Distribution Characteristics of Atmospheric Microplastics in Typical Desert Agricultural Regions.

We examined the distribution characteristics of atmospheric microplastics in typical desert agricultural regions, with a focus on the agricultural areas surrounding the Taklamakan Desert, Xinjiang, China. We collected samples of total suspended particulate matter (TSP), atmospheric deposition, and atmospheric dust using both active and passive collection methods. The chemical composition, particle size, shape, and color of atmospheric microplastics were examined using a stereomicroscope and a Fourier-transform infrared spectrometer to analyze their characteristics. The results showed that the primary chemical compositions of microplastics included polypropylene (PP), polyethylene, polyethylene terephthalate, polymethylmethacrylate, and cellophane. Particle sizes were mainly within the range of 0 to 1000 µm. Fibrous microplastics constituted the majority of the TSP and atmospheric deposition, whereas film-like microplastics constituted the largest proportion of atmospheric dustfall. The deposition flux of atmospheric microplastics in the first quarter was measured at 103.21 ± 22.12 particles/m2/day, which was lower than that observed in conventional agricultural areas. The abundance of microplastics in atmospheric dustfall was found to be 1.36 particles/g. The proportion of PP microplastics in atmospheric dustfall can be as high as 35%. Through a comparison of microplastic content in TSP during dust storms and under normal weather conditions, it was found that dust storms can lead to an increase in the abundance of microplastics within the atmospheric TSP. The present study provides a scientific basis for understanding the distribution of atmospheric microplastics in typical desert agricultural regions. Environ Toxicol Chem 2024;00:1-14. © 2024 SETAC.

Establishment of homotrimer collagen type I signature and its association with clinical manifestation and tertiary lymphoid structures formation in liver cancer.

Background: collagen type I is a fundamental composition of extracellular matrix. Typically it exists in the form of a heterotrimer, consisting of two α1 chains encoded by COL1A1 and one α2 chain encoded by COL1A2. However, in cancer a homotrimeric form of collagen type I comprises three α1 chains encoded by COL1A1 was founded. There is still a lack of transcriptional and histologic methods for detecting homotrimeric collagen type I. Furthermore, a comprehensive analysis of the pan-cancer distribution pattern and clinical relevance of homotrimeric collagen type I is conspicuously absent. Method: Using transcriptional and immunoflourance method, we established homocol signature, which is able to transcriptionally and histologically detect homotrimeric collagen type I. We investigated the diagnostic and prognostic potential of homocol as a novel cancer biomarker in a pan-cancer cohort. Furthermore, we assessed its association with clinical manifestations in a liver cancer cohort undergoing treatment at our institute. Result: Homotrimer Collagen Type I is predominantly expressed by cancer cells and is linked to several critical cancer hallmarks, particularly inflammatory response and proliferation. Survival analyses have indicated that a high Homocol expression is correlated with poor outcomes in most types of cancer studied. In terms of cancer detection, Homocol demonstrated strong performance in Receiver Operating Characteristic (ROC) analysis, with an Area Under Curve (AUC) of 0.83 for pan-cancer detection and between 0.72 and 0.99 for individual cancers.In cohorts undergoing PD1 treatment, we noted a higher presence of Homocol in the response group. In a Hepatocellular Carcinoma (HCC) clinical set, high Homocol expression was associated with an increased formation of intra-tumor tertiary lymphoid structures (TLS), larger tumor sizes, more advanced Barcelona Clinic Liver Cancer (BCLC) stages, higher microvascular invasion (MVI) grades, absence of a capsule, and an enriched para-tumor collagen presence. Conclusion: our research has led to the development of a novel gene signature that facilitates the detection of Homotrimer Collagen Type I. This may greatly assist efforts in cancer detection, prognosis, treatment response prediction, and further research into Homotrimer Collagen Type I.

Dynamic impacts of short-term bath administration of enrofloxacin on juvenile black seabream Acanthopagrus schlegelii.

