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Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
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As a critical step during innate response, the cytoplasmic ß subunit (IFN-γR2) of interferon-γ receptor (IFN-γR) is induced and translocates to plasma membrane to join α subunit to form functional IFN-γR to mediate IFN-γ signaling. However, the mechanism driving membrane translocation and its significance remain largely unknown. We found, unexpectedly, that mice deficient in E-selectin, an endothelial cell-specific adhesion molecule, displayed impaired innate activation of macrophages upon Listeria monocytogenes infection yet had increased circulating IFN-γ. Inflammatory macrophages from E-selectin-deficient mice had less surface IFN-γR2 and impaired IFN-γ signaling. BTK elicited by extrinsic E-selectin engagement phosphorylates cytoplasmic IFN-γR2, facilitating EFhd2 binding and promoting IFN-γR2 trafficking from Golgi to cell membrane. Our findings demonstrate that membrane translocation of cytoplasmic IFN-γR2 is required to activate macrophage innate response against intracellular bacterial infection, identifying the assembly of functional cytokine receptors on cell membrane as an important layer in innate activation and cytokine signaling.
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Selectina E/metabolismo , Imunidade Inata , Receptores de Interferon/metabolismo , Animais , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Membrana Celular/metabolismo , Selectina E/deficiência , Selectina E/genética , Complexo de Golgi/metabolismo , Interferon gama/sangue , Interferon gama/metabolismo , Listeria/patogenicidade , Ativação de Macrófagos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Transporte Proteico , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Transdução de Sinais , Receptor de Interferon gamaRESUMO
Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor ß (TGF-ß) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.
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Progressão da Doença , Eritroblastos/citologia , Proteínas do Tecido Nervoso/sangue , Baço/citologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Células Hep G2 , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/citologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica/genética , Transdução de SinaisRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.
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Hipertensão , Microglia , Animais , Hipertensão/metabolismo , Camundongos , Neurônios/fisiologia , Potássio/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
CD8α(+) dendritic cells (DCs) are specialized at cross-presenting extracellular antigens on major histocompatibility complex (MHC) class I molecules to initiate cytotoxic T lymphocyte (CTL) responses; however, details of the mechanisms that regulate cross-presentation remain unknown. We found lower expression of the lectin family member Siglec-G in CD8α(+) DCs, and Siglec-G deficient (Siglecg(-/-)) mice generated more antigen-specific CTLs to inhibit intracellular bacterial infection and tumor growth. MHC class I-peptide complexes were more abundant on Siglecg(-/-) CD8α(+) DCs than on Siglecg(+/+) CD8α(+) DCs. Mechanistically, phagosome-expressed Siglec-G recruited the phosphatase SHP-1, which dephosphorylated the NADPH oxidase component p47(phox) and inhibited the activation of NOX2 on phagosomes. This resulted in excessive hydrolysis of exogenous antigens, which led to diminished formation of MHC class I-peptide complexes for cross-presentation. Therefore, Siglec-G inhibited DC cross-presentation by impairing such complex formation, and our results add insight into the regulation of cross-presentation in adaptive immunity.
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Apresentação Cruzada , Células Dendríticas/imunologia , Lectinas/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Neoplasias Experimentais/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos/metabolismo , Antígenos CD8/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Lectinas/genética , Ativação Linfocitária , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/metabolismo , Fragmentos de Peptídeos/metabolismo , Fagocitose/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Transdução de Sinais , Carga Tumoral/genéticaRESUMO
The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger-type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase-like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8(+) T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8(+) T cells but not that of naive CD4(+) T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.
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Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/imunologia , Ativação Linfocitária/imunologia , Lisina/imunologia , Proteína-Tirosina Quinase ZAP-70/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ativação Linfocitária/genética , Lisina/genética , Lisina/metabolismo , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Fosforilação/imunologia , Poliubiquitina/imunologia , Poliubiquitina/metabolismo , Ligação Proteica/imunologia , Interferência de RNA , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Ubiquitina-Proteína Ligases , Ubiquitinação/imunologia , Proteína-Tirosina Quinase ZAP-70/metabolismoRESUMO
The Phyllanthaceae family comprises a diverse range of plants with medicinal, edible, and ornamental value, extensively cultivated worldwide. Polyploid species commonly occur in Phyllanthaceae. Due to the rather complex genomes and evolutionary histories, their speciation process has been still lacking in research. In this study, we generated chromosome-scale haplotype-resolved genomes of two octoploid species (Phyllanthus emblica and Sauropus spatulifolius) in Phyllanthaceae family. Combined with our previously reported one tetraploid (Sauropus androgynus) and one diploid species (Phyllanthus cochinchinensis) from the same family, we explored their speciation history. The three polyploid species were all identified as allopolyploids with subgenome A/B. Each of their two distinct subgenome groups from various species was uncovered to independently share a common diploid ancestor (Ancestor-AA and Ancestor-BB). Via different evolutionary routes, comprising various scenarios of bifurcating divergence, allopolyploidization (hybrid polyploidization), and autopolyploidization, they finally evolved to the current tetraploid S. androgynus, and octoploid S. spatulifolius and P. emblica, respectively. We further discuss the variations in copy number of alleles and the potential impacts within the two octoploids. In addition, we also investigated the fluctuation of metabolites with medical values and identified the key factor in its biosynthesis process in octoploids species. Our study reconstructed the evolutionary history of these Phyllanthaceae species, highlighting the critical roles of polyploidization and hybridization in their speciation processes. The high-quality genomes of the two octoploid species provide valuable genomic resources for further research of evolution and functional genomics.
