Bridged frameworks are widely recognized as privileged motifs in natural products and pharmaceuticals, and their distinctive three-dimensional architectures often underpin target recognition and bioactivity. However, their preparation remains a formidable challenge, with most strategies relying on either linear multi-step syntheses or structurally specialized substrates. Here we report a bridged scaffold editing strategy for heterocycles and carbocycles, which employs formaldehyde and ureas in a distinct multicomponent reaction, toward modular and efficient construction of diverse bridged polycycles. Notably, this protocol enables concurrent C(sp²)-H and unactivated C(sp³)-H functionalization, for directly assembling bridged polycyclic products from planar or quasi-planar cyclic substrates through regio- and diastereoselective multiple bond formations. Experimental and computational studies collectively elucidate the plausible reaction pathways underlying these transformations. By offering rapid and general access to three-dimensional polycyclic skeletons, this approach expands the molecular editing toolbox and provides a versatile platform for generating structurally unique compounds with potential applications in drug discovery.

Serrodes campana (Lepidoptera: Noctuidae) is an economically important moth distributed in subtropical and tropical Asia, but genomic resources for this species have been lacking. Here, we present a chromosome-level reference genome assembly for S. campana generated using PacBio HiFi long reads, Illumina short reads, Hi-C sequencing, and transcriptomic data from 12 RNA-seq samples. The final assembly spans 627.9 Mb, with a contig N50 of 21.4 Mb and a scaffold N50 of 21.6 Mb, and 99.29% of the assembled sequences were anchored to 31 pseudochromosomes. BUSCO assessment recovered 99.56% complete insect genes, supporting the high completeness of the assembly. We predicted 16,047 protein-coding genes, of which 96.65% were functionally annotated, and identified repetitive elements accounting for 33.79% of the genome. This genome assembly and associated annotation resources provide a foundation for gene annotation, comparative genomics, genome evolution studies, and investigations of host-associated biology in S. campana and related moth species.

Serrodes campana is an erebid moth of ecological and forestry relevance; its larvae are mainly associated with the soapberry tree, Sapindus mukorossi, whereas adults exhibit fruit-piercing behavior. However, stage- and tissue-resolved transcriptomic resources for this species remain limited. Here, using a chromosome-level reference genome, we performed a genome-guided transcriptome analysis of S. campana based on 12 RNA-seq libraries representing major developmental stages and key adult tissues. Global transcriptomic analyses revealed pronounced transcriptional differentiation across developmental stages and tissue types. Tissue-enriched gene sets and functional enrichment analyses identified distinct molecular signatures associated with developmental, sensory, and pheromone-associated tissues. Comparative analysis of female and male antennae further revealed sex-biased expression of several candidate chemosensory-related genes. Among 153 curated chemosensory-related candidate genes, most odorant receptor genes showed strong antennal enrichment, whereas other major chemosensory gene families displayed broader but still tissue-preferential expression patterns. In addition, an exploratory comparison of female terminal abdominal gland tissue and male terminal abdominal coremata revealed divergent expression profiles and highlighted candidate genes potentially associated with pheromone-related physiology, reproduction, and tissue-specific signaling. Together, this study provides the first genome-guided stage- and tissue-resolved transcriptomic resource for S. campana and offers a useful foundation for future studies of chemosensory detection, sex-biased gene expression, and pheromone-associated biology in this species.

Aging is a primary risk factor for chronic diseases, yet its progression varies among individuals and between sexes. Here, under the X-Age Project, we profiled the clinical aging phenome of the Multicentric Chinese Aging Study (mCAS) through a cross-sectional analysis of 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers. These profiles enabled sex-specific clinical aging clocks that revealed divergent aging trajectories between women and men during midlife that converged in later life. Phenome-wide analyses revealed age-related accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, such as carcinoembryonic antigen and human epithelial protein 4. These age-accumulating factors induced senescence-related phenotypes in human endothelial cells. Furthermore, a high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging. Together, this work establishes metabolic and tumor marker accumulation as actionable drivers of human aging, paving the way for personalized, sex-stratified geroprotective interventions.