Dynamic impacts of short-term enrofloxacin (ENR) exposure on juvenile marine fish are not well understood, and the underlying mechanisms remain unclear. We therefore investigated the accumulation and elimination of ENR in the liver of juvenile black seabream Acanthopagrus schlegelii. Meanwhile, the dynamic alterations of biochemical parameters and liver transcriptomes after short-term bath immersion and withdrawal treatment were explored. The results indicated that the contents of ENR in the liver were significantly increased after bath administration for 24 h, and then quickly declined to very low concentrations along with the decontamination time increasing. Judging from the changes in biochemical indicators and liver transcriptomic alterations, 0.5 and 1 mg/L ENR exposure for 24 h triggered oxidative stress, impairment of immune system, as well as aberrant lipid metabolism via differential molecular pathways. Interestingly, biochemical and transcriptome analysis as well as integrated biomarker response (IBR) values showed that more significant changes appeared in 1 mg/L ENR group at decontamination periods, which indicated that the impact of high dose ENR on juvenile A. schlegelii may persist even after depuration for 7 days. These results revealed that the risk of short-term bath of 1 mg/L ENR should not be overlooked even after depuration period. Therefore, attention should be paid to the dosage control when administering the drug to juvenile A. schlegelii, and the restoration of physiological disturbance may be an important factor in formulating a reasonable treatment plan.

Phytosterols: Physiological Functions and Potential Application.

Dietary intake of natural substances to regulate physiological functions is currently regarded as a potential way of promoting health. As one of the recommended dietary ingredients, phytosterols that are natural bioactive compounds distributed in plants have received increasing attention for their health effects. Phytosterols have attracted great attention from scientists because of many physiological functions, for example, cholesterol-lowering, anticancer, anti-inflammatory, and immunomodulatory effects. In addition, the physiological functions of phytosterols, the purification, structure analysis, synthesis, and food application of phytosterols have been widely studied. Nowadays, many bioactivities of phytosterols have been assessed in vivo and in vitro. However, the mechanisms of their pharmacological activities are not yet fully understood, and in-depth investigation of the relationship between structure and function is crucial. Therefore, a contemporaneous overview of the extraction, beneficial properties, and the mechanisms, as well as the current states of phytosterol application, in the food field of phytosterols is provided in this review.

Thermally Drawn-Based Microtubule Soft Continuum Robot for Cardiovascular Intervention.

Cardiovascular disease is becoming the leading cause of human mortality. In order to address this, flexible continuum robots have emerged as a promising solution for miniaturizing and automating vascular interventional equipment for diagnosing and treating cardiovascular diseases. However, existing continuum robots used for vascular intervention face challenges such as large cross-sectional sizes, inadequate driving force, and lack of navigation control, preventing them from accessing cerebral blood vessels or capillaries for medical procedures. Additionally, the complex manufacturing process and high cost of soft continuum robots hinder their widespread clinical application. In this study, we propose a thermally drawn-based microtubule soft continuum robot that overcomes these limitations. The proposed robot has cross-sectional dimensions several orders of magnitude smaller than the smallest commercially available conduits, and it can be manufactured without any length restrictions. By utilizing a driving strategy based on liquid kinetic energy advancement and external magnetic field for steering, the robot can easily navigate within blood vessels and accurately reach the site of the lesion. This innovation holds the potential to achieve controlled navigation of the robot throughout the entire blood vessel, enabling in situ diagnosis and treatment of cardiovascular diseases.

Characterization and antioxidant properties of three exopolysaccharides produced by the Cyclocarya paliurus endophytic fungus.

In recent years, the considerable potential of endophytic bacteria and fungi as prolific producers of exopolysaccharides (EPSs) have attracted interest. In this study, 56 endophytes were isolated from Cyclocarya paliurus, and the secondary metabolites of EPSs were extracted from Monascus purpureus, Penicillium citrinum and Aspergillus versicolor, screened, and named MPE, PCE and AVE, respectively. In this work, the physicochemical properties and antioxidant activities of three EPSs, their cell proliferation activity on IEC-6 and RAW264.7 were investigated. The three EPSs were mainly composed of neutral sugar and differ in microstructure. However, MPE had a loose structure, and PCE exhibited a dense and sheet-like structure. In addition, the three EPSs performed ordinary antioxidant activity in vitro but showed excellent cell proliferation activity on IEC-6 and RAW264.7. The cell proliferation activity of PCE was 1.4-fold that of the controls at a concentration of 800 µg/mL on IEC-6, and MPE exhibited 1.3-fold increase on RAW264.7. This study provided scientific evidence and insights into the application of endophytes as a novel plant resource possessing huge application potential.

