Sensing of Liver-Derived Nicotinamide by Intestinal Group 2 Innate Lymphoid Cells Links Liver Cirrhosis and Ulcerative Colitis Susceptibility.

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Tim-4 alleviates acute hepatic injury by modulating homeostasis and function of NKT cells.

T-cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4) is an immune checkpoint molecule, which involves in numerous inflammatory diseases. Tim-4 is mainly expressed on antigen presenting cells. However, increasing evidences have shown that Tim-4 is also expressed on natural killer T (NKT) cells. The role of Tim-4 in maintaining NKT cell homeostasis and function remains unknown. In this study, we explored the effect of Tim-4 on NKT cells in acute liver injury. This study found that Tim-4 expression on hepatic NKT cells was elevated during acute liver injury. Tim-4 deficiency enhanced IFN-γ, TNF-α expression while impaired IL-4 production in NKT cells. Loss of Tim-4 drove NKT cell effector lineages to be skewed to NKT1 subset. Furthermore, Tim-4 KO mice were more susceptible to α-GalCer challenge. In conclusion, our findings indicate that Tim-4 plays an important role in regulating homeostasis and function of NKT cells in acute liver injury. Therefore, Tim-4 might become a new regulator of NKT cells and a potential target for the therapy of acute hepatitis.

Identification of Wheat Glutamate Synthetase Gene Family and Expression Analysis under Nitrogen Stress.

Nitrogen (N), as the main component of biological macromolecules, maintains the basic process of plant growth and development. GOGAT, as a key enzyme in the N assimilation process, catalyzes α-ketoglutaric acid and glutamine to form glutamate. In this study, six GOGAT genes in wheat (Triticum aestivum L.) were identified and classified into two subfamilies, Fd-GOGAT (TaGOGAT2s) and NADH-GOGAT (TaGOGAT3s), according to the type of electron donor. Subcellular localization prediction showed that TaGOGAT3-D was localized in mitochondria and that the other five TaGOGATs were localized in chloroplasts. Via the analysis of promoter elements, many binding sites related to growth and development, hormone regulation and plant stress resistance regulations were found on the TaGOGAT promoters. The tissue-specificity expression analysis showed that TaGOGAT2s were mainly expressed in wheat leaves and flag leaves, while TaGOGAT3s were highly expressed in roots and leaves. The expression level of TaGOGATs and the enzyme activity of TaGOGAT3s in the leaves and roots of wheat seedlings were influenced by the treatment of N deficiency. This study conducted a systematic analysis of wheat GOGAT genes, providing a theoretical basis not only for the functional analysis of TaGOGATs, but also for the study of wheat nitrogen use efficiency (NUE).

NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance.

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis.

BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

TIPE1 limits virus replication by disrupting PKM2/ HIF-1α/ glycolysis feedback loop.

OBJECTIVE: Virus infection is a major threat to human health and remains a significant cause of death to date. Macrophages are important innate immune cells that exhibit indispensable roles in controlling virus replication. It was recently reported that metabolic adaption determines the functional state of macrophages. Thus, to further unravel the crucial factors involving in metabolic adaption of macrophages might provide the potential candidates for optimizing their anti-viral capabilities. METHODS: RT-PCR, Western blotting, virus plaque assay and HE were used to evaluate the viral load in virus-infected Tipe1M-KO and Tipe1f/f mice or cultured macrophages. RNA sequencing were performed with Tipe1M-KOor Tipe1f/f BMDMs upon virus infection. Extracellular acidification rate (ECAR) was applied for analyzing glycolysis rate in virus-infected BMDMs. Co-immunoprecipitation (Co-IP) assay and LC-MS/MS were used to determine the potential interacting proteins of TIPE1. RESULTS: TIPE1 level was significantly reduced in BMDMs infected with either RNA viruses or DNA virus. Deficiency of Tipe1 in macrophages increased viral load and aggravated tissue damage. Mechanistically, TIPE1 suppressed the glycolytic capacity of macrophages through interacting with PKM2 and promoting its ubiquitination degradation, which in turn decreased HIF1α transcription and viral replication in macrophages. CONCLUSIONS: TIPE1 functions as a novel regulator for metabolic reprogramming and virus infection in macrophages.

Dynamic Hybrid Module-Driven NK Cell Stimulation and Release for Tumor Immunotherapy.

Natural killer (NK) cells have become a powerful candidate for adoptive tumor immunotherapy, while their therapeutic efficacy in solid tumors remains unsatisfactory. Here, we developed a hybrid module with an injectable hydrogel and hydroxyapatite (HAp) nanobelts for the controlled delivery of NK cells to enhance the therapy of solid tumors. Surface-functionalized HAp nanobelts modified with agonistic antibodies against NKG2D and 4-1BB and cytokines IL-2 and IL-21 support survival and dynamic activation. Thus, the HAp-modified chitosan (CS) thermos-sensitive hydrogel not only improved the retention of NK cells for more than 20 days in vivo but also increased NK cell function by more than one-fold. The unique architecture of this biomaterial complex protects NK cells from the hostile tumor environment and improves antitumor efficacy. The generation of a transient inflammatory niche for NK cells through a biocompatible hydrogel reservoir may be a conversion pathway to prevent cancer recurrence of resectable tumors.

