The balance between nuclear import and export of NLRC5 regulates MHC class I transactivation.

Major histocompatibility complex (MHC) class I molecules play an essential role in regulating the adaptive immune system by presenting antigens to CD8 T cells. CITA (MHC class I transactivator), also known as NLRC5 (NLR family, CARD domain-containing 5), regulates the expression of MHC class I and essential components involved in the MHC class I antigen presentation pathway. While the critical role of the nuclear distribution of NLRC5 in its transactivation activity has been known, the regulatory mechanism to determine the nuclear localization of NLRC5 remains poorly understood. In this study, a comprehensive analysis of all domains in NLRC5 revealed that the regulatory mechanisms for nuclear import and export of NLRC5 coexist and counterbalance each other. Moreover, GCN5 (general control non-repressed 5 protein), a member of HATs (histone acetyltransferases), was found to be a key player to retain NLRC5 in the nucleus, thereby contributing to the expression of MHC class I. Therefore, the balance between import and export of NLRC5 has emerged as an additional regulatory mechanism for MHC class I transactivation, which would be a potential therapeutic target for the treatment of cancer and virus-infected diseases.

Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as a therapeutic strategy in CLL.

Dysregulation of messenger RNA (mRNA) translation, including preferential translation of mRNA with complex 5' untranslated regions such as the MYC oncogene, is recognized as an important mechanism in cancer. Here, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which is inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis performed in samples from patients with CLL and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibiting translation induced a proliferation arrest and a rewiring of MYC-driven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the eukaryotic initiation factor (eIF)4F translation complex and are targeted by FL3. Knockdown of PHBs resembled FL3 treatment. Importantly, inhibition of translation controlled CLL development in vivo, either alone or combined with immunotherapy. Finally, high expression of translation initiation-related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in patients with CLL. Overall, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for patients with CLL.

Interaction of Nmi and IFP35 Promotes Mutual Protein Stabilization and IRF3 and IRF7 Degradation to Suppress Type I IFN Production in Teleost Fish.

IFN-stimulated genes (ISGs) can act as effector molecules against viral infection and can also regulate pathogenic infection and host immune response. N-Myc and STAT interactor (Nmi) is reported as an ISG in mammals and in fish. In this study, the expression of Nmi was found to be induced significantly by the infection of Siniperca chuatsi rhabdovirus (SCRV), and the induced expression of type I IFNs after SCRV infection was reduced following Nmi overexpression. It is observed that Nmi can interact with IRF3 and IRF7 and promote the autophagy-mediated degradation of these two transcription factors. Furthermore, Nmi was found to be interactive with IFP35 through the CC region to inhibit IFP35 protein degradation, thereby enhancing the negative role in type I IFN expression after viral infection. In turn, IFP35 is also capable of protecting Nmi protein from degradation through its N-terminal domain. It is considered that Nmi and IFP35 in fish can also interact with each other in regulating negatively the expression of type I IFNs, but thus in enhancing the replication of SCRV.

Transcriptional Regulation and Signaling of Type IV IFN with Identification of the ISG Repertoire in an Amphibian Model, Xenopus laevis.

The type IV IFN (IFN-υ) is reported in vertebrates from fish to primary mammals with IFN-υR1 and IL-10R2 as receptor subunits. In this study, the proximal promoter of IFN-υ was identified in the amphibian model, Xenopus laevis, with functional IFN-sensitive responsive element and NF-κB sites, which can be transcriptionally activated by transcription factors, such as IFN regulatory factor (IRF)1, IRF3, IRF7, and p65. It was further found that IFN-υ signals through the classical IFN-stimulated gene (ISG) factor 3 (ISGF3) to induce the expression of ISGs. It seems likely that the promoter elements of the IFN-υ gene in amphibians is similar to type III IFN genes, and that the mechanism involved in IFN-υ induction is very much similar to type I and III IFNs. Using recombinant IFN-υ protein and the X. laevis A6 cell line, >400 ISGs were identified in the transcriptome, including ISGs homologous to humans. However, as many as 268 genes were unrelated to human or zebrafish ISGs, and some of these ISGs were expanded families such as the amphibian novel TRIM protein (AMNTR) family. AMNTR50, a member in the family, was found to be induced by type I, III, and IV IFNs through IFN-sensitive responsive element sites of the proximal promoter, and this molecule has a negative role in regulating the expression of type I, III, and IV IFNs. It is considered that the current study contributes to the understanding of transcription, signaling, and functional aspects of type IV IFN at least in amphibians.

