Explore the vast range of titles available.

EHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency was established as the cause of Kleefstra syndrome twenty years ago, the pathogenesis of G9a dysfunction in human disease remains largely unknown. Here, we report clinical and molecular correlates of six de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications and transcriptomic profiles similar to those of Kleefstra syndrome. In vitro studies revealed that these variants encode for structurally stable G9a proteins that are catalytically incompetent due to aberrant interactions either with histone H3 tail or with S-adenosylmethionine. Heterozygous mice carrying a patient-derived variant (Ehmt2 c.3385_3396del) exhibited growth retardation, facial/skull dysmorphia and aberrant behavior. EHMT2 variants described here likely exert dominant-negative effect on GLP/G9a complexes and thus genocopy the EHMT1 haploinsufficiency causing Kleefstra syndrome via a distinct molecular mechanism.

The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME. The tumor microenvironment can influence patient survival response to therapy. Here, the authors used single-cell sequencing to investigate the microenvironment of nasopharyngeal cancer and identify tumor-specific signatures in five stromal clusters of cells that may influence patient survival.

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma. Response rates to immunotherapies in patients with nasopharyngeal carcinoma (NPC) are still limited. Here the authors show that tumor-restricted CD70 correlates with regulatory T cell abundance and suppressive activity in NPC and that CD70 blockade improves response to anti-PD1 in preclinical models.

High oil and protein content make tetraploid peanut a leading oil and food legume. Here we report a high-quality peanut genome sequence, comprising 2.54 Gb with 20 pseudomolecules and 83,709 protein-coding gene models. We characterize gene functional groups implicated in seed size evolution, seed oil content, disease resistance and symbiotic nitrogen fixation. The peanut B subgenome has more genes and general expression dominance, temporally associated with long-terminal-repeat expansion in the A subgenome that also raises questions about the A-genome progenitor. The polyploid genome provided insights into the evolution of Arachis hypogaea and other legume chromosomes. Resequencing of 52 accessions suggests that independent domestications formed peanut ecotypes. Whereas 0.42–0.47 million years ago (Ma) polyploidy constrained genetic variation, the peanut genome sequence aids mapping and candidate-gene discovery for traits such as seed size and color, foliar disease resistance and others, also providing a cornerstone for functional genomics and peanut improvement.

Experienced temperatures significantly affect the health of older adults due to irreversible physiological declines. In heat exposure studies, temperature measurements in specific spaces cannot fully capture individuals’ thermal experience in daily life, as people naturally and actively move between spaces with distinct thermal environments. The dynamic temperature experienced by rural older individuals in complex daily lives remains unclear, which is crucial for understanding its impact on health. This study discusses the concept of individual experienced temperatures (IETs) and investigated the characteristics and patterns of older adults’ IET in rural China during winter. A new method and equipment for longitudinal and noninvasive IET monitoring were developed and collected 157,800 IET data points, which were organized into 362 valid datasets. The data was gathered in China’s cold climate zone and hot summer cold winter (HSCW) climate zone from December 2023 to February 2024. The results revealed that local climate and weather had a significant impact on older adults’ IET. Cold waves reduced IET, while the effects were alleviated by thermal adaptation behavior of older adults. Diurnal IET was categorized into three patterns (stable group, active group, and moderate group) using K‐means clustering analysis. The “stable group” was characterized by frequent IET fluctuations within a narrow and low temperature range. The “active group” was characterized by drastic IET fluctuations and high diurnal temperature range. The “moderate group” was characterized by low fluctuation frequency. For each participant, the majority of diurnal IET concentrated in one or two patterns. The IET of older adults exhibited significant individual variation. This research also discussed the significance of IET in comparison to traditional heat exposure studies. It highlights the dynamic and individualized nature of people’s heat exposure, contributing to the body of knowledge in this field. Furthermore, it provides greater accuracy and robustness in the result when assessing the health risks associated with exposure to varying temperatures. Recommendations for IET improvement were proposed from the perspectives of built environment optimization and policy support.

We develop a poly (lactic-co-glycolic acid)/β-calcium phosphate (PLGA/TCP)-based scaffold through a three-dimensional (3D) printing technique incorporating icaritin (ICT), a unique phytomolecule, and secretome derived from human fetal mesenchymal stem cells (HFS), to provide mechanical support and biological cues for stimulating bone defect healing. With the sustained release of ICT and HFS from the composite scaffold, the cell-free scaffold efficiently facilitates the migration of MSCs and promotes bone regeneration at the femoral defect site in the ovariectomy (OVX)-induced osteoporotic rat model. Furthermore, mechanism study results indicate that the combination of ICT and HFS additively activates the Integrin–FAK (focal adhesion kinase)–ERK1/2 (extracellular signal-regulated kinase 1/2)–Runx2 (Runt-related transcription factor 2) axis, which could be linked to the beneficial recruitment of MSCs to the implant and subsequent osteogenesis enhancement. Collectively, the PLGA/TCP/ICT/HFS (P/T/I/S) bioactive scaffold is a promising biomaterial for repairing osteoporotic bone defects, which may have immense implications for their translation to clinical practice.

Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor–normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (PTBP1, ESRP2 and MBNL1). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.