Urolithin A Hijacks ERK1/2-ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity.

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell-mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA-mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA-ERK1/2-ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA-treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.

Evaluation of aphid resistance on different rose cultivars and transcriptome analysis in response to aphid infestation.

BACKGROUND: The rose is one of the most important ornamental flowers in the world for its aesthetic beauty but can be attacked by many pests such as aphids. Aphid infestation causes tremendous damage on plant tissues leading to harmed petals and leaves. Rose cultivars express different levels of resistance to aphid infestation yet the information remains unclear. Not only that, studies about the transcriptional analysis on defending mechanisms against aphids in rose are limited so far. RESULTS: In this study, the aphid resistance of 20 rose cultivars was evaluated, and they could be sorted into six levels based on the number ratio of aphids. And then, a transcriptome analysis was conducted after aphid infestation in one high resistance (R, Harmonie) and one highly susceptibility (S, Carefree Wonder) rose cultivar. In open environment the majority of rose cultivars had the highest aphid number at May 6th or May 15th in 2020 and the resistance to infestation could be classified into six levels. Differential expression analysis revealed that there were 1,626 upregulated and 767 downregulated genes in the R cultivar and 481 upregulated and 63 downregulated genes in the S cultivar after aphid infestation. Pathway enrichment analysis of the differentially expressed genes revealed that upregulated genes in R and S cultivars were both enriched in defense response, biosynthesis of secondary metabolites (phenylpropanoid, alkaloid, and flavonoid), carbohydrate metabolism (galactose, starch, and sucrose metabolism) and lipid processing (alpha-linolenic acid and linolenic acid metabolism) pathways. In the jasmonic acid metabolic pathway, linoleate 13S-lipoxygenase was specifically upregulated in the R cultivar, while genes encoding other crucial enzymes, allene oxide synthase, allene oxide cyclase, and 12-oxophytodienoate reductase were upregulated in both cultivars. Transcription factor analysis and transcription factor binding search showed that WRKY transcription factors play a pivotal role during aphid infestation in the R cultivar. CONCLUSIONS: Our study indicated the potential roles of jasmonic acid metabolism and WRKY transcription factors during aphid resistance in rose, providing clues for future research.

Vaporization Phase Transition in Cryogenic Liquid Oxygen Sealing Film on Spiral Groove Faces.

The property of vaporization phase transition in liquid oxygen face seals is a key factor affecting the stability of mechanical face seals in many fields, especially under cryogenic conditions. Here, a numerical model based on the saturated vapor pressure is established to investigate the vaporization phase transition property of liquid oxygen sealing film. The novelty of this model is to take the influence of heat transfer and face distortions into consideration at the same time. The pressure and temperature distributions as well as face distortions are calculated, and then the property of vaporization phase transition and sealing performance are analyzed. It is found that spiral grooves may lead to the complex film temperature distributions and irregular vaporization distributions. With the increase in seal temperature and decrease in seal pressure, the vaporization area extends from the low-pressure side to the grooves area, and the vaporization rate increases rapidly. The more important thing is that the vaporization often brings a drastic fluctuation and non-monotonic change in opening force. Specifically, with the increase inin seal temperature from 55 K to 140 K, the opening force fluctuates violently, and the fluctuation range is more than 50%, showing an obvious instability. Finally, this study provides a design range of pressure and temperature values for liquid oxygen face seals. In these ranges, this kind of face seals can have a stable operation, which is beneficial to the practice engineering related to the complex properties of sealing fluid.

Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.

Beta-Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gαs/cAMP Signaling via USP5.

Inadequate ß-cell mass and insulin secretion are essential for the development of type 2 diabetes (T2D). TNF-α-induced protein 8-like 1 (Tipe1) plays a crucial role in multiple diseases, however, a specific role in T2D pathogenesis remains largely unexplored. Herein, Tipe1 as a key regulator in T2D, contributing to the maintenance of ß cell homeostasis is identified. The results show that the ß-cell-specific knockout of Tipe1 (termed Ins2-Tipe1BKO) aggravated diabetic phenotypes in db/db mice or in mice with high-fat diet-induced diabetes. Notably, Tipe1 improves ß cell mass and function, a process that depends on Gαs, the α subunit of the G-stimulating protein. Mechanistically, Tipe1 inhibited the K48-linked ubiquitination degradation of Gαs by recruiting the deubiquitinase USP5. Consequently, Gαs or cAMP agonists almost completely restored the dysfunction of ß cells observed in Ins2-Tipe1BKO mice. The findings characterize Tipe1 as a regulator of ß cell function through the Gαs/cAMP pathway, suggesting that Tipe1 may emerge as a novel target for T2D intervention.

