egg development and the ability to distinguish non-viable eggs are essential prerequisites for identifying the causes of hatching failure and applying appropriate conservation practices. The Crested ibis (Nipponia nippon), a flagship endangered species, has a long history of captive breeding, which has contributed to population recovery. However, little is known about the specific process and characteristics of its egg development. In this study, we provided the first comprehensive description of normal egg development in the Crested ibis, including both the changes observed in unfertilized eggs during incubation and embryonic development via candling (n = 106 eggs, with 1,423 candling images), a commonly used non-invasive method for assessing egg fertility and embryonic status, and offered a practical reference for assessing fertilization status and embryo viability. In addition, we estimated the timing of embryo mortality and found that most deaths occurred during mid-incubation (Day 7[~]15) (n = 12, 60.0%) and shortly before hatching (Day 23[~]29) (n = 7, 35.0%), highlighting these critical periods that require particular attention. This species-specific documentation of egg development provides a valuable reference for accurately assessing embryonic progress, evaluating environmental effects on survival, and guiding adaptive management, benefiting both captive breeding programs and field conservation efforts.

zoology↗

bioRxiv2025

Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics

Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathways affected by mtDNA-CN variation, we perturbed HEK 293T cells with ethidium bromide to deplete mtDNA. Using RNASeq and methylation microarrays, we evaluated transcriptomic and methylomic changes in treated cell lines. We observed an 8-fold decrease in mtDNA-CN and compensatory shifts in mitochondrial transcription to support mtDNA replication. Nuclear transcriptomic and methylomic analysis highlighted changes in metabolic pathways, including oxidative phosphorylation and canonical glycolysis. Longitudinal analyses revealed that the identified genes and pathways have different response timing, with nuclear response lagging behind mitochondrial response. These findings further elucidate the mechanisms behind mtDNA maintenance and responses to cellular energetics as well as mitochondrial-nuclear crosstalk dynamics.

genetics↗

bioRxiv2025

RNA viruses in water shape the viromes of shrimp and fish in aquaculture systems

Aquatic environments host immense RNA viral diversity, yet the extent to which waterborne viruses influence the virome of aquatic animals remains unclear. Here, we conducted a comprehensive longitudinal metatranscriptomic analysis of water, shrimp, and fish across multiple culture stages in aquaculture systems. We identified 3,211 RNA viruses spanning 21 viral supergroups, with 97.4% representing novel species. Water exhibited the greatest viral diversity (3,093 species), followed by shrimp (1,280) and fish (398), with most viruses detected in shrimp and fish also detected in water. Diversity analyses revealed increasing richness and significant compositional shifts in 92 high-abundance viruses (>1,000 RPM) across culture stages. Viral abundance in aquatic animals was strongly correlated with that in water, and the temporal trajectories of the 16 most abundant viruses were closely synchronized between water and shrimp. Furthermore, 337 virus species were shared among shrimp and two fish species, of which 309 were present in water. These findings demonstrated that RNA viruses in water shape the composition and dynamics of aquatic animal viromes, underscoring the importance of water virome surveillance and management for disease prevention in shrimp aquaculture.

microbiology↗

bioRxiv2025

An Implementation Intention Combining Reappraisal and Anger Counteraction Reduces Fear Reinstatement

Fear extinction requires exposure to the conditioned stimulus (CS), yet patients with fear- and anxiety-related disorders often avoid the CS, thereby undermining extinction learning. Implementation intention (II) is a self-regulation strategy that automates goal-directed behavior through "if-then" planning. Building on the approach motivation elicited by anger and the principle of emotion-action incompatibility, we designed a novel II: "If I feel afraid when seeing fish/bird images (the CSs), then I will remind myself that it is foolish to fear a mere picture, and I will clench my fists and feel angry with myself." This strategy aims to transform fear-driven avoidance into self-directed anger, thereby promoting reappraisal and approach behavior. In a three-day differential fear conditioning paradigm, participants who practiced this II during extinction exhibited shorter avoidance distances to the CS+ than the standard-extinction control group. On Day 3, reinstatement testing revealed significantly lower subjective fear, anger, threat expectancy, and avoidance in the II group. These findings suggest that the combined reappraisal-plus-anger II requires practice during extinction to effectively reduce fear return without inducing overt aggression, offering a promising direction for optimizing exposure-based therapies.

animal behavior and cognition↗

bioRxiv2025

Adaptive mutations at lysine residues of PRRSV nsp12 enable evasion of host proteasomal and selective autophagic degradation

