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RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8 + T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 ( Jak2 ); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy. Several mechanisms have been associated with transcriptional and post-transcriptional regulation of PD-L1 in cancer. Here the authors show that a RNA binding protein, DENR, positively regulates the translation of JAK2 and induces PD-L1 expression in tumor cells, associated with immune evasion.

Acoustic fault diagnosis technology equipment is non-contact, and the acoustic signal is easy to access. However, it is difficult to extract the feature information of the acoustic signal with low signal-to-noise ratio (SNR). In this paper, a fault diagnosis model (FDM) of axle box bearing based on Chirplet transform (CT) and support vector machine (SVM) is established to diagnose bearing fault based on acoustic signal. The availability of the model is verified by comparing with the vibration acceleration signal bearing fault diagnosis results, and the correctness of the model is verified by utilizing the open database of Western Reserve University. The acoustic-vibration comprehensive bearing fault diagnosis experiment platform (AVEP) is established to investigate the acoustic signal and acceleration signal diagnosis accuracy. The results suggest that, based on the FDM, the diagnosis accuracy and stability of acoustic signal are not as good as acceleration signal when the number of samples is small under the single condition; the diagnosis accuracy of acoustic signal is similar to that of acceleration signal when the number of samples is enough under the multiple condition, which provides a reference for the application of acoustic fault diagnosis technology in engineering in the future.

Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age-related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case-control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ''flat shape (FL)'', ''sloping shape (SL)'', ''2-4 kHz abrupt loss (AL) shape'' and ''8 kHz dip (8D) shape''. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p = 0.000472, OR = 1.599, 95%CI = 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p = 9.41E-05, OR = 1.945, 95%CI = 1.393~2.715; p = 0.000109, OR = 1.915, 95%CI = 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn't significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns.

Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation. How Treg cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study Treg cell–stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem-cell (HFSC) activation and HF regeneration. Ablation of the glucocorticoid receptor (GR) in Treg cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in Treg cells to induce transforming growth factor β3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation. The present study identifies crosstalk between Treg cells and HFSCs mediated by the GR–TGF-β3 axis, highlighting a possible means of manipulating Treg cells to support tissue regeneration.Skin Treg cell crosstalk with hair-follicle stem cells (HFSCs) can control hair regrowth. Here the authors show that glucocorticoid receptor signaling in skin Treg cells induces TGF-β3, which in turn facilitates HFSC proliferation.

Purpose To examine whether and how interleukin (IL)-1α is involved in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Nasal polyp (NP) and control tissues were collected from CRSwNP patients and control subjects. The expression of IL-1α and other proinflammatory cytokines (IL-1β, IL-8 and IL-13, etc.), as well as neutrophil and eosinophil accumulation, were examined in sinonasal tissues using immunohistochemical (IHC), immunofluorescent (IF) staining, qPCR, and Luminex, respectively. Moreover, the regulation of IL-1α expression and its effects on other proinflammatory cytokines were evaluated in cultured nasal epithelial cells (NECs). Results The mRNA and protein levels of IL-1α were significantly higher in NP tissues compared to that in control tissues. IL-1α in polyp tissues was mainly located in epithelial cells and neutrophils. Polyps IL-1α level was significantly associated with IL-8, IL-1β, IL-6, IL-4 and IL-13 production, as well as tissue neutrophil infiltration. Moreover, poly (I:C), lipopolysaccharides, Flagellin, R848 and cytokines (IL-4, IL-5, and IL-13) significantly increased the expression of IL-1α in cultured NECs in vitro, and recombinant IL-1α significantly promoted production of IL-8 and CXCL1 in cultured NECs. Conclusions These findings provided the evidence that IL-1α were significantly increased in NP tissues, which may contribute to tissue neutrophilia in CRSwNP patients in China.

B-cell activating factor of the TNF family is critical for the survival and maturation of B cells and play a role in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). In this study, nasal tissues were enrolled from 25 CRSwNP patients (asthmatic, 16; non-asthmatic, 9), 12 CRSsNP patients and ten control subjects, respectively. The immunoreactivity of BAFF, CD20 and CD138 were examined using immunohistochemistry staining. The mRNA expression of BAFF, CD20, εGLT, AID, GATA3 and CRTH2 were examined using real-time RT-PCR. The protein levels of BAFF, IL-5 and IgE were measured using ELISA assays and the Unicap system, respectively. We found the numbers of BAFF+ cells, CD20+ cells (B cells) and CD138+ cells (plasma cells) were significantly increased in polyp tissues compared with control groups. The concentrations of BAFF, IgE and IL-5 in tissue homogenates were also significantly increased in polyp tissues compared with control groups, and the BAFF protein level in the polyp homogenates was significantly associated with the IgE and IL-5 levels and with concomitant asthma in CRSwNP patients. Our findings indicate that BAFF expression is significantly increased in CRSwNP patients and may orchestrate inflammatory load in polyp tissues by regulating T and B cell-mediated response.

