Science China Life Sciences最新文献

Pigs are important agricultural animals and valuable biomedical models. The intestinal tract is a crucial digestive organ and the largest immune organ. However, the function of pig intestines at single-cell resolution remains poorly understood. Here, we created single-nucleus transcriptomic maps of the ileum and cecum for wild boars, Bama Xiang pigs, and Large White pigs, aged 30, 42, 150, and 730 d. Our atlas revealed 19 major cell types and 58 cellular subtypes, including several previously uncharacterized cellular subtypes, such as EBF1⁺ fibroblasts, TMEM163⁺ macrophages, and neuron subtypes expressing FCAMR. We discovered and confirmed that ileum neurons, rather than cecum neurons, can regulate inflammatory responses, highlighting interactions of neurons with dendritic cells (DCs) and lymphatic endothelial cells (LECs) through the NAMPT-INSR ligand-receptor pair in the ileum. Microbial-derived short-chain fatty acids, such as propionic acid and acetic acid, enhanced plasma cell differentiation and humoral immune responses by upregulating XBP1 and SDC1 expression, thereby endowing wild boars with a stronger immune response than domestic pigs. We identified and validated the enterocyte-enriched transcription factors FOXO1 and NR1H4 in wild boars, which contributed to the superior nutrient absorption of wild boars relative to domestic pigs. Furthermore, we comprehensively characterized the postnatal development of wild boar intestinal cells and revealed that plasma cells presented the most pronounced developmental changes. We identified highly conserved cell types and features between pig and human intestines. Overall, our work provides a foundation for improving pig feed conversion and health while also providing a reference for research on human intestinal diseases.

Orchids critically rely on mycorrhizal fungi for seed germination and seedling development, but the extent to which the fungus benefits from the orchid is less clear. Recent work in arbuscular mycorrhizae has suggested that plants can provide fatty acids (FAs) to fungi, but empirical evidence in orchids remains limited. Here, we combine lipidomic and transcriptomic analyses to test the hypothesis that the germination-promoting fungus Ceratobasidium sp. GS2 receives carbon in the form of FAs from Gymnadenia conopsea seeds during symbiotic germination. Confocal and transmission electron microscopy confirmed the potential of FA transfer from seeds to the fungus. Symbiosis resulted in significant changes in the lipid composition of the fungus, with increased concentrations of FAs in the external mycelium. RNA-seq showed upregulation of genes associated with FA synthesis in seeds and downregulation of de novo FA synthesis genes in fungi 12 d post-symbiosis, indicating that the increased amounts of FAs in the fungus may originate from the seeds. These results indicate that FAs absorbed by hyphae in the colonized inner cortex cells support hyphal growth, providing evidence for directional carbon flow from the orchid seeds to the fungus and supporting a "give now and get now" model of mutualism in orchid-fungus symbioses.

Controllable targeted protein degradation (controllable TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have emerged as transformative tools in drug discovery and molecular biology research. With the endogenous cellular degradation machinery, controllable TPD platforms allow for the precise targeting and regulated elimination of specific proteins within cells. Recent advances have expanded the spectrum of controllable degradation strategies, including photosensitive degrons, opto-PROTACs, auxin-inducible degron (AID) systems, small molecule-assisted shut-off (SMASh) techniques, and engineered E3 ubiquitin ligases such as ΔTRIM21 with enhanced targeted protein degradation efficiency (ΔTRIM-TPD). These emerging methodologies provide unprecedented control over protein stability, facilitating targeted therapeutic interventions for diseases such as cancer and infectious diseases, and significantly advancing fundamental biological research. This review systematically summarizes recent breakthroughs in controllable TPD strategies, elucidates their distinct molecular mechanisms, and highlights their promising therapeutic applications. The rapidly evolving field of controllable TPD represents a powerful and adaptable technological frontier, opening new avenues in precision medicine and providing versatile tools for the future of biomedical research.

Over the past three decades, the number of people with diabetes mellitus worldwide has surged dramatically, with diabetes mellitus now ranking as the ninth leading cause of death. Globally, about one in every eleven adults is affected by diabetes, with 90% of these cases being type 2 diabetes. Asia has emerged as a region for the rapidly escalating global epidemic of type 2 diabetes, particularly in developing countries such as China and India. While genetic predisposition partly determines an individual's susceptibility to type 2 diabetes, unhealthy diets and sedentary lifestyles are the primary drivers of the current global epidemic. Early life exposure and experience contribute to the development of impairment of glucose metabolism, including type 2 diabetes in later life. A healthy lifestyle as a routine in adulthood prevents the disease as an interventional target, including the maintenance of a healthy weight, a balanced diet, regular physical activity, and being free of smoking and alcohol consumption. Complications of diabetes impaired the quality of life and shortened the lifespan, including cardiovascular diseases, kidney diseases, visual impairment, neuropathies, peripheral artery diseases, and other emerging complications such as infections and chronic ulcerations. The trends of the epidemiological pattern represent the achievement of previous clinical and public health interventions and current challenges, which indicate the major tasks for clinicians and clinical researchers in the future.

During aging, bone marrow stromal cells (BMSCs) tend to differentiate more into adipocytes than into osteoblasts, resulting in decreased bone formation and contributing to age-related osteoporosis and impaired bone regeneration. However, the molecular mechanisms underlying this process remain unclear. In this study, we observed an increase in the expression of TRIM21 in aged BMSCs, particularly those involved in adipogenesis. This increase in TRIM21 levels shifted the osteoadipogenic balance toward adipogenesis in BMSCs, resulting in reduced bone formation and ultimately leading to age-related osteoporosis and impaired bone regeneration. Mechanistically, activation of the IL-1β-JNK MAPK pathway triggered the expression of TRIM21 in aged BMSCs, which then shifted the osteoadipogenic balance toward adipogenesis by facilitating the degradation of β-catenin through K48 ubiquitination. Therefore, our findings suggest a potential intrinsic mechanism for age-related bone loss and suggest that targeting TRIM21 could be beneficial for treating age-related osteoporosis and impaired bone regeneration.

Fungi, arthropods, and nematodes are chitin-containing organisms that cause severe damage to crop production. Plants can sense chitin to activate immunity against these invaders. In Arabidopsis thaliana (Arabidopsis), the lysin motif-containing receptor kinases (LysM-RKs) AtLYK5 and AtCERK1 are considered the primary chitin receptor and coreceptor for chitin binding and signaling, respectively. However, several studies indicate that AtCERK1 also possesses chitin-binding ability, raising a critical question: can AtCERK1 respond to chitin independently? To address this question, we generated an octuple mutant allele lacking all LysM receptors and hierarchically complemented the LysM-RKs involved in chitin perception. Our results revealed that while AtCERK1 alone could respond to chitin, it required an additional receptor to fully restore chitin-induced immune responses. Surprisingly, AtLYK4, the closest paralog of AtLYK5, forms a minimal chitin receptor complex with AtCERK1. Furthermore, we demonstrated that both N-glycosylation modifications of the extracellular domain of AtLYK4 and two key residues within its chitin-binding pocket were important for chitin recognition. Our findings not only revise the long-prevailing model of chitin perception but also define the core architecture of the chitin receptor complex in Arabidopsis. Additionally, we identify bipartite molecular determinants that regulate chitin-receptor interactions in plants.