Ac4C modification of lncRNA SIMALR promotes nasopharyngeal carcinoma progression through activating eEF1A2 to facilitate ITGB4/ITGA6 translation.

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.

Blocker-SELEX: a structure-guided strategy for developing inhibitory aptamers disrupting undruggable transcription factor interactions.

Despite the well-established significance of transcription factors (TFs) in pathogenesis, their utilization as pharmacological targets has been limited by the inherent challenges in modulating their protein interactions. The lack of defined small-molecule binding pockets and the nuclear localization of TFs do not favor the use of traditional tools. Aptamers possess large molecular weights, expansive blocking surfaces and efficient cellular internalization, making them compelling tools for modulating TF interactions. Here, we report a structure-guided design strategy called Blocker-SELEX to develop inhibitory aptamers (iAptamers) that selectively block TF interactions. Our approach leads to the discovery of iAptamers that cooperatively disrupt SCAF4/SCAF8-RNAP2 interactions, dysregulating RNAP2-dependent gene expression, which impairs cell proliferation. This approach is further applied to develop iAptamers blocking WDR5-MYC interactions. Overall, our study highlights the potential of iAptamers in disrupting pathogenic TF interactions, implicating their potential utility in studying the biological functions of TF interactions and in nucleic acids drug discovery.

Efferocytosis in dendritic cells: an overlooked immunoregulatory process.

Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.

Capillary-Driven Separate Gas-Liquid Transport: Alleviating Mass Transport Losses for Efficient Hydrogen Evolution.

Developing earth-abundant transition metal electrodes with high activity and durability is crucial for efficient and cost-effective hydrogen production. However, numerous studies in the hydrogen evolution reaction (HER) primarily focus on improving the inherent activity of catalysts, and the critical influence of gas-liquid countercurrent transport behavior is often overlooked. In this study, we introduce the concept of separate-path gas-liquid transport to alleviate mass transport losses for the HER by developing a novel hierarchical porous Ni-doped cobalt phosphide electrode (CoNix-P@Ni). The CoNix-P@Ni electrodes with abundant microvalleys and crack structures facilitate the gas-liquid cotransport by separating the bubble release and water supply paths. Visualization and numerical simulation results demonstrate that cracks primarily serve as water supply paths, with capillary pressure facilitating the transport of water from the cracks to the microvalleys. This process ensures the continuous wetting of electrolytes in the electrode, reduces hydrogen supersaturation near the active site, and increases hydrogen transport flux to the microvalleys for accelerating bubble growth. Additionally, the microvalleys act as preferential sites for bubble evolution, preventing bubble coverage on other active sites. By regulating the amount of nickel, the CoNi1-P@Ni electrode exhibited the smallest and densest microvalleys and cracks, achieving superior HER performance with an overpotential of 51 mV at 10 mA cm-2. The results offer a promising direction for constructing high-performance HER electrodes.

Recent Advances in Photodynamic Therapy for Vascular Abnormalities.

Abstract Background: Photodynamic therapy (PDT) is a minimally invasive therapy that was gradually established as a first-line treatment for vascular abnormalities. Its action depends on the appropriate wavelength of light and photosensitizer to produce toxic oxygen species and cause cell death. Objective: Several new clinical improvements and trends in PDT have been described in recent years. The aim of this review is to provide an overview of the current data from clinical trials. Methods: In this review, we introduce and generalize the wavelength, duration, dose, strength, and photosensitizer of PDT for the treatment of vascular abnormalities, such as circumscribed choroidal hemangiomas (CCH), choroidal neovascularization (CNV) and capillary malformation (CM). Results: The systematic review findings indicate that the application of PDT is a safe effective method to treat CCH, CNV and CM. However, PDT also has early onset side effects and late onset side effects. Conclusions: Based on the discussion of the effectiveness of PDT, we conclude that PDT has great potential for clinical use, although PDT has possible side effects.

CRYAB suppresses ferroptosis and promotes osteogenic differentiation of human bone marrow stem cells via binding and stabilizing FTH1.

