The Transcriptional Landscape of Immune-Response 3'-UTR Alternative Polyadenylation in Melanoma.

The prognosis of patients with malignant melanoma has been improved in recent decades due to advancements in immunotherapy. However, a considerable proportion of patients are refractory to treatment, particularly at advanced stages. This underscores the necessity of developing a new strategy to improve it. Alternative polyadenylation (APA), as a marker of crucial posttranscriptional regulation, has emerged as a major new type of epigenetic marker involved in tumorigenesis. However, the potential roles of APA in shaping the tumor microenvironment (TME) are largely unexplored. Herein, we collected two cohorts comprising melanoma patients who received immune checkpoint inhibitor (ICI) immunotherapy to quantify transcriptome-wide discrepancies in APA. We observed a global change in 3'-UTRs between responders and non-responders, which might involve DNA damage response, angiogenesis, PI3K-AKT signaling pathways, etc. Ten putative master APA regulatory factors for those APA events were detected via a network analysis. Notably, we established an immune response-related APA scoring system (IRAPAss), which exhibited a great performance of predicting immunotherapy response in multiple cohorts. Furthermore, we examined the correlation of APA with TME at the single-cell level using four single-cell immune profiles of tumor-infiltrating lymphocytes (TILs), which revealed an overall discrepancy in 3'-UTR length across diverse T cell populations, probably contributing to immunoregulation in melanoma. In conclusion, our study provides a transcriptional landscape of APA implicated in immunoregulation, which might lay the foundation for developing a new strategy for improving immunotherapy response for melanoma patients by targeting APA.

Diagnostic performance of magnetic resonance imaging and contrast-enhanced ultrasound in differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma: a meta-analysis.

PURPOSE: To compare the diagnostic ability between magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC). METHODS: Original studies reporting the diagnostic accuracy of MRI and CEUS in differentiating ICC from HCC were identified in PubMed and EMBASE databases. Histopathological examination was used as the reference standard for tumor diagnosis. Study quality was assessed using QUADAS-2 scale. Data were extracted to calculate the pooled diagnostic sensitivity, specificity, and diagnostic odds ratio (DOR) using a bivariate random-effects model, as well as the area under the curve (AUC). Sensitivity analysis, subgroup analysis, meta-regression, and investigation of publication bias were also performed. RESULTS: A total of 26 studies with 28 data subsets (18 on MRI, 10 on CEUS) were included, consisting of 4169 patients with 1422 ICC lesions and 2747 HCC lesions. Most MRI studies were performed at 3T with hepatobiliary agents, and most CEUS studies used SonoVue as the contrast agent. In MRI, the pooled sensitivity, specificity, DOR, and AUC in distinguishing ICC from HCC were 0.81 (0.79, 0.84), 0.90 (0.88, 0.91), 41.47 (24.07, 71.44), and 0.93 (0.90, 0.96), respectively. The pooled sensitivity, specificity, DOR, and AUC of CEUS were 0.88 (0.84, 0.90), 0.80 (0.78, 0.83), 42.06 (12.38, 133.23), and 0.93 (0.87, 0.99), respectively. Subgroup analysis and meta-regression analysis demonstrated significant heterogeneity among the studies associated with the type of contrast agent in MRI studies. No publication bias was found. CONCLUSION: Both MRI and CEUS showed excellent diagnostic performance in differentiating ICC from HCC. CEUS showed higher pooled sensitivity and MRI showed higher pooled specificity.

Quantitative diffusion weighted imaging in patients with hepatocellular carcinoma: effects of simultaneous multi-slice acceleration and gadoxetic acid administration.

PURPOSE: To investigate whether simultaneous multi-slice (SMS) acceleration and gadoxetic acid administration affect the quantitative apparent diffusion coefficient (ADC) and signal-to-noise ratio (SNR) measurement of DWI in patients with HCC. METHODS: This prospective study initially enrolled 208 patients with clinically suspected HCC. Free breathing SMS-DWI and conventional DWI (CON-DWI) were performed before and after gadoxetic acid administration. Lesion conspicuity, ADCs and SNRs of the HCC lesion and normal liver parenchyma were independently measured by two radiologists. The paired t test or Wilcoxon signed rank test was used to evaluate the differences of lesion conspicuity, ADCs and SNRs between SMS-DWI and CON-DWI, as well as those before and after gadoxetic acid administration. RESULTS: A total of 102 HCC patients (90 men and 12 women; mean age, 54.6 ± 11.7 years) were finally included for analysis. SMS-DWI and CON-DWI demonstrated comparable lesion conspicuity (P = 0.081-0.566). For the influence of SMS acceleration, the SNRs of liver parenchyma on enhanced SMS-DWI were significantly higher than enhanced CON-DWI (P = 0.015). For the influence of gadoxetic acid administration, the mean ADCs were significantly higher on enhanced SMS-DWI than unenhanced SMS-DWI (HCC, P = 0.013; liver parenchyma, P = 0.032). CONCLUSION: Quantitative ADC measurements of HCC and liver parenchyma were not affected by SMS acceleration, and SMS-DWI can provide higher SNR than CON-DWI. However, the ADC measurements can be affected by gadoxetic acid administration on SMS-DWI, so it is recommended to perform SMS-DWI before gadoxetic acid administration.

