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T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity. Intratumoral CD8+ T cells commonly display a dysfunctional state, however it remains unclear whether tumor cell metabolism actively promotes T-cell exhaustion. Here, the authors show that the tumor methionine recycling pathway has a central role in promoting T-cell dysfunction in hepatocellular carcinoma, contributing to tumor immune evasion.

Nitrate deposits are rare worldwide, especially potassium nitrate deposits; furthermore, their genesis remains disputed. There is a rare salt-lake type potassium nitrate deposit in the Dawadi area of Lop Nor at the eastern margin of the Tarim Basin, and the ore bodies show coexisting solid and liquid phases. Additionally, there are large sulphate-type potash deposits in the adjoining Luobei Depression, south of the Dawadi area. To determine why there are two different types of potash deposits in adjacent depressions with similar climates, field geological surveys were conducted and samples collected. It was found that the Tertiary clastic layer at the periphery of the Dawadi deposit was rich in high-salinity brine, with nitrate contents of up to 495–16,719 mg/L, much higher than those in the Luobei Depression, 1–35 mg/L. Additionally, a type of deep hydrothermal (Ca–Cl) brine was found in the fault zones, with nitrate contents of up to 8044 mg/L, dozens of times greater than that of ordinary groundwater. Using comprehensive analysis and research, we concluded that the Dawadi and Luobei depressions belong to different hydrological systems with no connection between them; thus, the two deposits belong to different metallogenic systems. Furthermore, groundwater played an important role in the mineralization of the potassium nitrate deposit, and a deep source may have been an important source of the ore-forming materials. The fault system widely developed in Lop Nor provides favorable channels for deep hydrothermal recharge, and the groundwater and deep hydrothermal brine could provide the source for the nitrate mineralization in the Dawadi Depression through water–rock reactions.

The Quaternary Lop Nor playa is the largest production base of potassium sulfate in the world. It has a mining history of more than 10 years, and its share in the Chinese potassium sulfate market is about 50% to-date. In this basin, the high-salinity potassium-rich brines are mainly contained in Middle Pleistocene–Holocene glauberite strata. Based on the monitoring of the underground brine table and geochemical analysis, this study reveals variations in the underground brine table and potassium-bearing grade before and after large-scale mining in the Lop Nor potash deposit. The results showed that the underground brine table and potassium sulfate grade decreased by varying degrees over sub-mineral areas after large-scale mining. The underground brine table declined by 8.5 m, on average, in the Luobei depression, by 6.4 m in the Tenglong platform and by 1.9 m in the Xinqing platform. However, the potassium-bearing grade showed the different trend. The Tenglong platform had the largest decline with average decreases in layers W 1 , W 2 and W 3 of 18.2%, 13.0% and 24.8%, respectively. In the Xinqing platform, the average decrease in layersW 2 and W 3 were 17.4% and 16.0% respectively. The Luobei depression decreases were relatively small (W 1 , W 2 and W 3 decreased 4.3%, 4.2% and 3.1%, respectively). This research provides a theoretical basis for the rational development and sustainable use of the potassium-rich brines in the Lop Nor basin.

Background Type 2 diabetes (T2D) is one of the most common chronic diseases. Studies on T2D are mainly built upon bulk-cell data analysis, which measures the average gene expression levels for a population of cells and cannot capture the inter-cell heterogeneity. The single-cell RNA-sequencing technology can provide additional information about the molecular mechanisms of T2D at single-cell level. Results In this work, we analyze three datasets of single-cell transcriptomes to reveal β -cell dysfunction and deficit mechanisms in T2D. Focused on the expression levels of key genes, we conduct discrimination of healthy and T2D β -cells using five machine learning classifiers, and extracted major influential factors by calculating correlation coefficients and mutual information. Our analysis shows that T2D β -cells are normal in insulin gene expression in the scenario of low cellular stress (especially oxidative stress), but appear dysfunctional under the circumstances of high cellular stress. Remarkably, oxidative stress plays an important role in affecting the expression of insulin gene. In addition, by analyzing the genes related to apoptosis, we found that the TNFR1-, BAX-, CAPN1- and CAPN2-dependent pathways may be crucial for β -cell apoptosis in T2D. Finally, personalized analysis indicates cell heterogeneity and individual-specific insulin gene expression. Conclusions Oxidative stress is an important influential factor on insulin gene expression in T2D. Based on the uncovered mechanism of β -cell dysfunction and deficit, targeting key genes in the apoptosis pathway along with alleviating oxidative stress could be a potential treatment strategy for T2D.

Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration. Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.