Ubiquitin signaling in viral infections can either enhance immune responses and degrade viral proteins or be exploited by viruses to target host antiviral factors. Porcine reproductive and respiratory syndrome virus (PRRSV) poses a significant threat to the pig industry, with its non-structural proteins (nsps) critical for virulence and replication. Here, we investigated the role of ubiquitination in the stability of PRRSV-encoded nsps and found that nsp12 was specifically degraded via the ubiquitin-proteasome system. Mechanistically, nsp12 underwent K48- and K63-linked polyubiquitination at lysine residues 89, 91, 127, and 130. RNF114 served as an E3 ubiquitin ligase for nsp12, with its enzymatic activity essential for both nsp12 degradation and viral replication. Additionally, nsp12 underwent ubiquitin-dependent selective autophagy through receptor-mediated recognition, wherein NBR1, SQSTM1, and NDP52 bridged its interaction with LC3 for autophagic degradation. Evolutionary analyses revealed that PRRSV nsp12 acquired non-lysine residues at positions 89, 127, and 130 during viral adaptation. Correspondingly, recombinant PRRSV strains carrying the K91/127/130R mutations within nsp12 exhibited enhanced replication, while a revertant strain with the R89K mutation in nsp12 showed attenuated infectivity. Mass spectrometry analysis further identified significant enrichment of ubiquitination-related modifications among nsp12-interacting proteins. These findings provide valuable insights for anti-PRRSV drug design and highlight the challenge posed by adaptive mutations in viral proteins to the swine industry. Author SummaryUbiquitination plays crucial roles in both proteasomal degradation and selective autophagy during viral infections, yet its impact on the stability of porcine reproductive and respiratory syndrome virus (PRRSV) nonstructural proteins (nsps) remains unexplored. Here, we found that nsp12 was targeted for proteasomal degradation through K48/K63-linked polyubiquitination at lysine residues 89, 91, 127, and 130, which requires the involvement of E3 ubiquitin ligase RNF114. Furthermore, nsp12 underwent receptor-mediated selective autophagic degradation through the action of NBR1, SQSTM1, and NDP52. Using reverse genetics technology, mutations of lysine to arginine in PRRSV nsp12 enhanced viral replication, whereas the reverse mutations reduced its infectivity. Our findings demonstrate that PRRSV evades host degradation by acquiring adaptive mutations within nsp12, which counteract ubiquitin-dependent clearance thus enhancing viral fitness. This novel mechanism illustrates a key viral immune evasion strategy and underlines the challenge in controlling PRRSV.

microbiology↗

bioRxiv2025

Hypobaric hypoxia drives citrate cycle reprogramming to suppress tumor progression

High altitude residents present lower tumor incidence and mortality than plain residents, suggesting that hypobaric hypoxia displays protective effect against tumor development. The results of our studies showed that hypobaric hypoxia exposure significantly suppressed tumor progression in subcutaneous bearing and lung metastasis tumor models. With single-cell transcriptome analysis, we identified HIF-1 pathway was significantly downregulated in tumor tissues with high altitude hypoxia, leading to decreased glycolysis and angiogenesis and improved antitumor immune response. Mechanistically, systemic hypoxia rewired citric acid cycle, with enhanced CS and IDH2 expression and reduced OGDH and SUCLG2 expression, to induce -ketoglutarate accumulation and succinate decline in tumor microenvironment, further mediating HIF-1 pathway inhibition. Moreover, hypobaric hypoxia treatment significantly improved the antitumor effects of adjuvant therapies (including chemotherapy, anti-angiogenic therapy and immunotherapy). Our findings reveal the role and mechanism of hypobaric hypoxia for tumor regression and yield new insights into tumor therapy.

cancer biology↗

bioRxiv2025

Commensal taxa in gut microbiota limit antibiotic resistance during extended oral antibiotic use

Certain bacterial infections, such as those involving prosthetics, can require antimicrobial therapy over months to years, potentially increasing the burden of antimicrobial resistance. Here we longitudinally track the antimicrobial resistome in mice during continuous antibiotic dosing over 21 months. The burden of antibiotic resistance genes (ARGs) initially increases, but, surprisingly, declines in later months, approaching levels observed in untreated animals. ARG burden is regulated by taxonomy and declines as ARG-harboring taxa that initially bloom are replaced by commensals. Furthermore, we find that the dynamics of antibiotic-induced ARG burden are influenced by age-related differences in microbial taxonomy and can be removed by fecal microbiota transplantation. We show that commensals may regulate the resistome by limiting the growth of ARG-harboring taxa, thereby providing antimicrobial expansion resistance.

microbiology↗