Boosted ammonium production by single cobalt atom catalysts with high Faradic efficiencies.

Efficient n = O bond activation is crucial for the catalytic reduction of nitrogen compounds, which is highly affected by the construction of active centers. In this study, n = O bond activation was achieved by a single-atom catalyst (SAC) with phosphorus anchored on a Co active center to form intermediate N-species for further hydrogenation and reduction. Unique phosphorus-doped discontinuous active sites exhibit better n = O activation performance than conventional N-cooperated single-atom sites, with a high Faradic efficiency of 92.0% and a maximum ammonia yield rate of 433.3 µg NH4·h-1·cm-2. This approach of constructing environmental sites through heteroatom modification significantly improves atom efficiency and will guide the design of future functional SACs with wide-ranging applications.

Suppression of neutrophil extracellular traps is responsible for the amelioration of chemotherapeutic intestinal injury by the natural compound PEITC.

Intestinal injury is one of the most debilitating side effects of many chemotherapeutic agents, such as irinotecan hydrochloride (CPT-11). Accumulating evidence indicates that neutrophil extracellular traps (NETs) play a critical role in the symptoms of ischemia and inflammation related to chemotherapy. The present study investigated the effects and possible mechanisms of phenethyl isothiocyanate (PEITC) in inhibiting NETs and alleviating chemotherapeutic intestinal injury. CPT-11 induced robust neutrophil activation, as evidenced by increased NETs release, intestinal ischemia, and mRNA expression of inflammatory factors. PEITC prolonged the clotting time of chemotherapeutic mice, improved the intestinal microcirculation, inhibited the expression of inflammatory factors, and protected the tight junctions of the intestinal epithelium. Both in vivo and in vitro experiments revealed that PEITC directly suppresses CPT-11-induced NETs damage to intestinal cells, resulting in significant attenuation of epithelial injury. These results suggest that PEITC may be a novel agent to relieve chemotherapeutic intestinal injury via inhibition of NETs.

A comparative study of platelet storage lesion in platelet-rich plasma under cryopreservation.

Platelet-rich plasma (PRP) has significant potential for various applications and holds clinical value in regenerative medicine. Cryopreservation is used to extend the preservation period of PRP, facilitating its clinical application. However, the potential negative effects of long-term cryopreservation on platelet storage lesion are still uncertain. In this study, PRP was stored at - 30 °C or - 80 °C. Platelet count, apoptosis, reactive oxygen species (ROS) content, and CD62P expression were assessed on the 14th and 28th days. The study also evaluated platelet mitochondria morphology and function, serotonin (5-HT) secretion by platelets, and the inflammatory activating effect of cryopreserved platelets in PRP. The results showed that there were no significant differences in platelet count, the content of 5-HT, and inflammatory effects between fresh PRP and PRP cryopreserved at both - 30 °C and - 80 °C. However, there was an increase in ROS level, apoptosis, and CD62P level after cryopreservation at both temperatures. Additionally, the levels of ROS, apoptosis, and CD62P in platelets were similar after storage at - 30 °C and - 80 °C. The main difference observed was that the morphology and function of mitochondria were severely damaged after storage at - 30 °C, while they were less affected at - 80 °C. Based on these findings, it can be concluded that storing PRP at - 80 °C is more suitable for achieving a better therapeutic effect in clinical applications, but cryopreservation could not replace the current standard.