Integrated Transcriptomics and Metabolomics Analysis of Two Maize Hybrids (ZD309 and XY335) under Heat Stress at the Flowering Stage.

High temperature around flowering has a serious impact on the growth and development of maize. However, few maize genes related to flowering under heat stress have been confirmed, and the regulatory mechanism is unclear. To reveal the molecular mechanism of heat tolerance in maize, two maize hybrids, ZD309 and XY335, with different heat resistance, were selected to perform transcriptome and metabolomics analysis at the flowering stage under heat stress. In ZD309, 314 up-regulated and 463 down-regulated differentially expressed genes (DEGs) were detected, while 168 up-regulated and 119 down-regulated DEGs were identified in XY335. By comparing the differential gene expression patterns of ZD309 and XY335, we found the "frontloaded" genes which were less up-regulated in heat-tolerant maize during high temperature stress. They included heat tolerance genes, which may react faster at the protein level to provide resilience to instantaneous heat stress. A total of 1062 metabolites were identified via metabolomics analysis. Lipids, saccharides, and flavonoids were found to be differentially expressed under heat stress, indicating these metabolites' response to high temperature. Our study will contribute to the identification of heat tolerance genes in maize, therefore contributing to the breeding of heat-tolerant maize varieties.

Mnox Nanoenzyme Armed CAR-NK Cells Enhance Solid Tumor Immunotherapy by Alleviating the Immunosuppressive Microenvironment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

SHMT2 promotes papillary thyroid cancer metastasis through epigenetic activation of AKT signaling.

Cancer cells alter their metabolism and epigenetics to support cancer progression. However, very few modulators connecting metabolism and epigenetics have been uncovered. Here, we reveal that serine hydroxymethyltransferase-2 (SHMT2) generates S-adenosylmethionine (SAM) to epigenetically repress phosphatase and tensin homolog (PTEN), leading to papillary thyroid cancer (PTC) metastasis depending on activation of AKT signaling. SHMT2 is elevated in PTC, and is associated with poor prognosis. Overexpressed SHMT2 promotes PTC metastasis both in vitro and in vivo. Proteomic enrichment analysis shows that AKT signaling is activated, and is positively associated with SHMT2 in PTC specimens. Blocking AKT activation eliminates the effects of SHMT2 on promoting PTC metastasis. Furthermore, SHMT2 expression is negatively associated with PTEN, a negative AKT regulator, in PTC specimens. Mechanistically, SHMT2 catalyzes serine metabolism and produces activated one-carbon units that can generate SAM for the methylation of CpG islands in PTEN promoter for PTEN suppression and following AKT activation. Importantly, interference with PTEN expression affects SHMT2 function by promoting AKT signaling activation and PTC metastasis. Collectively, our research demonstrates that SHMT2 connects metabolic reprogramming and epigenetics, contributing to the poor progression of PTC.

ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury.

Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models.

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.

Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity.

Hyperlipidemia impairs anti-tumor immune responses and is closely associated with increased human cancer incidence and mortality. However, the underlying mechanisms are not well understood. In the present study, we show that natural killer (NK) cells isolated from high-fat-diet mice or treated with oleic acid (OA) in vitro exhibit sustainable functional defects even after removal from hyperlipidemic milieu. This is accompanied by reduced chromatin accessibility in the promoter region of NK cell effector molecules. Mechanistically, OA exposure blunts P300-mediated c-Myc acetylation and shortens its protein half-life in NK cells, which in turn reduces P300 accumulation and H3K27 acetylation and leads to persistent NK cell dysfunction. NK cells engineered with hyperacetylated c-Myc mutants surmount the suppressive effect of hyperlipidemia and display superior anti-tumor activity. Our findings reveal the persistent dysfunction of NK cells in dyslipidemia milieu and extend engineered NK cells as a promising strategy for tumor immunotherapy.

Research progress on pathogenic and therapeutic mechanisms of Enterovirus A71.

In recent years, enterovirus A71 (EV-A71) infection has become a major global public health problem, especially for infants and young children. The results of epidemiological research show that EV-A71 infection can cause acute hand, foot, and mouth disease (HFMD) and complications of the nervous system in severe cases, including aseptic pediatric meningoencephalitis, acute flaccid paralysis, and even death. Many studies have demonstrated that EV-A71 infection may trigger a variety of intercellular and intracellular signaling pathways, which are interconnected to form a network that leads to the innate immune response, immune escape, inflammation, and apoptosis in the host. This article aims to provide an overview of the possible mechanisms underlying infection, signaling pathway activation, the immune response, immune evasion, apoptosis, and the inflammatory response caused by EV-A71 infection and an overview of potential therapeutic strategies against EV-A71 infection to better understand the pathogenesis of EV-A71 and to aid in the development of antiviral drugs and vaccines.