Effects of Different Drying Methods on Drying Characteristics, Microstructure, Quality, and Energy Consumption of Apricot Slices.

An appropriate drying method is crucial for producing high-quality dried apricots. In this study, the effects of four drying methods, hot air drying (HAD), infrared drying (IRD), pulse vacuum drying (PVD), and vacuum freeze-drying (VFD), on the drying kinetics and physical and nutritional characteristics of apricot slices were evaluated. PVD required the shortest time (16.25 h), followed by IRD (17.54 h), HAD (21.39 h), and VFD (34.64 h). VFD resulted in the best quality of apricot slices, with the smallest color difference (ΔE = 13.64), lowest water activity (0.312 ± 0.015) and browning degree (0.35), highest color saturation (62.84), lowest hardness (8.35 ± 0.47 N) and shrinkage (9.13 ± 0.65%), strongest rehydration ability (3.58 ± 0.11 g/g), a good microstructure, and high nutrient-retention rates (ascorbic acid content: 53.31 ± 0.58 mg/100 g, total phenolic content: 12.64 ± 0.50 mg GAE/g, and carotenoid content: 24.23 ± 0.58 mg/100 g) and antioxidant activity (DPPH: 21.10 ± 0.99 mmol Trolox/g and FRAP: 34.10 ± 0.81 mmol Trolox/g). The quality of PVD-treated apricot slices was second-best, and the quality of HAD-treated apricot slices was the worst. However, the energy consumption required for VFD was relatively high, while that required for PVD was lower. The results of this study provide a scientific basis for the large-scale industrial production of dried apricots.

Circular RNA circESYT2 serves as a microRNA-665 sponge to promote the progression of hepatocellular carcinoma through ENO2.

Circular RNAs (circRNAs) have emerged as crucial regulators in tumor progression, yet their specific role in hepatocellular carcinoma (HCC) remains largely uncharacterized. In this study, we utilized high-transcriptome sequencing to identify the upregulation of circESYT2 (hsa_circ_002142) in HCC tissues. Functional experiments carried out in vivo and in vitro revealed that circESYT2 played a significant role in maintaining the growth and metastatic behaviors of HCC. Through integrative analysis, we identified enolase 2 (ENO2) as a potential target regulated by circESYT2 through the competitive endogenous RNA sponge mechanism. Additional gain- or loss-of-function experiments indicated that overexpression of circESYT2 led to a tumor-promoting effect, which could be reversed by transfection of microRNA-665 (miR-665) mimic or ENO2 knockdown in HCC cells. Furthermore, the direct interaction between miR-665 and circESYT2 and between miR-665 and ENO2 was confirmed using RNA immunoprecipitation, FISH, RNA pull-down, and dual-luciferase reporter assays, highlighting the involvement of the circESYT2/miR-665/ENO2 axis in promoting HCC progression. These findings shed light on the molecular characteristics of circESYT2 in HCC tissues and suggest its potential as a biomarker or therapeutic target for HCC treatment.

Controlled reconstruction and application research of lateral overlying strata structure in high-gas mines with thick-hard roofs for a fully-mechanized top-caving face.

