Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.

Ta4C3-Modulated MOF-Derived 3D Crosslinking Network of VO2(B)@Ta4C3 for High-Performance Aqueous Zinc Ion Batteries.

A two-dimensional MXene (Ta4C3) was innovatively used herein to modulate the space group and electronic properties of vanadium oxides, and the MXene/metal-organic framework (MOF) derivative VO2(B)@Ta4C3 with 3D network cross-linking was prepared, which was then employed as a cathode to improve the performance of aqueous zinc ion batteries (ZIBs). A novel method combining HCl/LiF and hydrothermal treatments was used to etch Ta4AlC3 to obtain a large amount of accordion-like Ta4C3, and the V-MOF was then hydrothermally grown on the surface of the stripped Ta4C3 MXene. During the annealing process of V-MOF@Ta4C3, the addition of Ta4C3 MXene liberates the V-MOF from agglomerative stacking, allowing it to show additional active sites. More significantly, Ta4C3 prevents the V-MOF in the composite structure from converting into V2O5 of space group Pmmn but into VO2(B) of space group C2/m after annealing. A considerable advantage of VO2(B) for Zn2+ intercalation is provided by the negligible structural transformation during the intercalation process and the special tunnel transport channels, which have an enormous area (0.82 nm2 along the b axis). According to first-principles calculations, there is a strong interfacial interaction between VO2(B) and Ta4C3, which deliver remarkable electrochemical activity and kinetic performances for the storage of Zn2+. Therefore, the ZIBs prepared with the VO2(B)@Ta4C3 cathode material exhibit an ultra-high capacity of 437 mA h·g-1 at 0.1 A·g-1 while showing good cycle performance and dynamic performance. This study will offer a fresh approach and a reference for creating metal oxide/MXene composite structures.

Dual roles for CND1 in maintenance of nuclear and chloroplast genome stability in plants.

The coordination of chloroplast and nuclear genome status is critical for plant cell function. Here, we report that Arabidopsis CHLOROPLAST AND NUCLEUS DUAL-LOCALIZED PROTEIN 1 (CND1) maintains genome stability in the chloroplast and the nucleus. CND1 localizes to both compartments, and complete loss of CND1 results in embryo lethality. Partial loss of CND1 disturbs nuclear cell-cycle progression and photosynthetic activity. CND1 binds to nuclear pre-replication complexes and DNA replication origins and regulates nuclear genome stability. In chloroplasts, CND1 interacts with and facilitates binding of the regulator of chloroplast genome stability WHY1 to chloroplast DNA. The defects in nuclear cell-cycle progression and photosynthesis of cnd1 mutants are respectively rescued by compartment-restricted CND1 localization. Light promotes the association of CND1 with HSP90 and its import into chloroplasts. This study provides a paradigm of the convergence of genome status across organelles to coordinately regulate cell cycle to control plant growth and development.

PBLD inhibits angiogenesis via impeding VEGF/VEGFR2-mediated microenvironmental cross-talk between HCC cells and endothelial cells.

Sustained anti-angiogenesis therapy increases the level of tumor hypoxia, leading to increased expression of HIF-1a, thereby contributing to the resistance to anti-angiogenesis therapy in hepatocellular carcinoma (HCC). Here, we report that phenazine biosynthesis-like domain-containing protein (PBLD) inhibits hypoxia-induced angiogenesis via ERK/HIF-1a/VEGF axis in HCC cells. Bioinformatic analysis of the TCGA database and clinical samples validation also identify a negative correlation between PBLD and angiogenesis-related genes expression including HIF-1a. Apart from the downregulation of HIF-1a/VEGF expression in HCC cells, PBLD also blocks VEGF receptor 2 (VEGFR2) on endothelial cells via HCC-derived exosomal miR-940. PBLD also activates TCF4 transcriptional promotion effects on miR-940 by directly interacting with it. Together, PBLD exerts an inhibitory effect on angiogenesis not only via blocking the VEGFR2 expression in endothelial cells, but also through downregulating HIF-1a-induced VEGF expression and secretion in HCC cells. These explorations may provide a theoretical basis for exploring new targets and strategies to overcome resistance to anti-angiogenesis therapy.