SIRT6 positively regulates antiviral response in a bony fish, the Chinese perch Siniperca chuatsi.

SIRT6, a key member of the sirtuin family, plays a pivotal role in regulating a number of vital biological processes, including energy metabolism, oxidative stress, and immune system modulation. Nevertheless, the function of SIRT6 in bony fish, particularly in the context of antiviral immune response, remains largely unexplored. In this study, a sirt6 was cloned and characterized in a commercial fish, the Chinese perch (Siniperca chuatsi). The SIRT6 possesses conserved SIR2 domain with catalytic core region when compared with other vertebrates. Tissue distribution analysis indicated that sirt6 was expressed in all detected tissues, and the sirt6 was significantly induced following infection of infectious haemorrhagic syndrome virus (IHSV). The overexpression of SIRT6 resulted in significant upregulation of interferon-stimulated genes (ISGs), such as viperin, mx, isg15, irf3 and ifp35, and inhibited viral replication. It was further found that SIRT6 was located in nucleus and could enhance the expression of ISGs induced by type I and II IFNs. These findings may provide new information in relation with the function of SIRT6 in vertebrates, and with viral prevention strategy development in aquaculture.

Molecular cloning and functional analyses of C-C motif chemokine ligand 3 (CCL3) in mandarin fish Siniperca chuatsi.

Chemokines are critical molecules involved in immune reaction and immune system homeostasis, and some chemokines play a role in antiviral immunity. It is not known if the C-C motif chemokine ligand 3 (CCL3), a member of the CC chemokine family, possesses antiviral properties in fish. In this study, a ccl3 was cloned from the mandarin fish (Siniperca chuatsi), and it has an open reading frame (ORF) of 276 base pairs, which are predicted to encode a 91-amino acid peptide. Mandarin fish CCL3 revealed conserved sequence features with four cysteine residues and closely relationships with the CCL3s from other vertebrates based on the sequence alignment and phylogenetic analysis. The transcripts of ccl3 were notably enriched in immune-related organs, such as spleen and gills in healthy mandarin fish, and the ccl3 was induced in the isolated mandarin fish brain (MFB) cells following infection with infectious spleen and kidney necrosis virus (ISKNV). Moreover, in MFB cells, overexpression of CCL3 induced immune factors, such as IL1ß, TNFα, MX, IRF1 and IFNh, and exhibited antiviral activity against ISKNV. This study sheds light on the immune role of CCL3 in immune response of mandarin fish, and its antiviral defense mechanism is of interest for further investigation.

Atomically dispersed Fe atoms anchored on S and N-codoped carbon for efficient electrochemical denitrification.

Nitrate, a widespread contaminant in natural water, is a threat to ecological safety and human health. Although direct nitrate removal by electrochemical methods is efficient, the development of low-cost electrocatalysts with high reactivity remains challenging. Herein, bifunctional single-atom catalysts (SACs) were prepared with Cu or Fe active centers on an N-doped or S, N-codoped carbon basal plane for N2 or NH4+ production. The maximum nitrate removal capacity was 7,822 mg N ⋅ g-1 Fe, which was the highest among previous studies. A high ammonia Faradic efficiency (78.4%) was achieved at a low potential (-0.57 versus reversible hydrogen electrode), and the nitrogen selectivity was 100% on S-modified Fe SACs. Theoretical and experimental investigations of the S-doping charge-transfer effect revealed that strong metal-support interactions were beneficial for anchoring single atoms and enhancing cyclability. S-doping altered the coordination environment of single-atom centers and created numerous defects with higher conductivity, which played a key role in improving the catalyst activity. Moreover, interactions between defects and single-atom sites improved the catalytic performance. Thus, these findings offer an avenue for high active SAC design.

Polyploidy underlies co-option and diversification of biosynthetic triterpene pathways in the apple tribe.