Due to the large mining area, the fully-mechanized top-caving mining with thick-hard roof is easy to form cantilever structure on the lateral roof of the working face, which on the one hand causes high stress level of adjacent roadway and serious deformation of roadway, on the other hand causes gas accumulation in corners, which brings severe challenges to safe and efficient mining of the mine. In this study, a mine facing such problems in Jincheng, China was taken as the research object. Based on the mechanical characteristics of coal and rock, the characteristics of overlying strata activity in the mining process of working face are mastered, and the dual effects of controlled transformation of lateral overlying strata structure on stress field and gas field were revealed. On this basis, roadway reinforcement and gas drainage schemes were put forward and applied. The results showed that the strength of the hard rock stratum was high in the triaxial stress environment, and it was not easily destroyed. However, once the strata exceed their strength threshold, they break down. In addition, the strength of coal is relatively low, and it is continuously deformed when the force exceeds its strength. The overlying strata structure after thick-hard roof fully-mechanized top-caving mining evolves in the following manner: "long cantilever length formed by the main roof being broken in the initial stage, voussoir beam formed by the upper hard roof being broken in the middle stage, and double cantilever beam formed by overlying strata compaction." The stress carried by upper hard rock stratum is transferred to coal pillars, which is the main reason for the high stress environment of multi-purpose roadway with large coal pillars. The controlled transformation of lateral overlying strata structure by pre-splitting and roof cutting can realize the "transfer-unloading" of coal pillar stress and the "plugging and driving" of corner gas. Based on the hydraulic fracturing reconstruction of lateral overburden structure, the grouting reinforcement scheme of roadway and dynamic gas drainage scheme were put forward. The results demonstrated that after roof cutting, the maximum deformation of the surrounding rock in the multi-purpose roadway was reduced by approximately 90 %, and the maximum concentration of corner gas was decreased by 15.28 %. This approach successfully achieved a collaborative control effect on roadway surrounding rock stability and gas emission well within the safety limits.

Comprehensive Review of EGCG Modification: Esterification Methods and Their Impacts on Biological Activities.

Epigallocatechin gallate (EGCG), the key constituent of tea polyphenols, presents challenges in terms of its lipid solubility, stability, and bioavailability because of its polyhydroxy structure. Consequently, structural modifications are imperative to enhance its efficacy. This paper comprehensively reviews the esterification techniques applied to EGCG over the past two decades and their impacts on bioactivities. Both chemical and enzymatic esterification methods involve catalysts, solvents, and hydrophobic groups as critical factors. Although the chemical method is cost-efficient, it poses challenges in purification; on the other hand, the enzymatic approach offers improved selectivity and simplified purification processes. The biological functions of EGCG are inevitably influenced by the structural changes incurred through esterification. The antioxidant capacity of EGCG derivatives can be compromised under certain conditions by reducing hydroxyl groups, while enhancing lipid solubility and stability can strengthen their antiviral, antibacterial, and anticancer properties. Additionally, esterification broadens the utility of EGCG in food applications. This review provides critical insights into developing cost-effective and environmentally sustainable selective esterification methods, as well as emphasizes the elucidation of the bioactive mechanisms of EGCG derivatives to facilitate their widespread adoption in food processing, healthcare products, and pharmaceuticals.

Molecular Dynamics Simulation Research on Fe Atom Precipitation Behaviour of Cu-Fe Alloys during the Rapid Solidification Processes.

To explore the crystalline arrangement of the alloy and the processes involving iron (Fe) precipitation, we employed molecular dynamics simulation with a cooling rate of 2 × 1010 for Cu100-XFeX (where X represents 1%, 3%, 5%, and 10%) alloy. The results reveal that when the Fe content was 1%, Fe atoms consistently remained uniformly distributed as the temperature of the alloy decreased. Further, there was no Fe atom aggregation phenomenon. The crystal structure was identified as an FCC-based Cu crystal, and Fe atoms existed in the matrix in solid solution form. When the Fe content was 3%, Fe atoms tended to aggregate with the decreasing temperature of the alloy. Moreover, the proportion of BCC crystal structure exhibited no obvious changes, and the crystal structure remained FCC-based Cu crystal. When the Fe content was between 5% and 10%, the Fe atoms exhibited obvious aggregation with the decreasing temperature of the alloy. At the same time, the aggregation phenomenon was found to be more significant with a higher Fe content. Fe atom precipitation behaviour can be delineated into three distinct stages. The initial stage involves the gradual accumulation of Fe clusters, characterised by a progressively stable cluster size. This phenomenon arises due to the interplay between atomic attraction and the thermal motion of Fe-Fe atoms. In the second stage, small Fe clusters undergo amalgamation and growth. This growth is facilitated by non-diffusive local structural rearrangements of atoms within the alloy. The third and final stage represents a phase of equilibrium where both the size and quantity of Fe clusters remain essentially constant following the crystallisation of the alloy.

