Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are critical events for placentation. ...However, appropriate in vitro modelling system and regulatory programs of these two events are still lacking. Recent trophoblast organoid (TO) has advanced the molecular and mechanistic research in placentation. Here, we firstly generated the self-renewing TO from human placental villous and differentiated it into EVTs (EVT-TO) for investigating the differentiation events. We then co-cultured EVT-TO with freshly isolated decidual NKs for further study of cell communication. TO modelling of EVT differentiation as well as EVT interaction with dNK might cast new aspect for placentation research. Single-cell RNA sequencing (scRNA-seq) was applied for comprehensive characterization and molecular exploration of TOs modelling of EVT differentiation and interaction with dNKs. Multiple distinct trophoblast states and dNK subpopulations were identified, representing CTB, STB, EVT, dNK1/2/3 and dNKp. Lineage trajectory and Seurat mapping analysis identified the close resemblance of TO and EVT-TO with the human placenta characteristic. Transcription factors regulatory network analysis revealed the cell-type specific essential TFs for controlling EVT differentiation. CellphoneDB analysis predicted the ligand-receptor complexes in dNK-EVT-TO co-cultures, which relate to cytokines, immunomodulation and angiogenesis. EVT was known to affect the immune properties of dNK. Our study found out that on the other way around, dNKs could exert effects on EVT causing expression changes which are functionally important. Our study documented a single-cell atlas for TO and its applications on EVT differentiation and communications with dNKs, and thus provide methodology and novel research cues for future study of human placentation.
In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still ...poorly understood. In this study, we investigated the roles of cold‑inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC).
CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot.
Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)‑like population. Moreover, hyperthermia substantially improved the sensitivity of radiation‑resistant NPC cells and CSC‑like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti‑tumor‑killing activity of hyperthermia against NPC cells and CSC‑like cells, whereas ectopic expression of Cirbp compromised tumor‑killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC‑like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance.
Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.
The outbreak of the coronavirus disease-19 (COVID-19) has caused enormous stress among the public in China. Intellectual input from various aspects is needed to fight against COVID-19, including ...understanding of the public's emotion and behaviour and their antecedents from the psychological perspectives. Drawing upon the cognitive appraisal theory, this study examined three cognitive appraisals (i.e., perceived severity, perceived controllability, and knowledge of COVID-19) and their associations with a wide range of emotional and behavioural outcomes among the Chinese public.
Participants were 4607 citizens (age range: 17-90 years, Mage = 23.71 years) from 31 provinces in China and they took part in a cross-sectional survey online.
The results showed that the public's emotional and behavioural reactions were slightly affected by the outbreak of COVID-19. Moreover, the public had limited participation in the events regarding COVID-19 but actively engaged in precautionary behaviour. In addition, results of structural equation model with latent variables revealed that the three appraisals were differentially related to the outcome variables (i.e., negative emotion, positive emotion, sleep problems, aggression, substance use, mobile phone use, social participation, and precautionary behaviour).
The findings highlight the utility of cognitive appraisal, as a core process of coping stress, in explaining the public's emotion and behaviour in the encounter of public health concern. Practically, the findings facilitate the government and practitioners to design and deliver targeted intervention programs to the public.
Metastasis of tumor cells occurs through lymphatic vessels, blood vessels and transcoelomic spreading. Growing evidence from in vivo and in vitro studies has indicated that tumor lymphangiogenesis ...facilitates metastasis. However, the regulation of lymphangiogenesis in colon cancer remains unclear. The aims of this study were to identify key miRNAs in colon cancer lymphangiogenesis and to investigate its target and mechanism.
miRNA microarray analysis was conducted to identify miRNAs in human lymphatic endothelial cells (HLECs) that were regulated by co-cultured human colon cancer cells. Gain- and loss-of-function studies were performed to determine the function of miR-27a, a top hint, on lymphangiogenesis and migration in HLECs. Furthermore, bioinformatics prediction and experimental validation were performed to identify miR-27a target genes in lymphangiogenesis.
We found that expression of miR-27a in HLECs was induced by co-culturing with colon cancer cells. Over-expression of miR-27a in HLECs enhanced lymphatic tube formation and migration, whereas inhibition of miR-27a reduced lymphatic tube formation and migration. Luciferase reporter assays showed that miR-27a directly targeted SMAD4, a pivotal component of the TGF-β pathway. In addition, gain-of-function and loss-of-function experiments showed that SMAD4 negatively regulated the length of lymphatic vessels formed by HLECs and migration.