Whole-genome duplication (WGD) plays important roles in plant evolution and function, yet little is known about how WGD underlies metabolic diversification of natural products that bear significant medicinal properties, especially in nonmodel trees. Here, we reveal how WGD laid the foundation for co-option and differentiation of medicinally important ursane triterpene pathway duplicates, generating distinct chemotypes between species and between developmental stages in the apple tribe. After generating chromosome-level assemblies of a widely cultivated loquat variety and Gillenia trifoliata, we define differentially evolved, duplicated gene pathways and date the WGD in the apple tribe at 13.5 to 27.1 Mya, much more recent than previously thought. We then functionally characterize contrasting metabolic pathways responsible for major triterpene biosynthesis in G. trifoliata and loquat, which pre- and postdate the Maleae WGD, respectively. Our work mechanistically details the metabolic diversity that arose post-WGD and provides insights into the genomic basis of medicinal properties of loquat, which has been used in both traditional and modern medicines.

Screening of Spinal Muscular Atrophy Carriers and Prenatal Diagnosis in Pregnant Women in Yancheng, China.

Spinal muscular atrophy (SMA) is a neuromuscular disorder with an autosomal recessive inheritance pattern. Patients with severe symptoms may suffer respiratory failure, leading to death. The homozygous deletion of exon 7 in the SMN1 gene accounts for nearly 95% of all cases. Population carrier screening for SMA and prenatal diagnosis by amniocentesis for high-risk couples can assist in identifying the risk of fetal disease. We provided the SMA carrier screening process to 55,447 pregnant women in Yancheng from October 2020 to December 2022. Among them, 8185 participated in this process, with a participation rate of around 14.76% (95% CI 14.47-15.06%). Quantitative real-time polymerase chain reaction (qPCR) was used to detect deletions of SMN1 exons 7 and 8 (E7, E8) in screened pregnant women. 127 were identified as carriers (111 cases of E7 and E8 heterozygous deletions, 15 cases of E7 heterozygous deletions, and 1 case of E7 heterozygous deletions and E8 homozygous deletions), resulting in a carrying rate of around 1.55% (95% CI 1.30-1.84%). After genetic counseling, 114 spouses of pregnant women who tested positive underwent SMA carrier screening; three of them were screened as SMA carriers. Multiplexed ligation-dependent probe amplification (MLPA) was used for the prenatal diagnosis of the fetuses of high-risk couples. Two of them exhibited two copies of SMN1 exon 7 (normal), and the pregnancy was continued; one exhibited no copies of SMN1 exon 7 and exon 8 (SMA patient), and the pregnancy was terminated. Analyzing SMN1 mutations in Yancheng and provide clinical evidence for SMA genetic counseling and birth defect prevention. Interventional prenatal diagnosis for high-risk families can promote informed reproductive selection and prepare for the fetus's early treatment.

Effect of salinity on denitrification, membrane fouling and bacterial community in a fixed-bed biofilm membrane reactor.

In this study, a fixed-bed biofilm membrane bioreactor was used to assess denitrification and carbon removal performance, membrane fouling, composition, and the dynamics of microbial communities across 10 salinity levels. As salinity levels increased (from 0 to 30 g/L), the removal efficiency of total nitrogen and chemical oxygen demand decreased from 98 and 86% in Phase I to 25 and 45% in Phase X, respectively. Beyond a salinity level of 10 g/L, membrane fouling accelerated considerably. The analysis of fouling resistance distribution suggested that soluble microbial products (SMPs) were the primary cause of this phenomenon. The irregularity in microbial community succession reflected the varying adaptability of different bacteria to different salinity levels. The relative abundance of Sulfuritalea, Lentimircobium, Thauera, and Pseudomonas increased from 20.2 to 47.7% as the experiments progressed. Extracellular polymeric substances-related analysis suggested that Azospirillum plays a positive role in preserving the structural integrity of the biofilm carrier. The SMP-related analysis showed a positive correlation between Lentimircobium, Thauera, Pseudomonas, and the SMP content. These results suggested that these three bacterial genera significantly promoted the release of SMP under salt stress, which in turn led to severe membrane fouling.