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Genoma de Planta , Haplótipos , Hibridização Genética , Poliploidia , Genoma de Planta/genética , Haplótipos/genética , Filogenia , Especiação Genética , Evolução MolecularRESUMO
BACKGROUND & AIMS: The enteric nervous system (ENS), the gut's intrinsic nervous system critical for gastrointestinal function and gut-brain communication, is believed to mainly originate from vagal neural crest cells (vNCCs) and partially from sacral NCCs (sNCCs). Resolving the exact origins of the ENS is critical for understanding congenital ENS diseases but has been confounded by the inability to distinguish between both NCC populations in situ. Here, we aimed to resolve the exact origins of the mammalian ENS. METHODS: We genetically engineered mouse embryos facilitating comparative lineage-tracing of either all (pan-) NCCs including vNCCs or caudal trunk and sNCCs (s/tNCCs) excluding vNCCs. This was combined with dual-lineage tracing and 3-dimensional reconstruction of pelvic plexus and hindgut to precisely pinpoint sNCC and vNCC contributions. We further used coculture assays to determine the specificity of cell migration from different neural tissues into the hindgut. RESULTS: Both pan-NCCs and s/tNCCs contributed to established NCC derivatives but only pan-NCCs contributed to the ENS. Dual-lineage tracing combined with 3-dimensional reconstruction revealed that s/tNCCs settle in complex patterns in pelvic plexus and hindgut-surrounding tissues, explaining previous confusion regarding their contributions. Coculture experiments revealed unspecific cell migration from autonomic, sensory, and neural tube explants into the hindgut. Lineage tracing of ENS precursors lastly provided complimentary evidence for an exclusive vNCC origin of the murine ENS. CONCLUSIONS: sNCCs do not contribute to the murine ENS, suggesting that the mammalian ENS exclusively originates from vNCCs. These results have immediate implications for comprehending (and devising treatments for) congenital ENS disorders, including Hirschsprung's disease.
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Linhagem da Célula , Movimento Celular , Sistema Nervoso Entérico , Crista Neural , Animais , Crista Neural/citologia , Crista Neural/embriologia , Sistema Nervoso Entérico/embriologia , Camundongos , Técnicas de Cocultura , Camundongos Transgênicos , Nervo Vago/embriologia , Sacro/inervaçãoRESUMO
Understanding the neurobiological correlates of behavioral inhibition in patients with depression who committed violent offenses could contribute to the prediction and prevention of violence. The present study recruited 29 depressed patients with violent offenses (VD group), 27 depressed patients without violent behavior (NVD group), and 28 healthy controls (HC group) to complete a visual Go/NoGo task, during which their responses and electroencephalography were simultaneously recorded using an event-related potentiometer. The results showed that the VD group made more commission errors and responded more slowly relative to the NVD and HC groups. The P3 amplitude of the VD group was reduced in the frontal and central brain regions compared to the HC group and increased in the parietal regions compared to the NVD group. In comparison to Go stimuli, NoGo stimuli induced longer P3 latencies in frontal regions in both the VD and NVD groups; however, this difference was not statistically significant in the HC group. These results provide electrophysical evidence of behavioral inhibition deficits in patients with depression, especially in those with violent behaviors. The reduced P3 amplitude in the frontal-central regions, increased P3 amplitude in the parietal regions, and increased NoGo P3 latency may be potential electrophysiological features that can predict violent behavior in patients with depression.