BACKGROUND: Bone formation and homeostasis are greatly dependent on the osteogenic differentiation of human bone marrow stem cells (BMSCs). Therefore, revealing the mechanisms underlying osteogenic differentiation of BMSCs will provide new candidate therapeutic targets for osteoporosis. METHODS: The osteogenic differentiation of BMSCs was measured by analyzing ALP activity and expression levels of osteogenic markers. Cellular Fe and ROS levels and cell viability were applied to evaluate the ferroptosis of BMSCs. qRT-PCR, Western blotting, and co-immunoprecipitation assays were harnessed to study the molecular mechanism. RESULTS: The mRNA level of CRYAB was decreased in the plasma of osteoporosis patients. Overexpression of CRYAB increased the expression of osteogenic markers including OCN, OPN, RUNX2, and COLI, and also augmented the ALP activity in BMSCs, on the contrary, knockdown of CRYAB had opposite effects. IP-MS technology identified CRYAB-interacted proteins and further found that CRYAB interacted with ferritin heavy chain 1 (FTH1) and maintained the stability of FTH1 via the proteasome mechanism. Mechanically, we unraveled that CRYAB regulated FTH1 protein stability in a lactylation-dependent manner. Knockdown of FTH1 suppressed the osteogenic differentiation of BMSCs, and increased the cellular Fe and ROS levels, and eventually promoted ferroptosis. Rescue experiments revealed that CRYAB suppressed ferroptosis and promoted osteogenic differentiation of BMSCs via regulating FTH1. The mRNA level of FTH1 was decreased in the plasma of osteoporosis patients. CONCLUSIONS: Downregulation of CRYAB boosted FTH1 degradation and increased cellular Fe and ROS levels, and finally improved the ferroptosis and lessened the osteogenic differentiation of BMSCs.

Elevated expression of LCN13 through FXR activation ameliorates hepatocellular lipid accumulation and inflammation.

BACKGROUND: Lipocalin 13 (LCN13) is a member of the lipocalin family that consists of numerous secretory proteins. LCN13 high-expression has been reported to possess anti-obesity and anti-diabetic effects. Although metabolic dysfunction-associated steatotic liver diseases (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) are frequently associated with obesity and insulin resistance, the functional role of endogenous LCN13 and the therapeutic effect of LCN13 in MASH and related metabolic deterioration have not been evaluated. METHODS: We employed a methionine-choline deficient diet model and MASH cell models to investigate the role of LCN13 in MASH development. We sought to explore the effects of LCN13 on lipid metabolism and inflammation in hepatocytes under PA/OA exposure using Western blotting, real-time RT-PCR, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, oil red O staining. Using RNA sequencing, chromatin immunoprecipitation assay, and luciferase reporter assays to elucidate whether farnesoid X receptor (FXR) regulates human LCN13 transcription as a transcription factor. RESULTS: Our study found that LCN13 was down-regulated in MASH patients, MASH mouse and cell models. LCN13 overexpression in hepatocyte cells significantly inhibited lipid accumulation and inflammation in vitro. Conversely, LCN13 downregulation significantly exacerbated lipid accumulation and inflammatory responses in vivo and in vitro. Mechanistically, we provided the first evidence that LCN13 was transcriptionally activated by FXR, representing a novel direct target gene of FXR. And the key promoter region of LCN13 binds to FXR was also elucidated. We further revealed that LCN13 overexpression via FXR activation ameliorates hepatocellular lipid accumulation and inflammation in vivo and in vitro. Furthermore, LCN13-down-regulated mice exhibited aggravated MASH phenotypes, including increased hepatic lipid accumulation and inflammation. CONCLUSION: Our findings provide new insight regarding the protective role of LCN13 in MASH development and suggest an innovative therapeutic strategy for treating MASH or related metabolic disorders.

Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model.

BACKGROUND: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats. METHODS: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested. RESULTS: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region. CONCLUSION: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.

Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.

Effect of ultrahigh pressure processing (UHP) on physicochemical properties, antioxidant activity and anti-inflammatory activity of insoluble dietary fiber from Pholiota nameko.

The aim of this study was to evaluate the effect of ultrahigh pressure processing (UHP) of 200, 300, 400, 500, 600 and 700 MPa for 20, 40 and 30 min on physicochemical and bioactive properties of the insoluble dietary fiber Pholiota nameko (PN-IDF). The results revealed that UHP were capable of decreasing the particle size of PN-IDF and binding phenolic content. Moreover, UHP technique had an improving effect on the bioaccessible phenolic content, the water-holding capacity, the oil-holding capacity and the nitrite ion adsorption capacity. Further, UHP technique presented a promoting effect on the antioxidant activity by scavenging ABTS or DPPH free radicals and increasing reducing power, and the anti-inflammatory activity by inhibiting carrageenan-induced paw edema on PN-IDF. Overall, this study well proved that UHP technology could improve the physicochemical and functional quality of PN-IDF, which could be used as a promising green technique for functional food ingredients processing.

The E3 ligase NEURL3 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma by promoting vimentin degradation.

BACKGROUND: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood. METHODS: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3. RESULTS: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells. CONCLUSIONS: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment.

DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation.

Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments.

SHFL inhibits enterovirus A71 infection by triggering degradation of viral 3Dpol protein via the ubiquitin-proteasome pathway.

Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.

Immobilization of fatty acid photodecarboxylase in magnetic nickel ferrite nanoparticle.