Microorganisms and bacterial cellulose stability of Kombucha under different manufacture and storage conditions.

It is crucial to clarify the stability of Kombucha in the manufacture and storage stages due to the extensive study on the fermented products of Kombucha and the increase in the use of bacterial cellulose (BC). This study aimed to evaluate the stability of Kombucha in different manufacturing and storage temperatures within a certain time period. The stability of microorganisms and BC in Kombucha was investigated through regular replacement with the tea media at 28 and 25°C for manufacture, and the storage temperature of Kombucha was at 25, 4, and -20°C. Morphological observations of the BC in Kombucha ended at 28 and 25°C for manufacture and storage were performed using atomic force microscopy (AFM) before inoculation. The viable cell counts and AFM results showed that the stability of Kombucha during manufacture was better at 28°C than at 25°C, with higher microbial viability and BC productivity in the former at the time of manufacture, whereas 25°C was more favorable for the stability of Kombucha during storage. At the same temperature of 25°C, the manufacturing practice improved the microbial viability and BC stability compared with storage; the pH value of Kombucha was lower, and the dry weight of BC was higher during storage compared with manufacture. The maximum BC water holding capacity (97.16%) was maintained by storage at 4°C on day 63, and the maximum BC swelling rate (56.92%) was observed after storage at -20°C on day 7. The research was conducted to provide reference information for applying Kombucha and its BC in food and development in other industries.

Experimental Study on the Migration and Distribution of Microplastics in Desert Farmland Soil Under Drip Irrigation.

The microplastics (MPs) formed by broken plastic film may migrate in the soil under drip irrigation. To investigate the migration distribution of MPs in desert farmland soil under drip irrigation conditions, our study was conducted on farmland in Xinjiang (China). A MP drip irrigation penetration migration testing device was set up in combination with Xinjiang farmland irrigation methods to conduct a migration simulation experiment. The results showed that the migration amount of MPs in soil was significantly positively correlated with the amount of drip irrigation, and significantly negatively correlated with the soil depth; in addition, the relationship between the migration amount of MPs in different types of soil was: clay < sandy loam < sandy soil. Under drip irrigation conditions, the migration rates of MPs were 30.51%, 19.41%, and 10.29% in sandy soil, sandy loam soil, and clay, respectively. The migration ability of these three particle sizes of polyethylene MPs in soil was ranked as follows: 25 to 147 µm > 0 to 25 µm > 147 to 250 µm. When the drip irrigation volume was 2.6 to 3.2 L, horizontal migration distances of MPs exceeded 5 cm, and vertical migration distances reached more than 30 cm. Our findings provide reference data for the study of soil MP migration. Environ Toxicol Chem 2024;43:1250-1259. © 2024 SETAC.

Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis.

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3ß/ß-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of ß-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3ß signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.

Influence of High-Frequency Ultrasonic Vibration Load on Pore-Fracture Structure in Hard Rock: A Study Based on 3D Reconstruction Technology.

Rock fracture is a macroscopic fracturing process resulting from the initiation and propagation of microscopic cracks. Therefore, it is crucial to comprehend the damage and fracture mechanism of rock under ultrasonic vibration by investigating the evolutionary pattern of the meso-pore fracture structure in response to high-frequency vibrational loads, as explored in this study. Standard red sandstone samples with a diameter of 50 mm and height of 100 mm were subjected to ultrasonic high-frequency vibration tests. NMR and CT scans were conducted on the rock samples at different stages of ultrasonic vibration excitation to obtain the corresponding transverse relaxation time (T2) spectra and CT scan images for each layer. The NMR test results revealed that smaller pores formed within the rock under high-frequency vibration loads, with a noticeable expansion observed in micropores. Three-dimensional reconstruction analysis based on two-dimensional CT images demonstrated an increase in pore count by 145.56%, 122.67%, and 98.87%, respectively, for the upper, middle, and lower parts of the rock after 120 s of ultrasonic vibration excitation; furthermore, the maximum pore volume increased by 239.42%, 109.16%, and 18.99%, respectively, for these regions during this period as well. These findings contribute towards a deeper understanding regarding the mechanisms underlying rock fragmentation when exposed to high-frequency vibrational loads.

