CircBRD7 attenuates tumor growth and metastasis in nasopharyngeal carcinoma via epigenetic activation of its host gene.

BRD7 was identified as a tumor suppressor in nasopharyngeal carcinoma (NPC). Circular RNAs (CircRNAs) are involved in the occurrence and development of NPC as oncogenes or tumor suppressors. However, the function and mechanism of the circular RNA forms derived from BRD7 in NPC are not well understood. In this study, we first identified that circBRD7 was a novel circRNA derived from BRD7 that inhibited cell proliferation, migration, invasion of NPC cells, as well as the xenograft tumor growth and metastasis in vivo. Mechanistically, circBRD7 promoted the transcriptional activation and expression of BRD7 by enhancing the enrichment of histone 3 lysine 27 acetylation (H3K27ac) in the promoter region of its host gene BRD7, and BRD7 promoted the formation of circBRD7. Therefore, circBRD7 formed a positive feedback loop with BRD7 to inhibit NPC development and progression. Moreover, restoration of BRD7 expression rescued the inhibitory effect of circBRD7 on the malignant progression of NPC. In addition, circBRD7 demonstrated low expression in NPC tissues, which was positively correlated with BRD7 expression and negatively correlated with the clinical stage of NPC patients. Taken together, circBRD7 attenuates the tumor growth and metastasis of NPC by forming a positive feedback loop with its host gene BRD7, and targeting the circBRD7/BRD7 axis is a promising strategy for the clinical diagnosis and treatment of NPC.

Immune infiltration and clinical significance analyses of the cancer-associated fibroblast-related signature in skin cutaneous melanoma.

BACKGROUND: Skin cutaneous melanoma (SKCM) is one of the most aggressive cancers with high mortality rates. Cancer-associated fibroblasts (CAFs) play essential roles in tumor growth, metastasis and the establishment of a pro-tumor microenvironment. This study aimed to establish a CAF-related signature for providing a new perspective for indicating prognosis and guiding therapeutic regimens of SKCM patients. METHODS: In this study, the CAF-related genes were screened out based on melanoma-associated fibroblast markers identified from single-cell transcriptome analysis in the Gene Expression Omnibus (GEO) database and a CAF-related module identified from weighted gene co-expression analysis using The Cancer Genome Atlas (TCGA) dataset. We extracted these gene expression data of SKCM samples from TCGA and constructed a prognostic CAF-related signature. The prediction abilities of the signature for survival prognosis, tumor immune landscape and responses to chemo-/immunotherapies were evaluated in the TCGA-SKCM cohort. RESULTS: We suggested that CAFs were significantly involved in the clinical outcomes of SKCM. A 10-gene CAF-related model was constructed, and the high-CAF risk group exhibited immunosuppressive features and worse prognosis. Patients with high CAF score were more likely to not respond to immune checkpoint inhibitors but were more sensitive to some chemotherapeutic agents, suggesting a potential approach of chemotherapy/anti-CAF combination treatment to improve the SKCM patient response rate of current immunotherapies. CONCLUSIONS: The CAF-related risk score could serve as a robust prognostic indicator and personal assessment of this score could uncover the degree of immunosuppression and provide treatment strategies to improve outcomes in clinical decision-making in SKCM patients.

Loss-tailoring single-mode high-power supersymmetric lasers.

Diode lasers with high beam quality and high power have many promising applications. However, high beam quality is always in conflict with high power. In this Letter, we theoretically and experimentally confirm the mode instability property of supersymmetric structures at higher operating currents. Meanwhile, we propose a loss-tailoring diode laser based on a supersymmetric structure, which enables the higher-order lateral modes to obtain higher losses, raises the excitation threshold of the higher-order lateral modes, and achieves a stable fundamental-lateral-mode output at higher current operation. The device obtained a quasi-single-lobe lateral far-field distribution with the full width at half maximum (FWHM) of 7.58° at 350 mA under room temperature, which is a 65% reduction compared to the traditional Fabry-Perot (FP) diode lasers. Moreover, the M2 of 2.181@350 mA has an improvement of about 37% over traditional FP and supersymmetric structure lasers.