Abstract Fruit ripening and softening is primarily driven by fluctuations in hormone levels, which induce changes in cell turgor, adhesion, and cell wall remodeling. Although extensive research has examined the role of ethylene in promoting pear fruit ripening and softening, the molecular mechanisms underlying ethylene biosynthesis in pears (Pyrus L.) remain insufficiently understood, and the regulatory interactions between ethylene signal transduction and ethylene biosynthesis have yet to be fully elucidated. In this study, we characterize an ethylene-insensitive 3 (EIN3)/EIN3-Like transcription factor, PbrEIL1, which localizes to the nucleus and functions as a positive regulator of fruit ripening and softening by directly modulating ethylene biosynthesis. Transient transformation assays showed that overexpression of PbrEIL1 accelerated fruit ripening and softening in pear, whereas its silencing delayed these processes. Furthermore, PbrEIL1-overexpressing lines exhibited a significantly shorter ripening period and enhanced carotenoid accumulation compared with the wild type in the model plant tomato. The results of regulatory network analysis indicate that PbrEIL1 acts as a transcriptional activator that directly binds to the promoters of the ethylene biosynthesis genes PbrACS1 and PbrACS2, thereby activating their transcription. Moreover, overexpression of PbrACS1 and PbrACS2 also promoted ethylene production and accelerated pear fruit ripening and softening. In conclusion, the PbrEIL1–PbrACS1/2 module positively regulates pear fruit ripening and softening by controlling ethylene production, providing new insights into the regulatory mechanisms underlying these processes.

Human aging is characterized by complex structural and functional decline, but quantifying its heterogeneity and assessing biological age remain challenges. We present the mCAS (multicentric Chinese aging standardized cohort) developed from 2,019 Chinese individuals aged 18-91 years. Integrating high-dimensional clinical, physiological, and molecular-level data, we constructed a three-tiered aging framework: the core capacity clock (CC-clock) to quantify clinical physiological decline, the multimodal clock (MM-clock) with extensive parameter coverage and enhanced predictive precision, and organ-associated aging clocks. Cross-layer analysis demonstrates that plasma protein clocks not only capture chronological age but also serve as efficient proxies for systemic physiological capacity. Leveraging this framework for discovery, we identified the age-dependent accumulation of coagulation factors as a driver of multi-organ senescence and systemic inflammatory activation. This study provides a foundational framework that bridges molecular signatures with functional decline, identifies new biomarkers for aging assessment, and reveals a novel translational driver of aging.

soil detachment is a key variable of soil erosion model, it is strongly influenced on soil physicochemical properties and root characteristics driven by land-use. Therefore, identify the factors that influence soil detachment under different land-use type, and establish a predictive equation is highly important. Four representative land-use types (cropland, grassland, shrubland, woodland), including eight species on the Loess Plateau, were selected, and flume scouring tests were conducted under six shear stresses (4.54–16.06 Pa) to determine soil detachment. The results showed that soil detachment capacity of different species were 0.14–2.78 kg m−2 s−1, among which, Setaria italica var. germanica (Mill.) Schred (SU) and Pinus tabuliformis Carrie (YS) reported greatest and smallest values, respectively. Across various land-use types, cropland exhibited largest soil detachment capacity, increasing by 8.25, 2.03, and 3.22 folds compared with grassland, shrubland, and woodland, respectively. The transformation of land-use types inevitably induces alterations in soil properties and root characteristics, thereby exerting an influence on soil detachment processes. Soil detachment capacity decreased with an increase in soil bulk density, total porosity, water stable aggregate, root length density, and specific root length as power functions. Hydraulic parameters act as driving forces for soil detachment capacity, which increases with overland flow velocity, stream power, shear stress, and unit stream power as power functions. Finally, when soil properties, root characteristics and hydraulic are all considered, soil detachment capacity can be simulated by overland flow velocity (V), water stable aggregate (WSA), and specific root length (SRL) using power functions, with satisfactory model performance (R2 is 0.88, NSE is 0.76). These findings provide a scientific basis for targeted soil erosion control and rational land-use management on the Loess Plateau, offering actionable guidance for prioritizing vegetation restoration and optimizing land-use types in this region.

