Science China Life Sciences最新文献

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy worldwide with limited therapeutic options. Emerging evidence implicates intratumoral bacteria in ESCC pathogenesis. Here, we identified enriched levels of the Gram-positive bacterium Streptococcus mitis (S. mitis) in ESCC patient tumor tissues, which facilitated ESCC progression both in vitro and in vivo. Mechanistically, mitilysin (MLY), a virulence factor secreted by S. mitis, interacted with zinc finger protein 460 (ZNF460) and promoted its proteasomal degradation. Downregulation of this transcription factor suppressed the transcription of circular RNA circAAGAB, subsequently activating the miR-671-5p/GAS7c and PABP1/TNFAIP2 pathways to enhance ESCC cell proliferation and metastasis. Furthermore, we developed an S. mitis-targeted, mesoporous silica nanoparticle (MSN)-based drug delivery system, in which the MSN surface was decorated with an antibody against lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria (LTA-MSNs). When loaded with penicillin, circAAGAB, or both, LTA-MSNs precisely targeted intratumoral S. mitis in ESCC patient-derived xenograft (PDX) models, demonstrating potent tumor-suppressive efficacy. Collectively, our findings reveal that intratumoral S. mitis critically drives ESCC tumorigenesis and represents a promising therapeutic target.

Climate change has intensified the frequency and severity of urban droughts, exposing urban green spaces to abrupt and extreme water shortage that disrupts plant-microbe interactions and microbial multifunctionality. Understanding how rhizosphere and phyllosphere microbial communities respond to drought and how these shifts influence urban microbial functions is crucial for developing strategies to enhance the resilience of urban ecosystems under climate change. In this study, we conducted microcosm experiments simulating four drought intensities, integrating omics technologies with soil enzyme stoichiometry to investigate the effects of drought on microbial communities associated with Zoysia japonica (Steud) and urban microbial multifunctionality. Our results demonstrate that drought intensities significantly altered the compositions of bacterial and fungal communities in both the rhizosphere and phyllosphere. Moreover, drought enhanced microbial multifunctionality by significantly affecting 21 microbial functional potentials, including carbon fixation and denitrification. Although urban microbial multifunctionality largely returned to the control level after rehydration, five functions remained altered, including phyllosphere organic nitrogen mineralization and soil polyphenol oxidase activity. Biotic factors, particularly rhizosphere bacteria and fungi, directly influenced microbial multifunctionality during drought, whereas abiotic factors, such as electrical conductivity, dissolved organic carbon, and ammonium-nitrogen (NH₄⁺-N), had indirect effects. After rehydration, abiotic factors, especially pH and NH₄⁺-N, emerged as the main direct drivers. These findings underscore a shift from biotic to abiotic regulation of urban microbial multi-functionality across drought and rehydration, emphasizing the vital role of microbial communities in ecosystem resilience and the need to consider both biotic and abiotic factors in urban drought management.

The co-occurrence of KPC and NDM carbapenemases in Gram-negative bacteria presents a serious and expanding global health threat. This study characterized 338 KPC-2/NDM-1 dual-positive isolates from 23 countries, including 41 clinical strains sequenced through hybrid second- and third-generation platforms from China's national surveillance network. These isolates spanned six genera, 58 species, and 138 sequence types, reflecting substantial taxonomic and geographic diversity. Molecular analysis identified IncFII(p14) plasmids as the principal vectors for cross-genus dissemination of KPC-2, while IncX3, IncN, and IncFIB(pB171)/IncFII(Yp) plasmids were dominant carriers of NDM-1 among the studied strains. Codon usage analysis indicated stronger bias in KPC-2 plasmids (effective codon number: 39.17, optimal codons: 17) compared to NDM-1 plasmids (effective codon number: 41.25, optimal codons: 12), indicating differential evolutionary pressures. Dual-positive strains exhibited significantly higher virulence scores and broader resistance profiles than reference strains (P<0.001). Notably, only 14.6% of isolates harbored Type I-E CRISPR-Cas systems, all of which encoded the anti-CRISPR protein AcrIE10. Furthermore, Type II methyltransferase numbers were significantly enriched in dual-positive strains (P<0.005), suggesting a potential role in modulating host defense evasion. We propose that in Klebsiella spp., KPC-2 plasmids are typically acquired prior to NDM-1 plasmids and can form hybrid plasmids. In non-Klebsiella genera, dual resistance is primarily driven by independent acquisition of high-risk plasmids such as IncFII(p14) and IncX3, without a fixed temporal order. These findings highlight the convergence of global plasmid-mediated resistance, host-pathogen immune interplay, and pan-resistance evolution. Targeting high-risk plasmid lineages and host defense-modulating elements may be key to forecasting resistance emergence and guiding early interventions against dual-carbapenemase-producing pathogens.