Fatty acid photodecarboxylase in Chlorella variabilis NC64A (CvFAP) performed excellent ability to exclusively decarboxylate renewable fatty acids for C1-shortened hydrocarbons fuel production under visible light. However, the large-scale application by such an approach is limited by the free state of CvFAP catalyst, which is unstable for efficient biofuel production. In this study, CvFAP was immobilized in magnetic nickel ferrite (NiFe2O4) nanoparticles for facile recovery by a simple procedure. The shift of Ni 2p in electron binding energy was detected to clarify the interaction between Ni2+ and histidine of CvFAP. The coordination of NiFe2O4 and CvFAP contributed to an efficient affinity binding with an immobilization capacity of 98 mg/g carrier. Hydrocarbon fuel concentration of 3.7 mM was obtained by NiFe2O4@CvFAP-induced photoenzymatic decarboxylation. The high stability of CvFAP in terms of residual enzyme activity of 79.7% at pH 9.0 and that of 68% at organic solvent ratio of 60%, respectively, were observed.

Study on the structure, antioxidant activity and degradation pattern of polysaccharides isolated from lotus seedpod.

The lotus (Nelumbo nucifera Gaertn.) is the largest aquatic vegetable in Asia. The lotus seedpod (LS) is an inedible part of the mature flower receptacle of the lotus plant. However, the polysaccharide isolated from the receptacle has been less studied. The purification of LS resulted in two polysaccharides (LSP-1 and LSP-2). Both polysaccharides were found to be medium-sized HG pectin, with a Mw of 74 kDa. Their structures were elucidated via GC-MS and NMR spectrum and proposed as the repeating sugar units of GalA connected via α-1,4-glycosidic linkage, with LSP-1 having a higher degree of esterification. They have certain content of antioxidant and immunomodulatory activities. The esterification of HG pectin would have an adverse effect on these activities. Furthermore, the degradation pattern and kinetics of LSPs by pectinase conformed to the Michaelis-Menten model. There is a large amount of LS, resulting from the by-product of locus seed production, and thus a promising source for the isolation of the polysaccharide. The findings of the structure, bioactivities, and degradation property provide the chemical basis for their applications in the food and pharmaceutical industries.

Occurrence and multi-pathway health risk assessment of trihalomethanes in drinking water of Wuxi, China.

Chlorination is widely used to disinfect drinking water to keep humans safe from microorganisms. During chlorination, chlorine and its compounds react with contaminants to form disinfection by-products (DBPs). Toxicological and epidemiological studies have demonstrated that trihalomethanes (THMs) are the most widely investigated DBPs in drinking water, and their exposure has been associated with some adverse health effects. However, studies about risk characteristics in this field are limited. We estimated the health risks of THMs exposure in drinking water through multi-pathways, and systematically analyzed the factors influencing health risks of THMs in Wuxi, China. A total of 488 drinking water samples were collected and analyzed for THMs from four water treatment utilities from 2008 to 2016 in Wuxi. And water exposure parameters were obtained from 602 participants by structured questionnaires. The median concentration of THMs ranged from 6.71 µg/L to 9.18 µg/L. The cumulative cancer risk of THMs exposure through multi-pathways was 1.26 × 10-4, and CHBr2Cl made the largest contribution to the total cancer risk (48.25%). The non-cancer risk of THMs exposure was 2.02 × 10-1. Health risks of the exposure to THMs in drinking water in summer were significantly higher than that in winter (P = 0.0003 for cancer risk, and P = 5.95 × 10-7 for non-cancer risk). In our study, the average individual disability-adjusted life years (DALYs) lost was 1.27 × 10-4 per person-year (ppy). This study attempted to use DALYs for risk assessment of THMs, which will provide useful information for risk comparison and prioritization of hazards in drinking water. This suggested that potential higher risk might exist, and possible measures could be considered to decrease the health risks.

PHF14 enhances DNA methylation of SMAD7 gene to promote TGF-ß-driven lung adenocarcinoma metastasis.

Aberrant activation of TGF-ß signaling plays a pivotal role in cancer metastasis and progression. However, molecular mechanisms underlying the dysregulation of TGF-ß pathway remain to be understood. Here, we found that SMAD7, a direct downstream transcriptional target and also a key antagonist of TGF-ß signaling, is transcriptionally suppressed in lung adenocarcinoma (LAD) due to DNA hypermethylation. We further identified that PHF14 binds DNMT3B and serves as a DNA CpG motif reader, recruiting DNMT3B to the SMAD7 gene locus, resulting in DNA methylation and transcriptional suppression of SMAD7. Our in vitro and in vivo experiments showed that PHF14 promotes metastasis through binding DNMT3B to suppress SMAD7 expression. Moreover, our data revealed that PHF14 expression correlates with lowered SMAD7 level and shorter survival of LAD patients, and importantly that SMAD7 methylation level of circulating tumor DNA (ctDNA) can potentially be used for prognosis prediction. Together, our present study illustrates a new epigenetic mechanism, mediated by PHF14 and DNMT3B, in the regulation of SMAD7 transcription and TGF-ß-driven LAD metastasis, and suggests potential opportunities for LAD prognosis.