This study aimed to test the association between the European GWAS-identified risk IQGAP2 SNP rs457717 (A>G) and age-related hearing impairment (ARHI) in a Han male Chinese (HMC) population. A total of 2420 HMC subjects were divided into two groups [group 70+: >70 years ( n  = 1306), and group 70−: ≤70 years ( n  = 1114)]. The participants were categorised into case and control groups according to Z high scores for group 70− and the severity of hearing loss and different audiogram shapes identified by K-means cluster analysis for group 70+. The IQGAP2 tagSNP rs457717 was genotyped in accordance with the different ARHI phenotypes. The genotype distributions of IQGAP2 (AA/AG/GG) were not significantly different between the case and control groups ( P  = 0.613 for group 70−; P  = 0.602 for group 70+). Compared with genotype AA, the ORs of genotypes AG and GG for ARHI were not significantly different following adjustment for other environmental risk factors. We demonstrated that the IQGAP2 TagSNP rs457717 (A/G) was not associated with ARHI in HMC individuals.

Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (Ih). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger Ih, which was observed in parallel with increased potassium (K+) channel currents. Experimentally further enhancing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.

Migraine is a complex neurological disorder that severely compromises quality of life. Current therapies remain inadequate, creating an urgent need for precision medicine approaches. To bridge this gap, we integrated genome-wide association studies (GWASs) and multi-tissue expression quantitative trait loci (eQTL) data. Using Mendelian randomization (SMR/HEIDI) to identify putatively causal genes, followed by colocalization analysis, protein–protein interaction networks, and gene enrichment, we prioritized druggable targets. Phenome-wide association studies (PheWASs) further assessed their potential safety profiles. We identified 31 migraine-associated genes in whole blood, 20 in brain tissue, and 9 genes shared by both whole blood and brain regions. Among 13 druggable genes identified from the DGIdb and supporting literature, 10 passed colocalization validation. Eight genes (TGFB3, CHRNB1, BACE2, THRA, NCOR2, NR1D1, CHD4, REV3L) showed interactions with known drug targets, enabling the computational prediction of 41 potential repurposable drugs. Based on target druggability, PPI (protein–protein interaction) and favorable PheWAS profiles, NR1D1, THRA, NCOR2, and CHD4 are prioritized for drug development. Additionally, MICU1, UFL1, LY6G5C, and PPP1CC emerged as novel pathophysiological factors. This study establishes a multi-omics framework for precision migraine therapy, translating genetic insights into clinically actionable targets.

AimsMost crops are supplemented with selenium (Se) through the exogenous addition of inorganic Se fertilizer. There is a lack of in-depth research on organic Se fertilizers. Meanwhile, the dosage range between human Se deficiency and Se toxicity is narrow, so the Se content of agricultural products needs to be controlled within a reasonable interval.MethodsSe accumulation and speciation in rice were analyzed and compared during three different growth stages (late tillering stage, initiate heading stage, and full heading stage) using three Se fertilizers: selenite, fermented Se, and potassium selenocyanoacetate (Se-AAF) via the foliar application.ResultsThe Se content in rice sprayed with organic Se fertilizer was controlled in the relatively safe range and met the human Se supplement requirement compared to the sprayed sodium selenite, which was too high of a dose. The percentage of organic Se and protein Se in brown rice was found to be similar in all three Se fertilizers. The highest organic Se content of 91.57% was found in the grain of rice at the full heading stage by spraying Se-AAF. The main Se species in the grain was selenomethionine (SeMet), which reached 80% of the total Se. Se-methyl selenocysteine(SeMeCys) was found only in Se-AAF. The grain quality showed that all three Se fertilizers increased the consistency of gelatinization.ConclusionsAppropriately delaying the spraying time and selecting organic Se fertilizer as the Se source can help to produce green and safe selenium-rich rice.