Oxygen-Terminated Nb2CO2 MXene with Interfacial Self-Assembled COF as a Bifunctional Catalyst for Durable Zinc-Air Batteries.

The desirable air cathode in Zn-air batteries (ZABs) that can effectively balance oxygen evolution and oxygen reduction reactions not only needs to adjust the electronic structure of the catalyst but also needs a unique physical structure to cope with the complex gas-liquid environment. In this work, first-principles calculations were carried out to prove that oxygen-terminated Nb2CO2 MXene played an active role in enhancing the sluggish reaction of oxygen intermediates. Nb2CO2 MXene could also stimulate the spatial accumulation of discharge products, which was beneficial to improve the stability of secondary ZABs. Molecular dynamics simulation was used to show that the confinement effect of COF could effectively regulate the concentration of O2 on the surface of Nb2CO2@COF, which was conducive to an efficient and durable reaction. COF-LZU1 was self-assembled on the interface of Nb2CO2 MXene (Nb2CO2@COF) for the first time. The Nb2CO2@COF electrode had excellent OER/ORR overpotentials with the potential difference (ΔE) of 0.79 V. When applied to the configuration of ZABs, Nb2CO2@COF showed a power density of 75 mW cm-2 and favorable long-term charge/discharge stability, so it could be used as a potential candidate cathode for noble-metal-based catalysts. This idea of combining MXenes and COFs sheds some light on the design of ZABs.

HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression.

HMGA1 protein is an architectural transcription factor that has been implicated in the progression of multiple malignant tumors. However, the role of HMGA1 in the growth and metastasis of gastric cancer (GC) has not yet been elucidated. Here, we show that HMGA1 is overexpressed in GC cells and the high expression of HMGA1 was correlated with worse survival in GC patients using a bioinformatics assay. Functionally, HMGA1 affected the EdU incorporation, colony formation, migration and invasion of GC cells by exogenously increasing or decreasing the expression of HMGA1. Mechanistically, HMGA1 directly bound to the SUZ12 and CCDC43 promoter and transactivated its expression in GC cells. Inhibition of SUZ12 and CCDC43 attenuated the proliferation, migration and invasiveness of HMGA1-overexpressing GC cells in vitro. Moreover, both HMGA1 and SUZ12/CCDC43 were highly expressed in cancer cells but not in normal gastric tissues, and their expressions were positively correlated. Finally, a tail vein metastatic assay showed that HMGA1 promoted SUZ12/CCDC43-mediated GC cell metastasis in vivo. Our findings suggest that HMGA1 promotes GC growth and metastasis by transactivating SUZ12 and CCDC43 expression, highlighting HMGA1 as a potential prognostic biomarker in the treatment of GC.

Association of the tumour stroma percentage in the preoperative biopsies with lymph node metastasis in colorectal cancer.

BACKGROUND: Preoperative prediction of lymph node (LN) status is integral to determining the most appropriate treatment strategy for colorectal cancer (CRC). This study aimed to develop and validate a nomogram to predict LN metastasis in CRC preoperatively. METHODS: A total of 530 patients were enrolled and divided into training and validation cohorts. The tumour stroma percentage (TSP) of the preoperative biopsies was assessed. The risk factors for LN metastasis were selected, and a nomogram was constructed subsequently. The performance of the nomogram was assessed by using the AUROC and the calibration curve, and then validated in the validation cohort. RESULTS: High TSP was significantly associated with LN metastasis in both the training and validation cohorts. Computed tomography (CT)-reported T stage, CT-reported LN status, preoperative tumour differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9 and TSP were independent predictors of LN metastasis in CRC. A nomogram incorporating the six predictors was constructed. The nomogram yielded good discrimination and calibration, with an AUROC of 0.846 (95% CI: 0.807-0.886) and 0.809 (95% CI: 0.745-0.872) in the training and validation cohorts, respectively. CONCLUSIONS: Assessment of TSP in the preoperative biopsies provided additional information about the LN status. The nomogram was useful for tailored therapy in CRC preoperatively.