Preparation of hydrophobic porous Au-Ag alloy nanoparticle arrays and their SERS properties.

In this study, we prepared porous Au-Ag alloy nanoparticle arrays with hydrophobic surfaces through the polystyrene colloidal crystal template combined with the chemical etching method to realize rapid SERS detection for biochemical molecules. In the preparation process, the pore size of Au-Ag alloy nanoparticles could be adjusted by changing the deposition time of the Ag element. Furthermore, after depositing the Au film on the surface of the porous nanoparticle arrays, their surface changed from hydrophilic to hydrophobic. The hydrophobic surface can drive target molecules to locally aggregate. Meanwhile, the hydrophobic surface also possessed a large number of active "hot spots" due to the porous structure. For these reasons, the porous Au-Ag alloy nanoparticle arrays can enable rapid and trace SERS detection, which provide the material basis for the subsequent construction of the high-quality SERS substrate.

Isorhynchophylline attenuates proliferation and migration of synovial fibroblasts via the FOXC1/ß-catenin axis.

Rheumatoid arthritis (RA) is a common type of chronic inflammatory disease. Elucidating the mechanism of fibroblast-like synovial (FLS) as a pathologic factor in RA may address the urgent medical requirement for the treatment of RA. Isorhynchophylline (IRN) is a tetracyclic hydroxyindole alkaloid isolated from uncinaria, which has multiple biological activities and affects the progression of osteoarthritis. However, the role of IRN in rheumatoid arthritis remains unclear. Herein, our study aimed to elucidate the potential effect of IRN on RA and reveal its mechanism. Human FLS cell line MH7A cells were stimulated with TNF-α for 24 h to construct a cell model. CCK-8, Edu, wound healing, as well as transwell assays were conducted to detect the effects of IRN on cell proliferation and motility. ELISA and Immunoblot assays were further performed to detect the production of pro-inflammatory factors and the expression levels of MMPs. Immunoblot and Immunostaining assays were conducted to uncover the mechanism. ELISA, H&E staining, and Immunoblot assays were used to confirm the effects of IRN on RA in a CIA rat model. We revealed that IRN restrained TNF-α-stimulated MH7A cell proliferation and motility. In addition, IRN blocked the production of pro-inflammatory factors and MMPs in TNF-α-stimulated-MH7A cells. We further found that IRN restrained FOXC1/ß-catenin axis, and improved MH7A cell proliferation as well as migration via the FOXC1/ß-catenin axis. IRN restores CIA by inhibiting pro-inflammatory cytokines in synovial tissues. In summary, IRN attenuates proliferation and migration of FLS in RA via the FOXC1 mediated ß-catenin axis.

A study on the mechanism of Indium phosphide/zinc sulfide core/shell quantum dots influencing embryo incubation of rare minnow (Gobiocypris rarus).

Quantum dots (QDs) inhibit fish hatching, but the mechanism is still unclear. In this study, the effect of Indium phosphide/zinc sulfide quantum dots (InP/ZnS QDs) on the embryo incubation of rare minnow was investigated. Five experimental concentration groups were set up according to the preliminary experimental results, which were 0, 50, 100, 200 and 400 nM. A direct exposure method was adopted to expose embryos to InP/ZnS QDs solution. The results showed that InP/ZnS QDs significantly inhibited the embryo hatching rate, delayed embryo emergence, affected the expression of genes associated with hatching gland cells and hatching enzymes. InP/ZnS QDs also destroy the structure of the embryo chorion. In addition, QDs can cause oxidative stress in embryos. Transcriptional sequencing analysis showed that InP/ZnS QDs InP/ZnS QDs may have induced the production of a hypoxic environment and triggered induce abnormal cardiac muscle contraction, inflammatory response and apoptosis process in embryos. In conclusion, QDs influences embryo hatchability largely through egg chorion mediation.

Photon Counting CT: Technical Principles, Clinical Applications, and Future Prospects.

Photon-counting computed tomography (PCCT) is a new technique that utilizes photon-counting detectors to convert individual X-ray photons directly into an electrical signal, which can achieve higher spatial resolution, improved iodine signal, radiation dose reduction, artifact reduction, and multienergy imaging. This review introduces the technical principles of PCCT, and summarizes its first-in-human experience and current applications in clinical settings, and discusses the future prospects of PCCT.

The Association between Academic Schedule and Physical Activity Behaviors in University Students.