Background Therapeutic options for patients with hepatocellular carcinoma (HCC) are limited. Transarterial chemoembolization (TACE) is an interventional procedure used to deliver chemotherapy and embolizing agents directly to the tumor and is the procedure of choice for patients with intermediate stage HCC. While effective, more than 40% of patients do not respond to therapy, highlighting the need to investigate possible mechanisms of resistance. We sought to evaluate mechanisms of TACE resistance and evaluate a potential therapeutic target to overcome this resistance. Methods Using a prognostic gene signature which predicts TACE response (TACE Navigator) in a cohort of HCC patients who received TACE, patients were classified as responders and non-responders. Transcriptomic and gene pathway analysis were used to identify potential drivers of TACE resistance. Knockdown of the gene encoding rate limiting enzyme PKM2 using shRNA in HCC cell lines, as well as pharmacologic inhibition of PKM2 with shikonin using an in vitro TACE model measured response to chemotherapy under hypoxia. Finally, we replicated the TACE model with shikonin using patient derived cell line organoids (PDC). Functional studies were performed in vitro using immunoblotting, quantitative polymerase chain reaction, glycolysis and hypoxia assays. Results In patient non-responders, we identified enrichment of the glycolysis pathway, specifically of the gene encoding the rate-limiting enzyme PKM2. We identified four HCC cell lines which recapitulated a TACE responder-like and non-responder-like phenotype. PKM2 knockdown in HCC cell lines demonstrated a less proliferative and aggressive phenotype as well as improved drug sensitivity to both doxorubicin and cisplatin. In vitro TACE model demonstrated that TACE non-responder-like cells overcame therapeutic resistance and rendered them susceptible to therapy through PKM2 knockdown. Lastly, we obtained similar results using a pharmacologic PKM2 inhibitor, shikonin in both cell lines, and PDC organoids. Conclusion Elevated PKM2 is associated with treatment resistance and abbreviated survival in patients receiving TACE. Elevated PKM2 in vitro is associated with increased utilization of the glycolysis pathway, resulting in oxygen independent cell metabolism. Through PKM2 knockdown as well as with pharmacologic inhibition with shikonin, non-responder cells can be reprogrammed to act as responders and could improve TACE efficacy in patients.

Spatial cellular context is crucial in shaping intratumor heterogeneity. However, understanding how each tumor establishes its unique spatial landscape and what factors drive the landscape for tumor fitness remains significantly challenging. Here, we analyze over 2 million cells from 50 tumor biospecimens using spatial single-cell imaging and single-cell RNA sequencing. We develop a deep learning-based strategy to spatially map tumor cell states and their surrounding environmental architecture, and find that different tumor cell states can be organized into distinct clusters, or “villages,” each supported by unique microenvironments. Notably, tumor cell villages exhibit village-specific molecular co-dependencies between tumor cells and their microenvironment and are associated with patient outcomes. Perturbation of molecular co-dependencies via random spatial shuffling of the microenvironment results in destabilization of the corresponding villages. We validate our findings using single-cell, spatial, and bulk transcriptome data from 740 liver cancer patients. This study provides insights into understanding tumor spatial landscape and its impact on tumor aggressiveness. Understanding how each tumor establishes its unique spatial landscape and what factors drive the landscape for tumor fitness remains significantly challenging. Here, the authors employ spatial single-cell imaging and single-cell RNA sequencing to analyze 50 liver cancer biospecimens and find that different tumor cell states may be organized into distinct clusters, or ‘villages’.

BackgroundHepatocellular carcinoma (HCC) is a significant global cancer burden, with rising incidence and lacking a unified prevention strategy due to complex aetiologies. Viral exposures may shape host immunity via specific reactive viral antigens that could induce immune responses against hepatocarcinogenesis.ObjectiveWe aimed to characterise viral exposure differences between HCC patients and healthy individuals and identify potentially protective viral antigens against HCC.DesignWe profiled pan-viral serological antibody repertoires using a microbial phage library among 2647 study subjects and examined the biological activities of selective viral antigens on blood-derived immune cells from both healthy individuals and HCC patients.ResultWe identified 153 viral antigens with a significantly reduced serological response in HCC patients compared with healthy individuals. We also observed that a higher serological response to 153 viral antigens is associated with better clinical outcomes of patients with chronic liver diseases and HCC. These findings are consistent across different populations across sex, ethnicity and aetiology. We identified a common epitope (CE1) shared among 39% of reactive viral antigens that belong to the rhinovirus and enterovirus families. We demonstrated that CE1 could induce both CD4+ and CD8+ T-cell activation and CD8+ T-cell-mediated HCC cell killing.ConclusionsOur results suggest that past exposures to members of the Enterovirus genus may be advantageous for cancer patients, highlighting the potential for a viral peptide-based HCC vaccine.

Due to the lack of efficient and stable recycling methods and processes, the waste of carbon fiber-reinforced polymer (CFRP) poses a threat to the environment, while a large number of demand every year requires a lot of cost and energy to be used in manufacturing carbon fiber (CF). Therefore, there is an urgent need to develop an economical and efficient recycling process to deal with waste CFRP. In this study, CFRP in N-methylpyrrolidone (NMP) solution was swelled with the assistance of microwave irradiation. And the high efficiency and fast characteristics of microwave irradiation promoted the swelling of CFRP in NMP, which greatly reduced the pretreatment temperature and time. The CFRP was successfully swollen at 80 °C for only 0.5 h, then, they were decomposed in 8 M nitric acid for 7 h, the decomposition rate reached 74.6%, which greatly improved the reaction rate and finally retained about 70% of the CF mechanical properties. This method is helpful to reduce energy consumption in the recovery process and improve the stability of recycled CF (rCF), which provides a new direction and theoretical support for the recovery and reuse of CF.

This study proposes an innovative strategy for enhancing the damping properties of nitrile rubber (NBR) through the incorporation of highly epoxidized Eucommia ulmoides gum (EEUG). The introduced epoxy groups strongly interact with the molecular chains of NBR via polar interactions, significantly improving energy dissipation and damping performance. Dynamic mechanical analysis (DMA) demonstrates that increasing the epoxidation degree of EEUG leads to a notable rise in the tanδ peak value, reaching up to 1.855. Moreover, the damping peak temperature shifts markedly toward room temperature, effectively broadening the service temperature range of the material. The resulting NBR/EEUG composites exhibit high damping capacity over a wide temperature range while retaining excellent elasticity, providing a feasible approach for designing advanced environmentally adaptive damping materials.