Extreme low air temperature and reduced moisture jointly inhibit respiration in alpine grassland on the Qinghai-Tibetan Plateau.

Alpine grassland is the main vegetation on the Qinghai-Tibetan Plateau (QTP) and exhibits high sensitivity to extreme weather events. With global warming, extreme weather events are projected to become more frequent on the QTP. However, the impact of these extreme weather events on the carbon cycle of alpine grassland remains unclear. The long-term in-situ carbon fluxes data was collected from 2013 to 2022 at an alpine grassland site to examine the impact of extreme low air temperature (ELT) and reduced moisture (including air and soil) on carbon fluxes during the growing season. Our findings indicated that a significant increase in net ecosystem production (NEP) after 2019, with the average NEP increasing from 278.91 ± 43.27 g C m-2 year-1 during 2013-2018 to 415.45 ± 45.29 g C m-2 year-1 during 2019-2022. The ecosystem carbon use efficiency (CUE) increased from 0.38 ± 0.06 during 2013-2018 to 0.62 ± 0.11 during 2019-2022. By combining concurrently measured environmental factors and remote sensing data, we identified the factors responsible for the abrupt change in the NEP after 2019. This phenomenon was caused by an abrupt decrease in ecosystem respiration (Reco) after 2019, which resulted from the inhibition imposed by ELT and reduced moisture. In contrast, gross primary production (GPP) remained stable from 2013 to 2022, which was confirmed by the remotely sensed vegetation index. This study highlights that combined extreme weather events associated with climate change can significantly impact the NEP of alpine grassland, potentially affecting different carbon fluxes at different rates. These findings provide new insights into the mechanisms governing the carbon cycle of alpine grassland.

Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo.

Pancreatic cancer, one of the most aggressive malignancies, has no effective treatment due to the lack of targets and drugs related to tumour metastasis. SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer. However, highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered. Here, we developed a novel SIRT6 allosteric inhibitor, compound 11e, with maximal inhibitory potency and an IC50 value of 0.98 ± 0.13 µmol/L. Moreover, compound 11e exhibited significant selectivity against other histone deacetylases (HADC1‒11 and SIRT1‒3) at concentrations up to 100 µmol/L. The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses. Importantly, we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis. To our knowledge, this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer. It not only provides a promising lead compound for subsequent inhibitor development targeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity.

The occurrence of NAD+ as a non-canonical RNA cap has been demonstrated in diverse organisms. TIR domain-containing proteins present in all kingdoms of life act in defense responses and can have NADase activity that hydrolyzes NAD+. Here, we show that TIR domain-containing proteins from several bacterial and one archaeal species can remove the NAM moiety from NAD-capped RNAs (NAD-RNAs). We demonstrate that the deNAMing activity of AbTir (from Acinetobacter baumannii) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by known decapping enzymes. Heterologous expression of the wild-type but not a catalytic mutant AbTir in E. coli suppressed cell propagation and reduced the levels of NAD-RNAs from a subset of genes before cellular NAD+ levels are impacted. Collectively, the in vitro and in vivo analyses demonstrate that TIR domain-containing proteins can function as a deNAMing enzyme of NAD-RNAs, raising the possibility of TIR domain proteins acting in gene expression regulation.

Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma.

Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, we demonstrate that HCC with high MER proto-oncogene tyrosine kinase (MerTK) expression exhibits anti-PD-1/PD-L1 resistance in two syngeneic mouse models and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, MerTK renders HCC resistant to anti-PD-1/PD-L1 by limiting ferroptosis with the upregulation of SLC7A11 via the ERK/SP1 pathway and facilitating the development of an immunosuppressive tumor microenvironment (TME) with the recruitment of myeloid-derived suppressor cells (MDSCs). Sitravatinib, an inhibitor of MerTK, sensitizes resistant HCC to anti-PD-L1 therapy by promoting tumor ferroptosis and decreasing MDSC infiltration into the TME. In conclusion, we find that MerTK could serve as a predictive biomarker for patient stratification and as a promising target to overcome anti-PD-1/PD-L1 resistance in HCC.

Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.