BACKGROUND: University students sit too much, which is detrimental to their physical and mental health. Academic schedules, including scheduled education time and self-study time, may influence their physical activity behaviors. OBJECTIVES: To investigate (1) the association between scheduled education time and students' physical activity levels during weekdays; (2) the association between self-study time and students' physical activity levels during the weekdays and weekends. METHODS: 126 (68 Maastricht University (UM); 58 KU Leuven (KUL)) first-year undergraduate students in biomedical sciences (mean ± SD age: 19.3 ± 1.0, BMI: 22.0 ± 3.0, 17% men, 83% women) completed a demographics questionnaire and reported their academic activities with a 7-day logbook. Furthermore, their physical activity behavior was measured with the activPAL monitor for 7 days. Linear mixed models were used to examine the associations between university (UM versus KUL), academic activities (scheduled education time and self-study time), and students' activity levels. RESULTS: During weekdays, each hour of scheduled education time per day was significantly associated with a 1.3 min decrease of moderate to vigorous physical activity (MVPA) per day. Scheduled education time was not significantly associated with the sedentary time, light-intensity physical activity (LPA), and active sedentary behavior ratio. Each hour of self-study per day was significantly associated with 8 min more of sedentary time per day, 6 min less LPA per day, and 1.3 min less MVPA per day. Self-study time was not significantly associated with active sedentary behavior ratio. During the weekend, each hour of self-study time per day was associated with an additional 17.8 min of sedentary time per day and a reduction of 15.2 min of LPA per day. Self-study time was not significantly associated with the time spent doing MVPA and active sedentary behavior ratio. CONCLUSIONS: It could be more effective to change students' physical activity behaviors during self-study than during scheduled education time. Therefore, offering a study environment that reduces sedentary behavior and promotes light-intensity physical activity, is crucial.

InP/ZnS quantum dots cause liver damage in rare minnow (Gobiocypris rarus) larvae.

InP/ZnS quantum dots (QDs) are widely used in biomedical imaging and light-emitting component manufacturing industries, but there are few studies on their biological toxicity. In this study, we conducted experiments with rare minnow larvae and found that InP/ZnS QDs can cause liver damage. InP/ZnS QDs appeared only in the intestine of larvae and were not enriched in other parts of the larvae. The activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (AKP) increased, while the decrease in bile acid. InP/ZnS QDs caused hepatic cell nuclear lysis, abnormal cytoplasmic staining, and mitochondrial cristae reduction, swelling, and fragmentation. RNA-sequencing results revealed that InP/ZnS QDs exposure treatment affected the expression of genes involved in lipid metabolism, sterol synthesis, bile acid synthesis and other pathways. The excessive production of reactive oxygen species (ROS) induced by InP/ZnS QDs may be the main source of toxicity.

Effects of breaking up sitting with light-intensity physical activity on cognition and mood in university students.

BACKGROUND: University students often exhibit high levels of sedentary behavior that is negatively associated with cognition and mood. On the other hand, light-intensity physical activity (LIPA) may improve cognitive performance and mood. Therefore, this study investigated the acute effect of LIPA breaks during prolonged sitting on attention, executive functioning, and mood. METHODS: A randomized crossover design was used in this study. In total, 21 healthy adults (15 women, age = 24 ± 3 years, BMI = 23 ± 2 kg/m2 ) completed three prolonged sitting conditions: (1) without a demanding cognitive task (SIT), (2) with a demanding cognitive task (COGN), and (3) with every 25 min sitting interrupted by a 5-minute walk (INTERRUPT). Attention, executive function (response inhibition, task shifting, and working memory updating), and mood were assessed before and after each condition. RESULTS: Linear mixed models analyses showed that prolonged sitting frequently interrupted by LIPA (INTERRUPT) or with cognitively demanding activities (COGN) significantly improved task shifting compared to SIT. However, INTERRUPT did not significantly improve task shifting compared with COGN. No significant acute effects on attention, response inhibition, working memory updating, or mood were found. CONCLUSIONS: Frequent LIPA breaks or cognitively demanding activities have a selective, acute positive impact on one aspect of cognitive performance compared to idle sitting. No evidence was found that LIPA breaks have an acute improvement in attention, executive function, and mood compared to sitting with cognitive loading. To further investigate the effect of PA on cognitive performance, it is necessary to consider cognitive loading and control for the cognitive activity during sitting in the experimental design.

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer.

Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene-based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies.

PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.

Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.

Reproductive toxicity of InP/ZnS QDs in male rare minnow (Gobiocypris rarus).