Genome size variation and polyploidy prevalence in the genus Eragrostis are associated with the global dispersal in arid area.

Background: Biologists have long debated the drivers of the genome size evolution and variation ever since Darwin. Assumptions for the adaptive or maladaptive consequences of the associations between genome sizes and environmental factors have been proposed, but the significance of these hypotheses remains controversial. Eragrostis is a large genus in the grass family and is often used as crop or forage during the dry seasons. The wide range and complex ploidy levels make Eragrostis an excellent model for investigating how the genome size variation and evolution is associated with environmental factors and how these changes can ben interpreted. Methods: We reconstructed the Eragrostis phylogeny and estimated genome sizes through flow cytometric analyses. Phylogenetic comparative analyses were performed to explore how genome size variation and evolution is related to their climatic niches and geographical ranges. The genome size evolution and environmental factors were examined using different models to study the phylogenetic signal, mode and tempo throughout evolutionary history. Results: Our results support the monophyly of Eragrostis. The genome sizes in Eragrostis ranged from ~0.66 pg to ~3.80 pg. We found that a moderate phylogenetic conservatism existed in terms of the genome sizes but was absent from environmental factors. In addition, phylogeny-based associations revealed close correlations between genome sizes and precipitation-related variables, indicating that the genome size variation mainly caused by polyploidization may have evolved as an adaptation to various environments in the genus Eragrostis. Conclusion: This is the first study to take a global perspective on the genome size variation and evolution in the genus Eragrostis. Our results suggest that the adaptation and conservatism are manifested in the genome size variation, allowing the arid species of Eragrostis to spread the xeric area throughout the world.

TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models.

Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8+ T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.

Role of Tumor Necrosis Factor Receptor 1-Reactive Oxygen Species-Caspase 11 Pathway in Neuropathic Pain Mediated by HIV gp120 With Morphine in Rats.

BACKGROUND: Recent clinical research suggests that repeated use of opioid pain medications can increase neuropathic pain in people living with human immunodeficiency virus (HIV; PLWH). Therefore, it is significant to elucidate the exact mechanisms of HIV-related chronic pain. HIV infection and chronic morphine induce proinflammatory factors, such as tumor necrosis factor (TNF)α acting through tumor necrosis factor receptor I (TNFRI). HIV coat proteins and/or chronic morphine increase mitochondrial superoxide in the spinal cord dorsal horn (SCDH). Recently, emerging cytoplasmic caspase-11 is defined as a noncanonical inflammasome and can be activated by reactive oxygen species (ROS). Here, we tested our hypothesis that HIV coat glycoprotein gp120 with chronic morphine activates a TNFRI-mtROS-caspase-11 pathway in rats, which increases neuroinflammation and neuropathic pain. METHODS: Neuropathic pain was induced by repeated administration of recombinant gp120 with morphine (gp120/M) in rats. Mechanical allodynia was assessed using von Frey filaments, and thermal latency using hotplate test. Protein expression of spinal TNFRI and cleaved caspase-11 was examined using western blots. The image of spinal mitochondrial superoxide was examined using MitoSox Red (mitochondrial superoxide indicator) image assay. Immunohistochemistry was used to examine the location of TNFRI and caspase-11 in the SCDH. Intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) against TNFRI, caspase-11 siRNA, or a scavenger of mitochondrial superoxide was given for antinociceptive effects. Statistical tests were done using analysis of variance (1- or 2-way), or 2-tailed t test. RESULTS: Intrathecal gp120/M induced mechanical allodynia and thermal hyperalgesia lasting for 3 weeks ( P < .001). Gp120/M increased the expression of spinal TNFRI, mitochondrial superoxide, and cleaved caspase-11. Immunohistochemistry showed that TNFRI and caspase-11 were mainly expressed in the neurons of the SCDH. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Tempol (a scavenger of mitochondrial superoxide), or caspase-11 siRNA reduced mechanical allodynia and thermal hyperalgesia in the gp120/M neuropathic pain model. Spinal knockdown of TNFRI reduced MitoSox profile cell number in the SCDH; intrathecal Mito-T decreased spinal caspase-11 expression in gp120/M rats. In the cultured B35 neurons treated with TNFα, pretreatment with Mito-Tempol reduced active caspase-11 in the neurons. CONCLUSIONS: These results suggest that spinal TNFRI-mtROS-caspase 11 signal pathway plays a critical role in the HIV-associated neuropathic pain state, providing a novel approach to treating chronic pain in PLWH with opioids.