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Depressão , Potenciais Evocados , Humanos , Potenciais Evocados/fisiologia , Tempo de Reação/fisiologia , Eletroencefalografia , BiomarcadoresRESUMO
The cellular and molecular components required for the formation of premetastatic niche (PMN) to promote lung metastasis need to be further investigated. Lung epithelial cells have been reported to exhibit immunomodulatory roles in lung homeostasis and also to mediate immunosuppressive PMN formation in lung metastasis. Here, by single-cell sequencing, we identified a tumor-polarized subpopulation of alveolar type 2 (AT2) epithelial cells with increased expression of glutathione peroxidase 3 (GPX3) and high production of interleukin (IL)-10 in the PMN. IL-10-producing GPX3+ AT2 cells inhibited CD4+ T cell proliferation but enhanced regulatory T cell generation. Mechanistically, tumor exosome-inducing GPX3 expression is required for GPX3+ AT2 cells to preferentially produce IL-10 by stabilizing hypoxia-inducible factor 1 (HIF-1α) and promoting HIF-1α-induced IL-10 production. Accordingly, conditional knockout of GPX3 in AT2 cells suppressed lung metastasis in spontaneous metastatic models. Together, our findings reveal a role of tumor-polarized GPX3+ AT2 cells in promoting lung PMN formation, adding insights into immune evasion in lung metastasis and providing potential targets for the intervention of tumor metastasis.
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Células Epiteliais Alveolares , Interleucina-10 , Neoplasias Pulmonares , Células Epiteliais Alveolares/citologia , Linfócitos T CD4-Positivos/citologia , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Evasão TumoralRESUMO
Metabotropic glutamate receptor 2 (GRM2) is highly expressed in hippocampal dentate granule cells (DGCs), regulating synaptic transmission and hippocampal functions. Newborn DGCs are continuously generated throughout life and express GRM2 when they are mature. However, it remained unclear whether and how GRM2 regulates the development and integration of these newborn neurons. We discovered that the expression of GRM2 in adult-born DGCs increased with neuronal development in mice of both sexes. Lack of GRM2 caused developmental defects of DGCs and impaired hippocampus-dependent cognitive functions. Intriguingly, our data showed that knockdown of Grm2 resulted in decreased b/c-Raf kinases and paradoxically led to an excessive activation of MEK/ERK1/2 pathway. Inhibition of MEK ameliorated the developmental defects caused by Grm2 knockdown. Together, our results indicate that GRM2 is necessary for the development and functional integration of newborn DGCs in the adult hippocampus through regulating the phosphorylation and activation state of MEK/ERK1/2 pathway.SIGNIFICANCE STATEMENT Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature dentate granule cells (DGCs) in the hippocampus. It remains unclear whether GRM2 is required for the development and integration of adult-born DGCs. We provided in vivo and in vitro evidence to show that GRM2 regulates the development of adult-born DGCs and their integration into existing hippocampal circuits. Lack of GRM2 in a cohort of newborn DGCs impaired object-to-location memory in mice. Moreover, we revealed that GRM2 knockdown paradoxically upregulated MEK/ERK1/2 pathway by suppressing b/c-Raf in developing neurons, which is likely a common mechanism underlying the regulation of the development of neurons expressing GRM2. Thus, Raf/MEK/ERK1/2 pathway could be a potential target for brain diseases related to GRM2 abnormality.
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Giro Denteado , Sistema de Sinalização das MAP Quinases , Masculino , Feminino , Camundongos , Animais , Giro Denteado/fisiologia , Neurônios/fisiologia , Hipocampo/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Neurogênese/fisiologiaRESUMO
Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial-mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients' therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial.
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Adenocarcinoma de Pulmão , Anemia de Fanconi , Neoplasias Pulmonares , Humanos , Estruturas R-Loop , Reprogramação Metabólica , Evasão da Resposta Imune , Adenocarcinoma de Pulmão/genética , Comunicação Celular , Análise de Célula Única , Neoplasias Pulmonares/genética , Microambiente Tumoral/genéticaRESUMO
Two mitotic cyclin types, cyclin A and B, exist in higher eukaryotes, but their specialised functions in mitosis are incompletely understood. Using degron tags for rapid inducible protein removal, we analyse how acute depletion of these proteins affects mitosis. Loss of cyclin A in G2-phase prevents mitotic entry. Cells lacking cyclin B can enter mitosis and phosphorylate most mitotic proteins, because of parallel PP2A:B55 phosphatase inactivation by Greatwall kinase. The final barrier to mitotic establishment corresponds to nuclear envelope breakdown, which requires a decisive shift in the balance of cyclin-dependent kinase Cdk1 and PP2A:B55 activity. Beyond this point, cyclin B/Cdk1 is essential for phosphorylation of a distinct subset of mitotic Cdk1 substrates that are essential to complete cell division. Our results identify how cyclin A, cyclin B and Greatwall kinase coordinate mitotic progression by increasing levels of Cdk1-dependent substrate phosphorylation.