High-Enantioselectivity Adsorption Separation of Racemic Mandelic Acid and Methyl Mandelate by Robust Chiral UiO-68-Type Zr-MOFs.

Mandelic acid and its analogues are highly valuable medical intermediates and play an important role in the pharmaceutical industry, biochemistry, and life sciences. Therefore, effective enantioselective recognition and separation of mandelic acid are of great significance. In this study, two of our recently reported chiral amine-alcohol-functionalized UiO-68-type Zr-HMOFs 1 and 3 with high chemical stability, abundant binding sites, and large chiral pores were selected as chiral selectors for the enantioselective separation of mandelic acid (MA), methyl mandelate (MM), and other chiral molecules containing only one phenyl. Materials 1 and 3 exhibited excellent enantioselective separation performance for MA and MM. Especially for the separation of racemate MA, the enantiomeric excess values reached 97.3 and 98.9%, which are the highest reported values so far. Experimental and density functional theory (DFT) computational results demonstrated that the introduction of additional phenyls on the chiral amine alcohol pendants in 3 had somewhat impact on the enantioselective adsorption and separation of MA or MM compared with 1, but it was not significant. Further research on the enantioselective separation of those chiral adsorbates containing only one phenyl by material 1 indicated the crucial role of the groups directly bonded to the chiral carbons of the adsorbates in the selective separation of enantiomers, especially showing higher enantioselectivity for the adsorbates with two hydrogen-bonding groups directly bonded to its chiral carbon.

Nerve Injury-Induced γH2AX Reduction in Primary Sensory Neurons Is Involved in Neuropathic Pain Processing.

Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.

The emerging roles of the interaction between m6A modification and c-Myc in driving tumorigenesis and development.

N6-methyladenosine (m6A) is an extremely common and conservative posttranscriptional modification, that can specifically target and regulate the expression or stability of a series of tumor-related genes, thus playing critical roles in the occurrence and development of tumors. c-Myc is an important tumorigenic transcription factor that promotes tumorigenesis and development by mainly regulating the expression of downstream target genes. Increasing evidence shows that m6A modification, as well as abnormal expression and regulation of c-Myc, is critical molecular mechanisms driving tumorigenesis and development. Although more evidence has been uncovered about the individual roles of m6A modification or c-Myc in tumors, the interaction between m6A modification and c-Myc in tumorigenesis and development has not been systematically summarized. Therefore, this review is focused on the mutual regulation between m6A modification and c-Myc expression and stability as well as its roles in tumorigenesis and development. We also summarized the potential value of the interaction between m6A modification and m6A expression and stability in tumor diagnosis and treatment, which provides a specific reference for revealing the mechanism of tumor occurrence and development as well as clinical diagnosis and treatment.

Improved profiling of low molecular weight serum proteome for gastric carcinoma by data-independent acquisition.

Low molecular weight proteins (LMWPs) in the bloodstream participate in various biological processes and are closely associated with disease status, whereas identification of serous LMWPs remains a great technical challenge due to the wide dynamic range of protein components. In this study, we constructed an integrated LMWP library by combining the LMWPs obtained by three enrichment methods (50% ACN, 20% ACN + 20 mM ABC, and 30 kDa) and their fractions identified by the data-dependent acquisition method. With this newly constructed library, we comprehensively profiled LMWPs in serum using data-independent acquisition and reliably achieved quantitative results for 75% serous LMWPs. When applying this strategy to quantify LMWPs in human serum samples, we could identify 405 proteins on average per sample, of which 136 proteins were with a MW less than 30 kDa and 293 proteins were with a MW less than 65 kDa. Of note, pre- and post-operative gastric carcinoma (GC) patients showed differentially expressed serous LWMPs, which was also different from the pattern of LWMP expression in healthy controls. In conclusion, our results showed that LMWPs could efficiently distinguish GC patients from healthy controls as well as between pre- and post-operative statuses, and more importantly, our newly developed LMWP profiling platform could be used to discover candidate LMWP biomarkers for disease diagnosis and status monitoring.

Low-cost and efficient confocal imaging method for arabidopsis flower.