Sugar transporter proteins (STPs) are integral to sugar transport and distribution in plants, regulating key physiological processes such as growth, development, and responses to biotic and abiotic stresses. Despite pear’s economic importance in the world, the roles of STP family members in pear fruit remain largely unexplored. Here, we identified 19 STP genes in pear (Pyrus bretschneideri Rehd) and classified them into four phylogenetic groups (I–IV), all containing the conserved Sugar_tr domain. Transcriptome analysis showed that the expression peak of PbrSTP10 in the fruit flesh coincided with the period of rapid sugar accumulation. Promoter activity assays confirmed elevated transcription of PbrSTP10 at this stage. Functional complementation in a sugar uptake-deficient yeast strain and subcellular localization assays demonstrated that PbrSTP10 is a plasma membrane-localized transporter mediating proton-dependent fructose and glucose uptake. Further functional analyses indicated that overexpression of PbrSTP10 significantly increased the fructose and glucose contents in tomato fruits, pear fruits, and pear calli. Weighted gene co-expression network analysis (WGCNA) centered on PbrSTP10 identified several putative co-regulators of sugar accumulation. Collectively, these results provide valuable genetic resources and mechanistic insights for leveraging STPs to enhance pear fruit quality.

Immunosenescence drives organismal aging, yet quantifying its heterogeneity to uncover therapeutic targets remains challenging. We construct a human immune aging clock from single-cell multi-omics data of nearly 1.2 million human peripheral blood mononuclear cells from 230 individuals, precisely mapping immune aging. T cell (TC) transcriptomes are key predictors, revealing hallmarks such as naive cell loss and clonal contraction. This framework identifies the transcription factor RUNX1, whose expression declines with age in TCs, as a central regulator. Functional studies demonstrate that RUNX1 deletion in young TCs induces senescence, while its restoration in aged CD8+ TCs alleviates senescent phenotypes in vitro and in vivo. Our study provides a quantitative tool for assessing immunosenescence and nominates RUNX1 as a target for rejuvenating aged immunity.

In 2024, we identified and sequenced 52 avian influenza A (H9N2) virus strains in Laos. Using the established H9N2 genomic classification system, a novel HA gene clade of the A/chicken/Beijing/1/94-like (BJ/94-like) lineage, designated Clade 4.6.20, was identified. This new clade is phylogenetically distinct from the previously described clades, and the representative strains in this new Clade 4.6.20 presented a low cross reactivity to the antisera of other clades, suggesting antigenic drift of the viruses between the new Clade 4.6.20, and other clades in the dominant lineage of Clade 4.6. In addition, all the newly identified viruses in Clade 4.6.20 possessed HA-L226 and NP-N52 mutations, which are associated with human-type receptor binding and human MxA-related innate immunity escape, respectively. Our findings underscore the necessity of global surveillance network and cooperation to monitor the evolution of AIVs, update vaccine seed strains, and develop new vaccines with high effectiveness against H9N2 AIVs circulating globally, which threaten poultry and human health.

