Background: Structural variation (SV) acts as an essential mutational force shaping the evolution and function of the human genome. However, few studies have examined the role of SVs in high-altitude adaptation and little is known of adaptive introgressed SVs in Tibetans so far. Results: Here, we generate a comprehensive catalog of SVs in a Chinese Tibetan (n = 15) and Han (n = 10) population using nanopore sequencing technology. Among a total of 38,216 unique SVs in the catalog, 27% are sequence-resolved for the first time. We systematically assess the distribution of these SVs across repeat sequences and functional genomic regions. Through genotyping in additional 276 genomes, we identify 69 Tibetan-Han stratified SVs and 80 candidate adaptive genes. We also discover a few adaptive introgressed SV candidates and provide evidence for a deletion of 335 base pairs at 1p36.32. Conclusions: Overall, our results highlight the important role of SVs in the evolutionary processes of Tibetans’ adaptation to the Qinghai-Tibet Plateau and provide a valuable resource for future high-altitude adaptation studies.

As two major types of primary liver cancers, the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have been well studied separately. However, a systemic assessment of the similarities and differences between the TIME of HCC and ICC is still lacking. In this study, we pictured a landscape of combined TIME of HCC and ICC by sequencing and integrating 41 single-cell RNA-seq samples from four different tissue types of both malignancies. We found that T cells in HCC tumors generally exhibit higher levels of immunosuppression and exhaustion than those in ICC tumors. Myeloid cells in HCC and ICC tumors also exhibit distinct phenotypes and may serve as a key factor driving the differences between their TIMEs. Besides, we identified a cluster of EGR1⁺ macrophages specifically enriched in HCC tumors. Together, our study provides new insights into cellular composition, states and interactions in the TIMEs of HCC and ICC, which could pave the way for the development of future therapeutic targets for liver cancers.

Single-cell transcriptomics offers opportunities to investigate ligand-receptor (LR) interactions between heterogeneous cell populations within tissues. However, most existing tools for the inference of intercellular communication do not allow prioritization of functional LR associations that provoke certain biological responses in the receiver cells. In addition, current tools do not enable the identification of the impact on the downstream cell types of the receiver cells. We present CommPath, an open-source R package and webserver, to analyze and visualize the LR interactions and pathway-mediated intercellular communication chain with single-cell transcriptomic data. CommPath curates a comprehensive signaling pathway database to interpret the consequences of LR associations and therefore infers functional LR interactions. Furthermore, CommPath determines cell-cell communication chain by considering both the upstream and downstream cells of user-defined cell populations. Applying CommPath to human hepatocellular carcinoma dataset shows its ability to decipher complex LR interaction patterns and the associated intercellular communication chain, as well as their changes in disease versus homeostasis.

Radiation-induced brain injury (RIBI) is one of the most common and fatal complications of cranial radiation therapy (CRT); however, no effective intervention is available currently. Metformin has been reported to have anti-RIBI activity as a first-line anti-diabetic drug. However, the mechanism of action is unclear. An RIBI mice model and an in vitro cell model under 30 and 10 Gy ⁶⁰Co γ-rays exposure were established to investigate the mechanism of metformin in RIBI. The results showed that pre-treatment with metformin protects hippocampal neurogenesis in the brain of mice and improves learning and memory ability after irradiation. Further investigations revealed that metformin pretreatment reduces inflammation and decreases DNA damage in the in vitro BV2 cell line. In addition, we observed that metformin inhibits the activation of IκB and IRF-3, which are downstream components of the cGAS-STING pathway. These findings suggest that metformin might protect the brain from RIBI, at least partly, through the cGAS pathway, making it a potential therapeutic drug for RIBI.

Extreme cold causes myocardial injury; however, cold acclimation (CA) enhances myocardial tolerance. This study investigated whether brown adipose tissue (BAT)-derived extracellular vesicles (BAT-EVs) contribute to CA-induced cardioprotection. Mice were subjected to CA or acute cold stress. Cardiac function was assessed using echocardiography and biomarkers. Interscapular BAT (iBAT) ablation has confirmed the necessity of iBAT. EVs were characterized and tested in HL-1 cardiomyocytes. Transcriptomics and specific gene knockdowns have identified key molecular mechanisms. CA preserved cardiac function and integrity under -25 °C stress, and these effects were abolished by iBAT ablation. EVs from CA mice mediate this protection by mitigating cardiomyocyte apoptosis. Mechanistically, lncRNA Morrbid was enriched in iBAT and serum EVs after CA. iBAT-specific Morrbid knockdown significantly attenuates EV-mediated protection. Furthermore, Morrbid was associated with upregulation of Serpine1 in cardiomyocytes; silencing Serpine1 abolished anti-apoptotic benefits. This study identified a BAT-Heart axis where CA stimulates the release of Morrbid-enriched EVs. These vesicles serve as an important mechanism to confer remote cardioprotection, potentially by upregulating cardiac Serpine1 and suppressing apoptosis, highlighting a potential therapeutic strategy for cold-induced injury.

Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow are highly vulnerable to radiation-induced damage. Systematic delineation of lineage-specific transcription factor (TF) programs, together with in silico perturbation analyses, provides a valuable approach for identifying regulators capable of accelerating hematopoietic reconstruction after irradiation. Here, using single-cell RNA sequencing (scRNA-seq), we characterized the dynamics of HSPCs at both cellular abundance and transcriptional regulation levels following irradiation and used in silico TF perturbation to predict their effects on lineage commitment. We found that granulocyte–macrophage progenitor (GMP) differentiation is consistently prioritized after irradiation, accompanied by enhanced activity of proliferation-associated drivers. Network-based TF profiling identified Tcf7l2 as a previously unrecognized regulator of early lymphoid differentiation. In silico perturbation further functionally predicted TFs driving differentiation in HSPCs after irradiation, and Hsf1, a factor with pharmacological activation potential, was selected for validation via in vivo celastrol treatment and in vitro knockdown. Collectively, our findings uncover the transcriptional programs governing HSPC lineage biases after radiation exposure and highlight the utility of in silico TF perturbation as a strategy for guiding the therapeutic interventions for radiation-induced hematopoietic injury.