For an extensive period of time apical meristem (SAM) has been considered as a mysterious organ, due to its small, hidden and dynamic structure. Confocal imaging, combined with fluorescent reporters, enables researchers to unveil the mechanisms underlying cellular activities, such as gene expression, cell division, growth patterns and cell-cell communications. Recently, a series of protocols were developed for confocal imaging of inflorescence meristem (IM) and floral meristem (FM). However, the requirement of high configuration, such as the need of a water-dipping lens without coverslip and the specialized turrets associated with fixed-stage microscopes, impedes the wide adoption of these methods. We exploited an improved object slide and matching method aiming to decrease the configuration requirement. Following this protocol, various dry microscope lenses can be selected with flexibility for building 3D images of IM and FM.

A glimpse of deep-sea adaptation in chemosynthetic holobionts: Depressurization causes DNA fragmentation and cell death of methanotrophic endosymbionts rather than their deep-sea Bathymodiolinae host.

Bathymodiolinae mussels are typical species in deep-sea cold seeps and hydrothermal vents and an ideal model for investigating chemosynthetic symbiosis and the influence of high hydrostatic pressure on deep-sea organisms. Herein, the potential influence of depressurization on DNA fragmentation and cell death in Bathymodiolinae hosts and their methanotrophic symbionts were surveyed using isobaric and unpressurized samples. As a hallmark of cell death, massive DNA fragmentation was observed in methanotrophic symbionts from unpressurized Bathymodiolinae while several endonucleases and restriction enzymes were upregulated. Additionally, genes involved in DNA repair, glucose/methane metabolism as well as two-component regulatory system were also differentially expressed in depressurized symbionts. DNA fragmentation and programmed cell death, however, were rarely detected in the host bacteriocytes owing to the orchestrated upregulation of inhibitor of apoptosis genes and downregulation of caspase genes. Meanwhile, diverse host immune recognition receptors were promoted during depressurization, probably enabling the regain of symbionts. When the holobionts were subjected to a prolonged acclimation at atmospheric pressure, alternations in both the DNA fragmentation and the expression atlas of aforesaid genes were continuously observed in symbionts, demonstrating the persistent influence of depressurization. Contrarily, the host cells demonstrated certain tolerance against depressurization stress as expression level of some immune-related genes returned to the basal level in isobaric samples. Altogether, the present study illustrates the distinct stress responses of Bathymodiolinae hosts and their methanotrophic symbionts against depressurization, which could provide further insight into the deep-sea adaptation of Bathymodiolinae holobionts while highlighting the necessity of using isobaric sampling methods in deep-sea research.

Introducing High Density of Very Active Sites and Stepwise Postmodification for Tailoring the Porosity of Highly Demanding Cr3+-Based Metal-Organic Frameworks.

Chromium(III)-based metal-organic frameworks (Cr-MOFs) are highly robust and porous and have been very attractive in a wide range of investigations. However, the harsh direct synthetic conditions not only impede the synthesis of new Cr-MOFs but also restrict the introduction of functional groups into them. Postsynthetic modification has somewhat alleviated such difficulties; nevertheless, it still suffered from procedures that are tedious and conditions that are not mild, which often result in low concentration of the functional groups introduced. To overcome these shortcomings, here, in this paper, we supplied a new route and prepared a benzyl alcohol functionalized Cr-SXU-2 from the judiciously designed benzyl alcohol functionalized Fe-SXU-2 through solvent-assisted metal metathesis strategy. The functionalized Cr-SXU-2 shows well-preserved crystallinity, porosity, and high chemical stability. The benzyl alcohol group can be converted into a very active benzyl bromide group in an almost quantitative yield and thus for the first time produce the benzyl bromide functionalized MOF, Cr-SXU-2-Br, in which the -Br group can be exchanged by a nucleophilic group. As a proof of concept, -N3 was introduced and transformed into other active sites via "click reaction" to further tailor the interior of Cr-SXU-2. All these functionalized Cr-MOFs showed improved adsorption performance in contrast to the nonfunctionalized one. This step-by-step postmodification process not only diversifies the functionalization of robust MOFs but also opens a new route to employ many different functional groups in the demanding highly stable Cr-MOF platforms.

Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc-mediated microRNA-141 transcription.

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.

Modulator-Induced Zr-MOFs Diversification and Investigation of Their Properties in Gas Sorption and Fe3+ Ion Sensing.

In this paper, we synthesized three Zr-MOFs (Zr-SXU-1, Zr-SXU-2, and Zr-SXU-3) composed of identical ligands and metal clusters by using tetratopic carboxylic ligand PBPTTBA as the ligand and benzoic acids as modulators. These three Zr-MOFs showed different structures and topologies, and the connectivity of the Zr clusters varied from 8 in Zr-SXU-3, to 10 in Zr-SXU-1, and finally to 12 in Zr-SXU-2 due to the modulators used. Among them, Zr-SXU-1 represents an unusual 6-node network and [6(10)(11)7] transitivity. Besides, Zr-SXU-2 can only be obtained by using ditopic carboxylic acid as a second modulator when using benzoic acid as the main modulator, which is not reported in other Zr-MOFs synthesis. The adsorption and luminescence tests demonstrated their potential as gas reservoirs, separators, and sensors and also showed the importance of structure topologies to the applications.

Synthesis and properties of dithienylethene-functionalized switchable antibacterial agents.

Photopharmacology involving azobenzene has offered a viable alternative for combating bacterial resistance. However, the degradation and potential toxicity of azobenzene limit its further study in vivo. Therefore, searching for an appropriate photoswitch for further clinical application is highly desirable. Herein a series of dithienylethene-functionalized switchable antibacterial agents have been designed and prepared by the introduction of the dithienylethene scaffold into fluoroquinolones. And it was found that these switchable antibacterial agents displayed good photochromism and fluorescence switching behaviors upon irradiation with UV/Vis light in DMSO. Surprisingly, methoxy-substituted dithienylethenes 3a and 3b exhibited fluorescence turn-on behavior. Furthermore, it was found that all of the open-isomers showed partial antibacterial activity on E. coli and S. aureus compared with the native drugs. Apart from 2a and 2b, the other switchable antibacterial agents showed a large difference in antibacterial activity on Gram-negative E. coli between the open and closed forms, in which the antimicrobial activity of the ring-closed isomers for 1b and 3b was 16 times that of the corresponding ring-open isomers. DFT calculations showed that the ring-closed isomers of 1b and 3b presented a rigid "S-type" conformation, which may be conducive to forming more stable complexes with the DNA gyrase of E. coli.

Development of calcium-modified biochar for enhanced phytoremediation of human-induced salt pollutants (HISPs).

Soil salinization is a major environmental hazard that limits land availability. Human-induced salt pollutants (HISPs) are regularly presented in large quantities on the contaminated site (such as brine leakages and salt-water spills), causing a devastating shock with high salt stress to the ecosystem. For instance, Saskatchewan resulted in a 48% drop in wheat production and a 0.3% decline in provincial GDP. As the calcium-modified biochar can potentially ameliorate the negative effects of HISPs on plants and improve the plant, phytoremediation with calcium-modified biochar can have increased detoxification of hazardous pollutants from sites. Therefore, the objective of our study was to develop a biochar-assisted phytoremediation employing diverse approaches to calcium modification for the sustainable removal of HISPs. The co-pyrolyzed calcium biochar achieved a remarkable removal rate of 18.06%, reducing salinity from 9.44 to 7.81 dS/m. During a 90-day long-term phytoremediation, the overall reduction rate of calcium-modified biochar stimulated the germination and growth of Thinopyrum ponticum. The result of post-treatment further indicated that co-pyrolyzed biochar with Ca transferred salt into the plant compared to Ca-coated biochar, which only immobilized HISPs on its surface. These results offer two different treatment approaches for diverse situations involving HISPs contamination, addressing current in-situ spills and providing a calcium-related biochar technology for further research in desalination.

Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of Pin1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of Pin1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of Pin1, which induced Pin1 degradation with a DC50 value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, Pin1 inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted Pin1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer.

Purpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

Insights into phage-bacteria interaction in cold seep Gigantidas platifrons through metagenomics and transcriptome analyses.