Long non-coding RNAs (lncRNAs) play essential roles in plant growth and development. However, their expression variability and contribution to phenotypic changes during the domestication of fruit crops remain unclear. Here, we generated approximately 3.5T of strand-specific RNA sequencing data from wild, landrace, and improved pear varieties and identified 12 422 lncRNAs that exhibited higher tissue specificity and lower sequence conservation than protein-coding genes. Roughly 74% of lncRNAs overlapped with transposable elements (TEs) and significantly impacted sequence diversity, expression variation, and tissue-specific expression. DNA methylation explained approximately 32% of the expression variation of lncRNAs across accessions. Selective sweeps revealed 857 and 519 lncRNAs under domestication and improvement, respectively. These selected lncRNAs were associated with traits such as fruit size, sugar content, and stone cell content. Metabolome profiling revealed a consistent reduction in lignin-related metabolites during pear domestication and improvement. Integrating transcriptome and metabolome analyses, we established a lncRNA-mRNA co-expression network associated with lignin biosynthesis. The regulatory role of lncRNA-pys within this network was functionally validated through transgenic experiments, demonstrating that overexpressing lncRNA-pys led to an increase in lignin content in pear. This study represents the first effort to unveil the contributions of lncRNAs under human selection to the domestication traits of fruit crops.

Red fruit flesh is a rare occurrence in pears (Pyrus spp.), yet it is an attractive trait as anthocyanin enrichment would add nutritional value and novelty for consumers. Previous research has focused on red-skinned phenotypes in pear fruit, but the potential regulatory mechanisms controlling red flesh remain unclear. Here, we identified the Homeodomain leucine zipper (HD-ZIP) family transcription factor PyHAT5 as a controlling factor using transcriptome analysis of pear fruit flesh at 3 different developmental stages in a hybrid population of red-fleshed and white-fleshed pears. The expression level of PyHAT5 was significantly negatively correlated (correlation coefficient of -0.94) with anthocyanin content in the flesh. Overexpression of PyHAT5 inhibited anthocyanin accumulation in pear tissues (skin and callus), peach (Prunus persica) flesh, and tobacco (Nicotiana tabacum) leaves, while virus-induced silencing of PyHAT5 promoted intense coloration of the pear skin. Further analysis found that PyHAT5 protein interacts with PyMYB10, thereby blocking the formation and transcriptional activity of the PyMYB10-PybHLH3 complex. Additionally, we identified through yeast 2-hybrid screening that an E3 ubiquitin ligase, PyAIP2, interacts with PyHAT5 and may promote its ubiquitination and degradation. Overexpression of PyAIP2 promoted anthocyanin biosynthesis in the pear skin, while knockdown of PyAIP2 had the opposite effect. Our findings reveal a regulatory module, PyAIP2-PyHAT5-PyMYB10, that plays a critical role in regulating anthocyanin biosynthesis in red-fleshed pear. These findings also advance our understanding of the regulation of anthocyanin biosynthesis in other tissues and provide genetic knowledge for advancing breeding in pear.

ABSTRACT Three‐dimensional (3D) chromatin architecture plays a fundamental role in eukaryotic gene regulations, its functional significance in perennial fruit trees remains poorly characterized despite extensive applications in crop genomics. Here, we developed high‐resolution (∼5 kb) Hi‐C maps of Pyrus and compared 3D genomic architecture of three representative pear species: the wild Asian pear ‘Duli’ (P. betuleafolia), the cultivated Asian pear ‘Dangshansuli’ (P. bretschneideri), and the cultivated European pear ‘Early red Doyene du Comice’ (P. communis). Approximately 78% of compartment and 73% of TAD‐like domains are conserved among the three species. Interspecific structural variation correlates with TAD‐like boundary repositioning, which is associated with altered expression levels of genes near these boundaries. The variations in TAD‐like boundaries among three species correlated with differentially expressed whole‐genome duplication (WGD) and single‐copy genes. Furthermore, integration of pear population data identified 234 domestication‐ and 3605 divergence‐associated genes near TAD‐like boundaries, which are enriched in cell development pathways. One candidate gene—PyYABBY, located in a different TAD‐like boundary between P. bretschneideri and P. communis, is confirmed to enhance leaf size. This study revealed 3D genomic divergence among three Pyrus species, demonstrating the functional and evolutionary roles of TAD‐like structures in genome organization, thereby providing insights for crop trait evolution research.

Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.