Integrated transcriptomics and metabolomics reveal protective effects on heart of hibernating Daurian ground squirrels.

Hibernating mammals are natural models of resistance to ischemia, hypoxia-reperfusion injury, and hypothermia. Daurian ground squirrels (spermophilus dauricus) can adapt to endure multiple torpor-arousal cycles without sustaining cardiac damage. However, the molecular regulatory mechanisms that underlie this adaptive response are not yet fully understood. This study investigates morphological, functional, genetic, and metabolic changes that occur in the heart of ground squirrels in three groups: summer active (SA), late torpor (LT), and interbout arousal (IBA). Morphological and functional changes in the heart were measured using hematoxylin-eosin (HE) staining, Masson staining, echocardiography, and enzyme-linked immunosorbent assay (ELISA). Results showed significant changes in cardiac function in the LT group as compared with SA or IBA groups, but no irreversible damage occurred. To understand the molecular mechanisms underlying these phenotypic changes, transcriptomic and metabolomic analyses were conducted to assess differential changes in gene expression and metabolite levels in the three groups of ground squirrels, with a focus on GO and KEGG pathway analysis. Transcriptomic analysis showed that differentially expressed genes were involved in the remodeling of cytoskeletal proteins, reduction in protein synthesis, and downregulation of the ubiquitin-proteasome pathway during hibernation (including LT and IBA groups), as compared with the SA group. Metabolomic analysis revealed increased free amino acids, activation of the glutathione antioxidant system, altered cardiac fatty acid metabolic preferences, and enhanced pentose phosphate pathway activity during hibernation as compared with the SA group. Combining the transcriptomic and metabolomic data, active mitochondrial oxidative phosphorylation and creatine-phosphocreatine energy shuttle systems were observed, as well as inhibition of ferroptosis signaling pathways during hibernation as compared with the SA group. In conclusion, these results provide new insights into cardio-protection in hibernators from the perspective of gene and metabolite changes and deepen our understanding of adaptive cardio-protection mechanisms in mammalian hibernators.

Metastasis and immunosuppression promoted by mtDNA and PD-L1 in extracellular vesicles are reversed by WGP ß-glucan in oral squamous cell carcinoma.

The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) ß-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP ß-glucan could elevate CD4+ and CD8+ T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP ß-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.

Downregulation of AT-rich interaction domain 2 underlies natural killer cell dysfunction in oral squamous cell carcinoma.

The immune system plays a significant role in controlling oral squamous cell carcinoma (OSCC) initiation and progression. Natural killer (NK) cells actively participate in antitumor immunity but become dysfunctional or exhausted in the tumor microenvironment. To explore the mechanisms of NK cell dysfunction in OSCC, we characterized the expression and function of AT-rich interaction domain 2 (ARID2) in NK cells in a murine OSCC model. ARID2 was downregulated in tongue NK cells compared with splenic NK cells. Notably, ARID2 was significantly decreased in NK cells with an exhausted phenotype and weakened antitumor function. ARID2 knockdown resulted in the upregulation of programmed cell death protein 1 (PD-1) and downregulation of interferon-gamma (IFN-γ), tumor necrosis factor (TNF), granzyme B and perforin in NK cells. As a result, ARID2 knockdown impaired NK cell cytotoxicity. Besides, ARID2 overexpression suppressed the expression of PD-1 and lymphocyte-activation gene 3, and promoted the expression of IFN-γ, TNF, granzyme B and perforin in NK cells which were adoptively transferred into OSCC-bearing mice. Taken together, our study implies that the OSCC microenvironment triggers ARID2 downregulation in intratumoral NK cells. In turn, ARID2 downregulation results in PD-1 upregulation on NK cells and subsequently impairs NK cell cytotoxicity. Therefore, we uncovered a novel mechanism of NK cell dysfunction in OSCC.

Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder. Abnormally increased levels of High Mobility Group Box 1 (HMGB1) protein associate with thrombocytopenia and therapeutic outcome in ITP. Previous studies proposed that a natural inhibitor of HMGB1, 18ß-glycyrrhetinic acid (18ß-GA), could be used for its anti-inflammatory and immune-modulatory effects, although its ability to correct immune balance in ITP is unclear. In this study, we showed that plasma HMGB1 correlated negatively with platelet counts in ITP patients, and confirmed that 18ß-GA stimulated the production of regulatory T cells (Treg), restored the balance of CD4+ T-cell subsets and enhanced the suppressive function of Treg through blocking the effect on HMGB1 in patients with ITP. HMGB1 short hairpin RNA interference masked the effect of 18ß-GA in Treg of ITP patients. Furthermore, we found that 18ß-GA alleviated thrombocytopenia in mice with ITP. Briefly, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to induce a murine model of severe ITP. The proportion of circulating Treg increased significantly, while the level of plasma HMGB1 and serum antiplatelet antibodies decreased significantly in ITP mice along 18ß-GA treatment. In addition, 18ß-GA reduced phagocytic activity of macrophages towards platelets both in ITP patients and ITP mice. These results indicate that 18ß-GA has the potential to restore immune balance in ITP via inhibition of HMGB1 signaling. In short, this study reveals the role of HMGB1 in ITP, which may serve as a potential target for thrombocytopenia therapy.

Observation of Exceptional Points in Thermal Atomic Ensembles.

Exceptional points (EPs) in non-Hermitian systems have recently attracted wide interest and spawned intriguing prospects for enhanced sensing. However, EPs have not yet been realized in thermal atomic ensembles, which is one of the most important platforms for quantum sensing. Here we experimentally observe EPs in multilevel thermal atomic ensembles and realize enhanced sensing of the magnetic field for 1 order of magnitude. We take advantage of the rich energy levels of atoms and construct effective decays for selected energy levels by employing laser coupling with the excited state, yielding unbalanced decay rates for different energy levels, which finally results in the existence of EPs. Furthermore, we propose the optical polarization rotation measurement scheme to detect the splitting of the resonance peaks, which makes use of both the absorption and dispersion properties and shows an advantage with enhanced splitting compared with the conventional transmission measurement scheme. Additionally, in our system both the effective coupling strength and decay rates are flexibly adjustable, and thus the position of the EPs are tunable, which expands the measurement range. Our Letter not only provides a new controllable platform for studying EPs and non-Hermitian physics, but also provide new ideas for the design of EP-enhanced sensors and opens up realistic opportunities for practical applications in the high-precision sensing of magnetic field and other physical quantities.

PT-Symmetric Feedback Induced Linewidth Narrowing.

Narrow linewidth is a long-pursued goal in precision measurement and sensing. We propose a parity-time symmetric (PT-symmetric) feedback method to narrow the linewidths of resonance systems. By using a quadrature measurement-feedback loop, we transform a dissipative resonance system into a PT-symmetric system. Unlike the conventional PT-symmetric systems that typically require two or more modes, here the PT-symmetric feedback system contains only a single resonance mode, which greatly extends the scope of applications. The method enables remarkable linewidth narrowing and enhancement of measurement sensitivity. We illustrate the concept in a thermal ensemble of atoms, achieving a 48-fold narrowing of the magnetic resonance linewidth. By applying the method in magnetometry, we realize a 22-times improvement of the measurement sensitivity. This work opens the avenue for studying non-Hermitian physics and high-precision measurements in resonance systems with feedback.

Disturbing NLRP3 acetylation and inflammasome assembly inhibits androgen receptor-promoted inflammatory responses and prostate cancer progression.

Chronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa tumorigenesis and inflammatory response. However, little is known about the AR-regulated NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high-grade PCa and observed that NLRP3 inflammasome-associated genes were upregulated in high-grade PCa compared with that in low-grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR-3-a circRNA derived from the AR gene-which is involved in the AR-regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR-3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR-3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression.