Science China Life Sciences最新文献

Measurable residual disease (MRD) is a powerful prognostic factor of relapse in acute myeloid leukemia (AML). We applied the single-cell RNA sequencing to bone marrow (BM) samples from patients with (n=20) and without (n=12) MRD after allogeneic hematopoietic stem cell transplantation. A comprehensive immune landscape with 184,231 cells was created. Compared with CD8⁺ T cells enriched in the MRD-negative group (MRD-_CD8), those enriched in the MRD-positive group (MRD+_CD8) showed lower expression levels of cytotoxicity-related genes. Three monocyte clusters (i.e., MRD+_M) and three B-cell clusters (i.e., MRD+_B) were enriched in the MRD-positive group. Conversion from an MRD-positive state to an MRD-negative state was accompanied by an increase in MRD-_CD8 clusters and vice versa. MRD-enriched cell clusters employed the macrophage migration inhibitory factor pathway to regulate MRD-_CD8 clusters. These findings revealed the characteristics of the immune cell landscape in MRD positivity, which will allow for a better understanding of the immune mechanisms for MRD conversion.

Antibody diversification is essential for an effective immune response, with somatic hypermutation (SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase (AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions (indels). These mutational outcomes contribute to antibody affinity maturation. The mechanisms responsible for generating point mutations and indels involve the base excision repair (BER) and mismatch repair (MMR) pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard, translesion synthesis (TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies (bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.

Mammalian hair cells (HCs) are arranged spirally along the cochlear axis and correspond to different frequency ranges. Serving as primary sound detectors, HCs spatially segregate component frequencies into a topographical map. HCs display significant diversity in anatomical and physiological characteristics, yet little is known about the organization of the cochleotopic map of HCs or the molecules involved in this process. Using single-cell RNA sequencing, we determined the distinct molecular profiles of inner hair cells and outer hair cells, and we identified numerous position-dependent genes that were expressed as gradients. Newly identified genes such as Ptn, Rxra, and Nfe2l2 were found to be associated with tonotopy. We employed the SCENIC algorithm to predict the transcription factors that potentially shape these tonotopic gradients. Furthermore, we confirmed that Nfe2l2, a tonotopy-related transcription factor, is critical in mice for sensing low-to-medium sound frequencies in vivo. the analysis of cell-cell communication revealed potential receptor-ligand networks linking inner hair cells to spiral ganglion neurons, including pathways such as BDNF-Ntrk and PTN-Scd4, which likely play essential roles in tonotopic maintenance. Overall, these findings suggest that molecular gradients serve as the organizing principle for maintaining the selection of sound frequencies by HCs.

The oxidative pentose phosphate (OPP) pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids (AAAs), which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth. However, genetic evidence linking the two pathways is largely unclear. In this study, we identified 6-phosphogluconate dehydrogenase 2 (PGD2), the rate-limiting enzyme of the cytosolic OPP pathway, through suppressor screening of arogenate dehydrogenase 2 (adh2) in Arabidopsis. Our data indicated that a single amino acid substitution at position 63 (glutamic acid to lysine) of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2, thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2. Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue. Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities, thus exhibiting distinct AAAs producing capability. These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2. The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.

Epstein-Barr virus (EBV), the first identified human tumor virus, is implicated in various human malignancies, infectious mononucleosis, and more recently, multiple sclerosis. Prophylactic vaccines have the potential to effectively prevent EBV infection. Glycoprotein B (gB) serves as the fusogen and plays a pivotal role in the virus entry process, making it a critical target for EBV vaccine development. Surface membrane proteins of enveloped viruses serve as native conformational antigens, making them susceptible to immune recognition. Utilizing lipid membrane-bound viral antigens is a promising strategy for effective vaccine presentation in this context. In this study, we employed a truncated design for gB proteins, observing that these truncated gB proteins prompted a substantial release of extracellular vesicles (EVs) in insect cells. We verified that EVs exhibited abundant gB proteins, displaying the typical virus particle morphology and extracellular vesicle characteristics. gB EVs demonstrated a more efficient humoral and cellular immune response compared with the gB ectodomain trimer vaccine in mice. Moreover, the antisera induced by the gB EVs vaccine exhibited robust antibody-dependent cytotoxicity. Consequently, gB EVs-based vaccines hold significant potential for preventing EBV infection and offer valuable insights for vaccine design.

The coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) developed into a global health emergency. Systemic microthrombus caused by SARS-CoV-2 infection is a common complication in patients with COVID-19. Cardiac microthrombosis as a complication of SARS-CoV-2 infection is the primary cause of cardiac injury and death in patietns with severe COVID-19. In this study, we performed single-cell sequencing analysis of the right ventricular free wall tissue from healthy donors, patients who died during the hypercoagulable period of characteristic coagulation abnormality (CAC), and patients who died during the fibrinolytic period of CAC. We collected 61,187 cells enriched in 24 immune cell subsets and 13 cardiac-resident cell subsets. We found that in the course of SARS-CoV-2 infected heart microthrombus, MYO1E^highRASGEF1B^highmonocyte-derived macrophages promoted hyperactivation of the immune system and initiated the extrinsic coagulation pathway by activating chemokines CCL3, CCL5. This series of events is the main cause of cardiac microthrombi following SARS-CoV-2 infection. In a SARS-CoV-2 infected heart microthrombus, excessive immune activation is accompanied by an increase in cellular iron content, which in turn promotes oxidative stress and intensifies intercellular competition. This induces cells to alter their metabolic environment, resulting in increased sugar uptake via the glycosaminoglycan synthesis pathway. In addition, high levels of reactive oxygen species generated by elevated iron levels promote increased endogenous malondialdehyde synthesis in a subpopulation of cardiac endothelial cells. This exacerbates endothelial cell dysfunction and exacerbates the coagulopathy process.

Ovarian endometrioma (OE), also known as "chocolate cysts," is a cystic mass that develops in the ovaries due to endometriosis and is a common gynecological condition characterized by the growth of endometrial tissue outside the uterus, leading to symptoms such as dysmenorrhea, pelvic pain, and infertility. However, the precise molecular and cellular mechanisms driving this pathophysiology remain largely unknown, posing challenges for diagnosis and treatment. Here, we employed integrated single-cell transcriptomic profiling of over 52,000 individual cells from endometrial tissues of OE patients and healthy donors and identified twelve major cell populations. We identified notable alterations in cell type-specific proportions and molecular signatures associated with OE. Notably, the activation of IGFBP5⁺ macrophages with pro-inflammatory properties, NK cell exhaustion, and aberrant proliferation of IQCG⁺ and KLF2⁺ epithelium are key features and may be the potential mechanisms underlying the pathogenesis of OE. Collectively, our data contribute to a better understanding of OE at the single cell level and may pave the way for the development of novel therapeutic strategies.

Soil is the largest carbon (C) reservoir in terrestrial ecosystems and plays a crucial role in regulating the global C cycle and climate change. Increasing nitrogen (N) deposition has been widely considered as a critical factor affecting soil organic carbon (SOC) storage, but its effect on SOC components with different stability remains unclear. Here, we analyzed extensive empirical data from 304 sites worldwide to investigate how SOC and its components respond to N addition. Our analysis showed that N addition led to a significant increase in bulk SOC (6.7%), with greater increases in croplands (10.6%) and forests (6.0%) compared to grasslands (2.1%). Regarding SOC components, N addition promoted the accumulation of plant-derived C (9.7%-28.5%) over microbial-derived C (0.2%), as well as labile (5.7%) over recalcitrant components (-1.2%), resulting in a shift towards increased accumulation of plant-derived labile C. Consistently, N addition led to a greater increase in particulate organic C (11.9%) than mineral-associated organic C (3.6%), suggesting that N addition promotes C accumulation across all pools, with more increase in unstable than stable pools. The responses of SOC and its components were best predicted by the N addition rate and net primary productivity. Overall, our findings suggest that N enrichment could promote the accumulation of plant-derived and non-mineral associated C and a subsequent decrease in the overall stability of soil C pool, which underscores the importance of considering the effects of N enrichment on SOC components for a better understanding of C dynamics in soils.