Pears (Pyrus spp.) are self-incompatible crops with broad genetic diversity. High heterozygosity and technical limitations result in gaps within reference genomes. Our study presents the telomere-to-telomere, haplotype-resolved genomes of a representative Asian pear 'Dangshansuli' (Pyrus bretschneideri) and a European pear 'Max Red Bartlett' (Pyrus communis). Haplotype-specific genes exhibited notable differences from biallelic genes regarding transposable content, methylation patterns and expression levels. Allele-specific expression analysis suggested that the dominance effect is vital in the formation of fruit quality of pears. Population analysis of 362 accessions revealed that interspecific introgression increased pear diversity. We constructed a graph-based genome and identified structural variations associated with agronomic traits. A 286-bp insertion in the promoter region, along with differential expression of PyACS1, was identified between Asian and European pears, which exhibit distinct fruit-softening characteristics. Further experiments demonstrated the role of PyACS1 in fruit softening. Overall, this study provided insights into genetic variation and will facilitate pear improvement.

Pyrus pyrifolia, commonly known as sand pear, is a key economic fruit tree in temperate regions that possesses highly diverse germplasm resources for pear quality improvement. However, research on the relationship between resistance and fruit quality traits in the breeding of fruit species like pear is limited. Pan-transcriptomes effectively capture genetic information from coding regions and reflect variations in gene expression between individuals. Here, we constructed a pan-transcriptome based on 506 samples from different tissues of sand pear, and explored the intrinsic relationships among phenotypes and the selection for disease resistance during improvement based on expression presence/absence variations (ePAVs). The pan-transcriptome in this study contains 156,744 transcripts, among which the novel transcripts showed significant enrichment in the defense response. Interestingly, disease resistance genes are highly expressed in landraces of pear but have been selected against during the improvement of this perennial tree species. We found that the genetically diverse landraces can be divided into two subgroups and inferred that they have undergone different dispersal processes. Through co-expression network analysis, we confirmed that the formation of stone cells in pears, the synthesis of fruit anthocyanins, and the ability to resist stress are interrelated. They are jointly regulated by several modules, and the expression of regulatory genes has significant correlations with these three processes. Moreover, we identified candidate genes such as HKL1 that may affect sugar content and are missing from the reference genome. This study provides insights into the associations between complex fruit traits, while providing a database resource for pear disease resistance and fruit quality breeding.

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age‐related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual’s physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions. In this Perspective, members of the Aging Biomarker Consortium outline the X-Age Project, an Aging Biomarker Consortium plan for building standardized aging clocks in China. The authors discuss the project roadmap and its aims of decoding aging heterogeneity, detecting accelerated aging early and evaluating geroprotective interventions.

Seasonal influenza activity significantly decreased in China during the coronavirus disease 2019 (COVID-19) pandemic, yet the H3N2 virus led to three epidemic waves. Understanding the characteristics of H3N2 epidemic viruses is essential for recognizing influenza during COVID-19 and for updating vaccines. In this study, we analyzed 579 respiratory samples from patients exhibiting influenza-like symptoms, collected in 2019–2022, leading to the successful sequencing of 36 complete H3N2 genomes. Genomic analysis indicated that the epidemic strains from these periods belonged to different hemagglutinin (HA) clades and exhibited phylogenetic divergence from the concurrently used vaccine strains. Significant antigenic differences were identified through cross-hemagglutination inhibition (HI) and cross-microneutralization (MN) assays. Furthermore, pathogenicity studies showed that representative strains replicated in Madin-Darby canine kidney‌ (MDCK) cells, with varying abilities, and all replicated more effectively at 37 °C compared to 33 °C. These strains also replicated well in the respiratory tracts of mice and guinea pigs. The findings indicate a mismatch between circulating H3N2 viruses and recommended vaccine strains, highlighting the need for improved international cooperation and epidemiological surveillance of influenza viruses post-COVID-19. Optimizing effective vaccine strain update strategy and developing a universal influenza vaccine are crucial for future preparedness.