LOW PHOTOSYNTHETIC EFFICIENCY 1 is required for light-regulated photosystem II biogenesis in Arabidopsis.

Photosystem II (PSII), a multisubunit protein complex of the photosynthetic electron transport chain, functions as a water-plastoquinone oxidoreductase, which is vital to the initiation of photosynthesis and electron transport. Although the structure, composition, and function of PSII are well understood, the mechanism of PSII biogenesis remains largely elusive. Here, we identified a nuclear-encoded pentatricopeptide repeat (PPR) protein LOW PHOTOSYNTHETIC EFFICIENCY 1 (LPE1; encoded by At3g46610) in Arabidopsis, which plays a crucial role in PSII biogenesis. LPE1 is exclusively targeted to chloroplasts and directly binds to the 5' UTR of psbA mRNA which encodes the PSII reaction center protein D1. The loss of LPE1 results in less efficient loading of ribosome on the psbA mRNA and great synthesis defects in D1 protein. We further found that LPE1 interacts with a known regulator of psbA mRNA translation HIGH CHLOROPHYLL FLUORESCENCE 173 (HCF173) and facilitates the association of HCF173 with psbA mRNA. More interestingly, our results indicate that LPE1 associates with psbA mRNA in a light-dependent manner through a redox-based mechanism. This study enhances our understanding of the mechanism of light-regulated D1 synthesis, providing important insight into PSII biogenesis and the functional maintenance of efficient photosynthesis in higher plants.

M-type thioredoxins are involved in the xanthophyll cycle and proton motive force to alter NPQ under low-light conditions in Arabidopsis.

KEY MESSAGE: M-type thioredoxins are required to regulate zeaxanthin epoxidase activity and to maintain the steady-state level of the proton motive force, thereby influencing NPQ properties under low-light conditions in Arabidopsis. Non-photochemical quenching (NPQ) helps protect photosynthetic organisms from photooxidative damage via the non-radiative dissipation of energy as heat. Energy-dependent quenching (qE) is a major constituent of NPQ. However, the mechanism underlying the regulation of qE is not well understood. In this study, we demonstrate that the m-type thioredoxins TRX-m1, TRX-m2, and TRX-m4 (TRX-ms) interact with the xanthophyll cycle enzyme zeaxanthin epoxidase (ZE) and are required for maintaining the redox-dependent stabilization of ZE by regulating its intermolecular disulfide bridges. Reduced ZE activity and accumulated zeaxanthin levels were observed under TRX-ms deficiency. Furthermore, concurrent deficiency of TRX-ms resulted in a significant increase in proton motive force (pmf) and acidification of the thylakoid lumen under low irradiance, perhaps due to the significantly reduced ATP synthase activity under TRX-ms deficiency. The increased pmf, combined with acidification of the thylakoid lumen and the accumulation of zeaxanthin, ultimately contribute to the elevated stable qE in VIGS-TRX-m2m4/m1 plants under low-light conditions. Taken together, these results indicate that TRX-ms are involved in regulating NPQ-dependent photoprotection in Arabidopsis.

The marriage of AIE and interface engineering: convenient synthesis and enhanced photovoltaic performance.

As a promising option out of all of the well-recognized candidates that have been developed to solve the coming energy crisis, polymer solar cells (PSCs) are a kind of competitive clean energy source. However, as a convenient and efficient method to improve the efficiency of PSCs, the inherent mechanism of the interfacial modification was still not so clear, and interfacial materials constructed with new units were limited to a large degree. Here we present a new kind of interfacial material consisting of AIE units for the first time, with an efficiency of 8.94% being achieved by inserting TPE-2 as a cathode interlayer. This is a relatively high PCE for PC71BM:PTB7-based conventional PSCs with a single-junction structure. Different measurements, including TEM, AFM, SEM, GIXRD, UPS, SKPM, and SCLC, were conducted to investigate the properties in detail. All of the obtained experimental results confirmed the advantages of the utilization of new interfacial materials with AIE characteristics in polymer solar cells, thus providing an additional choice to develop new organic cathode interfacial layers with high performances.