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Proteína Quinase CDC2/metabolismo , Ciclina A/metabolismo , Ciclina B/metabolismo , Mitose , Proteína Fosfatase 2/metabolismo , Proteína Quinase CDC2/genética , Linhagem Celular , Ciclina A/genética , Ciclina B/genética , Humanos , Proteína Fosfatase 2/genéticaRESUMO
Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.
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The acoustic coding metasurfaces (ACMs) have the ability to manipulate complex acoustic behavior by reconstructing the coding sequence. In particular, the design of broadband coding enhances the versatility of ACMs. ACMs offer significant advantages over traditional metasurfaces, including a limited number of units and flexible wave control performance. The unit quantity is determined by 2n, with 1-bit utilizing 2 units, 2-bit using 4 units, and 3-bit employing 8 units. Utilizing multiple bits allows for precise control over the phase of sound waves and enables the realization of more intricate acoustic functions. To address the requirements of broadband multi-bit applications, this paper presents the development of novel 3-bit broadband reflected acoustic coding metasurfaces (BACMs) with eight coding units. These metasurfaces are systematically designed using the bottom-up topology optimization method. A constant phase difference of 45° can be achieved across all eight coding units within a broad frequency range. Additionally, the spiral distribution of phase differences enables the construction of an acoustic vortex metasurface. Moreover, by combining the convolution method, the strategies are outlined for constructing vortex-focusing metasurfaces and vortex beam manipulation metasurfaces. These 3-bit coding metasurfaces possess significant potential in the fields of acoustic particle suspension and acoustic communication.
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BACKGROUND: Adenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor immune environment is unclear. METHODS: RNA-seq data were obtained from the Cancer Genome Atlas and Genotype-Tissue Expression databases. Using the single-cell RNA-sequencing dataset for LIHC obtained from the China National Genebank Database, the communication between malignant cells and T cells in response to different PRKAA2 expression patterns was evaluated. In addition, the association between PRKAA2 expression and T-cell evolution during tumor progression was explored using Pseudotime analysis, and the role of PRKAA2 in metabolic reprogramming was explored using the R "scMetabolis" package. Functional experiments were performed in LIHC HepG2 cells. RESULTS: AMPK subunits were expressed in tissue-specific and substrate-specific patterns. PRKAA2 was highly expressed in LIHC tissues and was associated with poor patient prognosis. Tumors with high PRKAA2 expression displayed an immune cold phenotype. High PRKAA2 expression significantly promoted LIHC immune escape. This result is supported by the following evidence: 1) the inhibition of major histocompatibility complex class I (MHC-I) expression through the regulation of interferon-gamma activity in malignant cells; 2) the promotion of CD8+ T-cell exhaustion and the formation of CD4+ Treg cells in T cells; 3) altered interactions between malignant cells and T cells in the tumor immune environment; and 4) induction of metabolic reprogramming in malignant cells. CONCLUSIONS: Our study indicate that PRKAA2 may contribute to LIHC progression by promoting metabolic reprogramming and tumor immune escape through theoretical analysis, which offers a theoretical foundation for developing PRKAA2-based strategies for personalized LIHC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Proteínas Quinases Ativadas por AMP , Carcinoma Hepatocelular/genética , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Neoplasias Hepáticas/genética , Exaustão das Células T , Linfócitos T Reguladores , Evasão TumoralRESUMO
The problems of low polishing efficiency and serious surface damage in the processing of silicon carbide (SiC) ceramics are well-known. In view of the above problems, a new method of photocatalytic vibration composite polishing (PVCP) combined with a compound control strategy was proposed. A vibration-assisted device was developed, and a compound control system was designed for the device to improve the trajectory tracking accuracy. Experiments were carried out to verify the effectiveness of the vibration-assisted device and the compound control system. In addition, methyl orange degradation and fading experiments, redox potential measurement experiments, and SiC ceramic surface hardness characterization experiments were carried out to reveal the effects of vibration and photocatalytic parameters on polishing solution oxidation and SiC ceramic surface mechanical properties. Finally, the effects of photocatalysis, vibration frequency, amplitude, and the compound control system on the polishing effect were analyzed. The results show that when the UV intensity is 100%, the polishing force is 3-4N, the vibration frequency is 400 Hz, the amplitude is 15 µm, and the surface roughness of SiC ceramics is reduced by about 11 nm after the introduction of the compound control system, which verifies the effectiveness of the combination of the compound control system and PVCP.