Hypoxia is associated with systemic inflammation and oxidative stress, both of which contribute to sepsis development, yet whether impaired lung function is associated with a higher sepsis risk remains unclear. Leveraging data from 312,805 UK Biobank participants, we assessed baseline lung function as percentages of predicted forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), and defined normal lung function as FEV₁⩾80% predicted and an FEV₁/FVC ratio ⩾ 0.70. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of sepsis incidence and sepsis-related mortality in relation to different measures of lung function. Stratified, sensitivity, and mediation analyses were conducted to assess potential effect modifications, result robustness, and mediation effect, respectively. During a median follow-up of 13.7 years, 8,906 incident cases of sepsis and 1,664 cases of 28-day mortality following sepsis occurred. In the multivariable-adjusted model, compared with the highest quartile, the lowest quartile of FVC% predicted or FEV₁% predicted was associated with an increased risk of sepsis and sepsis-related mortality (FVC% predicted: sepsis incidence, HR=1.35, 95% CI: 1.27-1.43, 28-day mortality following sepsis, HR=1.49, 95% CI: 1.29-1.72; FEV₁% predicted: sepsis incidence, HR=1.42, 95% CI: 1.34-1.52, 28-day mortality following sepsis, HR=1.75, 95% CI: 1.51-2.02; all P_trend<0.001). Similarly, compared with individuals with normal lung function, those with impaired lung function had a higher risk of sepsis and sepsis-related mortality (sepsis incidence: HR=1.33, 95% CI: 1.27-1.39; 28-day mortality following sepsis: HR=1.57, 95% CI: 1.42-1.73; both P-values<0.001). These associations remained consistent across stratified and sensitivity analyses. Mediation analyses revealed that inflammatory biomarkers, such as C-reactive protein (CRP), accounted for 1.2%-16.3% of the associations. Collectively, these findings demonstrate that lung function impairment is associated with an increased risk of sepsis and sepsis-related mortality, and these associations are partially mediated through inflammatory responses.

Elevated lactate levels are a hallmark of severe infections and are associated with poor outcomes in sepsis patients, but the underlying mechanisms remain poorly understood. Recent findings have shown that lactate can covalently modify histones (e.g., histone lactylation) in macrophages, acting as a critical epigenetic regulator of inflammatory response. Here, we demonstrate that histone lactylation also occurs in neutrophils-the first immune cells mobilized during acute inflammation-and is functionally important for their activation. Using both DMSO-differentiated HL-60 (dHL-60) cells and primary neutrophils, we found that LPS stimulation significantly increased intracellular lactate levels and histone lactylation, particularly at the H4K8 site. These changes enhanced cytokine release, ROS production, and chemotaxis. Lactate further amplified these effects, while inhibition of glycolysis or p300 suppressed them. Multi-omics analyses revealed substantial enrichment of H4K8la at the promoter region of WTAP, a key m⁶A methyltransferase component, promoting its expression via CEBP/β recruitment. WTAP knockdown significantly reduced m⁶A modifications of TLR2 mRNA and impaired its stability. Both WTAP knockdown and TLR2 inhibition markedly dampened the inflammatory responses. Importantly, this glycolysis-H4K8la-WTAP-TLR2 axis was further validated in LPS-induced septic mice and pediatric sepsis patients, highlighting its clinical relevance. In summary, our findings uncover a novel lactate-driven epigenetic-post-transcriptional regulatory circuit that amplifies neutrophil inflammatory responses, expanding the regulatory framework of innate immunity and providing potential therapeutic targets for hyperinflammation.

Currently, targeting the Wnt/β-catenin pathway to promote bone formation is a primary strategy for the development of osteoporosis drugs. Here, we demonstrate that vinculin promotes bone mass increase and fracture repair by elevating the β-catenin protein levels in mesenchymal stem cells (MSCs). Furthermore, it is revealed that vinculin is required for sclerostin-neutralizing antibody (Scl-Ab) to increase the bone mass in mice. We find that promoter accessibility and the expression of the Vcl gene, which encodes vinculin, are reduced in the MSCs from elderly human individuals, and vinculin knockdown impairs osteoblast differentiation in vitro. Genetic deletion of Vcl in Prx1-expressing cells in mice leads to pronounced bone loss in weight-bearing long bones, but not in the non-weight-bearing skull, primarily attributed to severely impaired bone formation, characterized by reduced osteoblastic and increased adipogenic differentiation. Unexpectedly, vinculin loss decreases the β-catenin protein levels by approximately 80% in MSCs in vitro and in the bone. Mechanistically, β-catenin and blocks GSK-3 phosphorylation and the subsequent ubiquitin-proteasomal degradation of β-catenin, thereby stabilizing β-catenin. Thus, mutating the β-catenin GSK-3 phosphorylation sites abolishes the ability of vinculin deficiency to destabilize β-catenin, and the pharmacological inhibition of GSK-3 activity restores the bone loss induced by vinculin ablation in mice. Furthermore, deleting vinculin expression in chondrocytes impairs bone fracture healing, while a hydrogel containing MSCs overexpressing vinculin in mice promotes fracture healing. Importantly, vinculin loss abolishes the ability of sclerostin-neutralizing antibody Scl-Ab, a current primary anti-osteoporotic treatment, to increase bone mass in mice. Thus, we demonstrate that the vinculin-β-catenin axis in MSCs promotes bone formation and fracture healing and is essential for the effectiveness of current osteoporosis drugs.

Retinoblastoma (RB) is the most common pediatric intraocular malignancy and seriously threatens vision and survival if not treated early. However, effective targeted therapies remain unavailable owing to the lack of well-defined molecular targets beyond RB1 gene mutations. There is a critical need to identify novel therapeutic targets. Through transcriptomic analysis of four RB-related datasets (GSE125903, GSE110811, GSE97508, and GSE24673) from the Gene Expression Omnibus (GEO) database, we identified proline-rich 11 (PRR11) as a significantly overexpressed gene in RB. Single-cell transcriptomic analysis revealed that PRR11 exhibits heterogeneous expression in different RB cell types, at particularly high levels in tumor-related populations such as cone precursor-like cells and MKI67⁺ photo-receptorness-decreased cells. Functional studies demonstrated that PRR11 promotes RB cell proliferation and tumor growth both in vitro and in vivo. Coimmunoprecipitation mass spectrometry (co-IP/MS) revealed that OTUB1, a deubiquitinase, interacts with and stabilizes PRR11, sustaining its high expression in RB cells. The proteomic analysis further revealed that Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is a downstream adaptor downregulated by PRR11. Suppression of DKK3 by PRR11 leads to aberrant activation of the Wnt/β-catenin signaling pathway, thereby upregulating cyclin D1 and promoting S/G2M cell cycle progression. These findings establish PRR11 as an oncogenic driver in RB and highlight the OTUB1-PRR11-DKK3 axis as a regulatory mechanism of Wnt/β-catenin signaling in RB tumorigenesis. Targeting PRR11 and its downstream pathways provides a potential and novel therapeutic strategy for RB treatment.