Viruses are crucial for regulating deep-sea microbial communities and biogeochemical cycles. However, their roles are still less characterized in deep-sea holobionts. Bathymodioline mussels are endemic species inhabiting cold seeps and harboring endosymbionts in gill epithelial cells for nutrition. This study unveiled a diverse array of viruses in the gill tissues of Gigantidas platifrons mussels and analyzed the viral metagenome and transcriptome from the gill tissues of Gigantidas platifrons mussels collected from a cold seep in the South Sea. The mussel gills contained various viruses including Baculoviridae, Rountreeviridae, Myoviridae and Siphovirdae, but the active viromes were Myoviridae, Siphoviridae, and Podoviridae belonging to the order Caudovirales. The overall viral community structure showed significant variation among environments with different methane concentrations. Transcriptome analysis indicated high expression of viral structural genes, integrase, and restriction endonuclease genes in a high methane concentration environment, suggesting frequent virus infection and replication. Furthermore, two viruses (GP-phage-contig14 and GP-phage-contig72) interacted with Gigantidas platifrons methanotrophic gill symbionts (bathymodiolin mussels host intracellular methanotrophic Gammaproteobacteria in their gills), showing high expression levels, and have huge different expression in different methane concentrations. Additionally, single-stranded DNA viruses may play a potential auxiliary role in the virus-host interaction using indirect bioinformatics methods. Moreover, the Cro and DNA methylase genes had phylogenetic similarity between the virus and Gigantidas platifrons methanotrophic gill symbionts. This study also explored a variety of viruses in the gill tissues of Gigantidas platifrons and revealed that bacteria interacted with the viruses during the symbiosis with Gigantidas platifrons. This study provides fundamental insights into the interplay of microorganisms within Gigantidas platifrons mussels in deep sea.

Ferroptosis: a critical mechanism of N6-methyladenosine modification involved in carcinogenesis and tumor progression.

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation. It occurs when multiple redox-active enzymes are ectopically expressed or show abnormal function. Hence, the precise regulation of ferroptosis-related molecules is mediated across multiple levels, including transcriptional, posttranscriptional, translational, and epigenetic levels. N6-methyladenosine (m6A) is a highly evolutionarily conserved epigenetic modification in mammals. The m6A modification is commonly linked to tumor proliferation, progression, and therapy resistance because it is involved in RNA metabolic processes. Intriguingly, accumulating evidence suggests that dysregulated ferroptosis caused by the m6A modification drives tumor development. In this review, we summarized the roles of m6A regulators in ferroptosis-mediated malignant tumor progression and outlined the m6A regulatory mechanism involved in ferroptosis pathways. We also analyzed the potential value and application strategies of targeting m6A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

TFAP2A is involved in neuropathic pain by regulating Grin1 expression in glial cells of the dorsal root ganglion.

Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A-Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics.

Phosphorylation Promotes the Accumulation of PERIOD Protein Foci.

Circadian clock drives the 24-h rhythm in our behavior and physiology. The molecular clock consists of a series of transcriptional/translational feedback loops operated by a number of clock genes. A very recent study reported that the clock protein PERIOD (PER) is organized into discrete foci at the nuclear envelope in fly circadian neurons, which is believed to be important for controlling the subcellular localization of clock genes. Loss of inner nuclear membrane protein lamin B receptor (LBR) leads to disruption of these foci, but how they are regulated is yet unknown. Here, we found that PER foci are likely phase-separated condensates, the formation of which is mediated by intrinsically disordered region in PER. Phosphorylation promotes the accumulation of these foci. Protein phosphatase 2A, which is known to dephosphorylate PER, hampers the accumulation of the foci. On the other hand, the circadian kinase DOUBLETIME (DBT) which phosphorylates PER enhances the accumulation of the foci. LBR likely facilitates PER foci accumulation by destabilizing the catalytic subunit of protein phosphatase 2A, MICROTUBULE STAR (MTS). In conclusion, here, we demonstrate a key role for phosphorylation in promoting the accumulation of PER foci, while LBR modulates this process by impinging on the circadian phosphatase MTS.