A highly sensitive and selective fluorescent probe for hypochlorite in pure water with aggregation induced emission characteristics.

As a reactive oxygen species (ROS), hypochlorite (OCl-) plays a crucial role in oxidative stress and signal transduction, controlling a wide range of physiological functions. In addition, the wide use of OCl- in the treatment of food and water might possibly threaten human health if the residual quantity was out of limits. Currently, sensitive methods employed to selectively monitor OCl- in aqueous samples in situ are still scarce and badly needed. Boron esters or acids are considered to be suitable functional groups for the detection of hydrogen peroxide due to their reliable reactivity. In this work, we try to develop a highly sensitive and selective OCl- probe (TPE2B) based on the mechanism of aggregation induced emission (AIE). Due to the distinct increase in water solubility of TPE2OH, which is generated from the reaction between TPE2B and OCl-, the strong emission of TPE2B is quenched dramatically. The response speed was as fast as 30 seconds with a detection limit as low as 28 nM. Additionally, test papers were also fabricated and exhibited a highly sensitive response to 0.1 mM OCl-.

Optimization of Light-Harvesting Pigment Improves Photosynthetic Efficiency.

Maximizing light capture by light-harvesting pigment optimization represents an attractive but challenging strategy to improve photosynthetic efficiency. Here, we report that loss of a previously uncharacterized gene, HIGH PHOTOSYNTHETIC EFFICIENCY1 (HPE1), optimizes light-harvesting pigments, leading to improved photosynthetic efficiency and biomass production. Arabidopsis (Arabidopsis thaliana) hpe1 mutants show faster electron transport and increased contents of carbohydrates. HPE1 encodes a chloroplast protein containing an RNA recognition motif that directly associates with and regulates the splicing of target RNAs of plastid genes. HPE1 also interacts with other plastid RNA-splicing factors, including CAF1 and OTP51, which share common targets with HPE1. Deficiency of HPE1 alters the expression of nucleus-encoded chlorophyll-related genes, probably through plastid-to-nucleus signaling, causing decreased total content of chlorophyll (a+b) in a limited range but increased chlorophyll a/b ratio. Interestingly, this adjustment of light-harvesting pigment reduces antenna size, improves light capture, decreases energy loss, mitigates photodamage, and enhances photosynthetic quantum yield during photosynthesis. Our findings suggest a novel strategy to optimize light-harvesting pigments that improves photosynthetic efficiency and biomass production in higher plants.

The bHLH transcription factor bHLH104 interacts with IAA-LEUCINE RESISTANT3 and modulates iron homeostasis in Arabidopsis.

Iron (Fe) is an indispensable micronutrient for plant growth and development. The regulation of Fe homeostasis in plants is complex and involves a number of transcription factors. Here, we demonstrate that a basic helix-loop-helix (bHLH) transcription factor, bHLH104, belonging to the IVc subgroup of bHLH family, acts as a key component positively regulating Fe deficiency responses. Knockout of bHLH104 in Arabidopsis thaliana greatly reduced tolerance to Fe deficiency, whereas overexpression of bHLH104 had the opposite effect and led to accumulation of excess Fe in soil-grown conditions. The activation of Fe deficiency-inducible genes was substantially suppressed by loss of bHLH104. Further investigation showed that bHLH104 interacted with another IVc subgroup bHLH protein, IAA-LEUCINE RESISTANT3 (ILR3), which also plays an important role in Fe homeostasis. Moreover, bHLH104 and ILR3 could bind directly to the promoters of Ib subgroup bHLH genes and POPEYE (PYE) functioning in the regulation of Fe deficiency responses. Interestingly, genetic analysis showed that loss of bHLH104 could decrease the tolerance to Fe deficiency conferred by the lesion of BRUTUS, which encodes an E3 ligase and interacts with bHLH104. Collectively, our data support that bHLH104 and ILR3 play pivotal roles in the regulation of Fe deficiency responses via targeting Ib subgroup bHLH genes and PYE expression.