Our data indicated that colon cancer cell induced the expression of miR-27a in HLECs, which promoted lymphangiogenesis by targeting SMAD4. Our finding implicated miR-27a as a potential target for new anticancer therapies in colon cancer.
Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells ...drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to 'drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.
Summary
Glycosylation is a conserved set of post‐translational modifications that exists in all eukaryotic cells. During the last decade, the role of glycosylation in plant pathogenic fungi has ...received significant attention and considerable progress has been made especially in Ustilago maydis and Magnaporthe oryzae. Here, we review recent advances in our understanding of the role of N‐glycosylation, O‐glycosylation and glycosylphosphatidylinositol (GPI) anchors during plant infection by pathogenic fungi. We highlight the roles of these processes in regulatory mechanisms associated with appressorium formation, host penetration, biotrophic growth and immune evasion. We argue that improved knowledge of glycosylation pathways and the impact of these modifications on fungal pathogenesis is overdue and could provide novel strategies for disease control.
Pyrene is a good oxygen-sensitive probe with high fluorescence quantum yield, suitable sensitivity, and high photostability when dispersed in gas-permeable organic polymers, but it is a carcinogen ...and environmental pollutant and tends to aggregate and/or evaporate at high temperature/low pressure. In this work, we show that pyrene can be easily and firmly encapsulated in a metal–organic zeolite SOD-Zn(mim)2 (Hmim = 2-methylimidazole, MAF-4 or ZIF-8) via an in situ loading strategy, giving fluorescence O2-sensing materials not only with fast response, high photostability, and tunable sensitivity but also free of pyrene aggregation/leak and interference by other quenchers. Moreover, these host–guest inclusion crystals can be easily fabricated as thin film sensors and aerodynamic coatings.
Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota ...has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.
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•High abundance of F. nucleatum correlates with decreased efficacy of immunotherapy in CRC•F. nucleatum diminished the sensitivity to anti-PD-1 mAb through succinic acid•Succinic acid decreased anti-PD-1 mAb sensitivity by impairing CD8+ T cell immunity•Elimination of intestinal F. nucleatum resensitizes tumors to immunotherapy in CRC
Jiang et al. report that F. nucleatum-derived succinic acid diminished sensitivity to anti-PD-1 mAb in colorectal cancer by impairing CD8+ T cell-mediated antitumor immunity. These findings offer insights into microbiota-metabolite-immune crosstalk in colorectal cancer and potential strategies for improving clinical response to immunotherapy.
Herein, we introduce a 4.0 V class high‐voltage cathode material with a newly recognized sodium superionic conductor (NASICON)‐type structure with cubic symmetry (space group P213), Na3V(PO3)3N. We ...synthesize an N‐doped graphene oxide‐wrapped Na3V(PO3)3N composite with a uniform carbon coating layer, which shows excellent rate performance and outstanding cycling stability. Its air/water stability and all‐climate performance were carefully investigated. A near‐zero volume change (ca. 0.40 %) was observed for the first time based on in situ synchrotron X‐ray diffraction, and the in situ X‐ray absorption spectra revealed the V3.2+/V4.2+ redox reaction with high reversibility. Its 3D sodium diffusion pathways were demonstrated with distinctive low energy barriers. Our results indicate that this high‐voltage NASICON‐type Na3V(PO3)3N composite is a competitive cathode material for sodium‐ion batteries and will receive more attention and studies in the future.
A new NASICON‐type high‐voltage cathode material of Na3V(PO3)3N was synthesized and its electrochemical performance was improved by carbon matrix decoration. An in‐depth investigation of the material was performed through in situ XAS and XRD, and its 3D sodium pathways were clearly identified through DFT calculations.
Protein post-translational modifications play critical roles in cellular processes, development and stress response. The small ubiquitin-like modifier (SUMO) to proteins is one of the essential ...modifications in eukaryotes, but its function remains largely unknown in plant pathogenic fungi.
We present a comprehensive analysis combined with proteomic, molecular and cellular approaches to explore the roles of sumoylation in the model plant fungal pathogen, Magnaporthe oryzae.
We found the SUMO pathway plays key roles in colony growth, conidia formation and virulence to the host, as well as cell-cycle-related phenotypes. Sumoylation is also involved in responding to different stresses. Affinity purification identified 940 putative SUMO substrates, many of which were reported to be involved in development, stress response and infection. Interestingly, four septins were also shown to be sumoylated. Mutation of consensus sumoylation sites in each septin all resulted in reduced virulence to the host and dislocation of septins in appressoria. Moreover, sumoylation is also involved in extracellular secretion of different effector proteins.
Our study on the functions of sumoylation provides novel insight into development and infection of the rice blast fungus.
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