InP/ZnS quantum dots (QDs) stand out among cadmium-free alternatives for higher exciton Bohr radius and strong quantum confined effect. In this study, the reproductive toxicity and mechanism of InP/ZnS QDs at different concentrations in male Chinese rare minnows (Gobiocypris rarus) were investigated. The results showed that QDs in 800 nmol/L concentration group could enter the testes after 1 d of exposure and caused changes in the structure of the testes, including the scattered distribution of seminal vesicles, reduction in germ cells and vacuolation in some areas of interstitial cells. The expression levels of androgen receptor (Ar) and doublesex and mab-3 related transcription factor 1 (Dmrt1) and the tight junction protein-related genes ß-catenin and occludin were upregulated in rare minnows. The sperm quality and ATP content of parents in the 800 nmol/L treatment group were significantly decreased. Continuous detection of the development of F1 generation embryos showed that parental exposure to InP/ZnS QDs reduced the heart rate and spontaneous movement frequency of F1 generation embryos, and the fertilization rate of the F1 generation in the 800 nmol/L treatment group was significantly reduced. In general, the sperm quality and testicular structure of adult rare minnows were not significantly affected by concentrations below 400 nmol/L. High-concentration InP/ZnS QDs exposure can damage the integrity of the blood-testis barrier (BTB) and cause reproductive damage to the parents of rare minnows, which will continue to the next generation and affect their development.

Parental exposure to CdSe/ZnS QDs affects cartilage development in rare minnow (Gobiocypris rarus) offspring.

Cartilage development is a sensitive process that is easily disturbed by environmental toxins. In this study, the toxicity of CdSe/ZnS quantum dots on the skeleton of the next generation (F1) was evaluated using rare minnows (Gobiocypris rarus) as model animals. Four-month-old sexually mature parental rare minnows (F0) were selected and treated with 0, 100, 200, 400 and 800 nmol/L CdSe/ZnS quantum dots for 4 days. Embryos of F1 generation rare minnows were obtained by artificial insemination. The results showed that with increasing maternal quantum dots exposure, the body length of F1 embryos decreased, the overall calcium content decreased, and the deformity and mortality rates increased. Alcian blue staining results showed that the lengths of the craniofacial mandible, mandibular arch length, mandibular width, and CH-CH and CH-PQ angles of larvae of rare minnows increased; histological hematoxylin-eosin staining further indicated that quantum dots affected the development of chondrocytes. Furthermore, high concentrations of CdSe/ZnS quantum dots inhibited the transcript expression of the bmp2b, bmp4, bmp6, runx2b, sox9a, lox1 and col2α1 genes. In conclusion, CdSe/ZnS quantum dots can affect the skeletal development of F1 generation embryos of rare minnows at both the individual and molecular levels, the damage to the craniofacial bone is more obvious, and the toxic effect of high concentrations of quantum dots (400 nmol/L and 800 nmol/L) is more significant.

Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection.

There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD-L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD-L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD-L1 on sEVs are specifically bound to their receptors, LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual-targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.

Engineering Cell Membrane-Based Nanovesicles for Melanoma Tumor Treatment.

Malignant melanoma has a poor prognosis because of its strong ability to invade tissues and metastasize. Immune checkpoint blockades significantly improve the clinical response in the development of melanoma. However, there are some obstacles to overcome, such as cost and limited application. Therefore, prospective approaches remain to be exploited. We designed cellular nanovesicles (NVs) expressing PD-1 to reactivate T cells by disrupting the PD-1/PD-L1 immunoinhibitory pathway. Furthermore, siNF90 was wrapped into PD-1 NVs to inhibit the proliferation of tumor cells. Such a dual target effect is helpful for the treatment of melanoma. In addition, our results showed that treatment with PD-1 @siNF90 NVs inhibited the growth of melanoma tumors and extended the survival time of mice, exhibiting a better effect than PD-1 NVs alone. The data also verified that the percentage of CD8+ T cells in tumors was highest after PD-1 @siNF90 NVs treatment. To sum up, PD-1 @siNF90 NVs could serve as safe and effective blockers in the treatment of melanoma.

Toxic effects of ZnSe/ZnS quantum dots on the reproduction and genotoxiticy of rare minnow (Gobiocypris rarus).

ZnSe/ZnS quantum dots (QDs) have excellent optical properties, but researchers have not clearly determined whether they cause harm to organisms. In the present study, the effect of ZnSe/ZnS QDs on the parents and offspring of rare minnow were evaluated for the first time. Exposure to ZnSe/ZnS QDs altered the testicular structure, caused sperm DNA damage and decreased sperm motility in males. They also suppressed the expression of reproduction-related genes, such as androgen receptor (Ar), DM-related transcription factor 1 (Dmrt1), estrogen receptor (Er), and X-ray repair cross complementing gene 1 (Xrcc1). Continued monitoring of the F1 generation revealed that the embryonic development of the F1 generation was abnormal and the growth index of the F1 generation of adult fish showed hormesis. A comet assay showed that the F1 generation still had DNA damage in the 400 and 800 nmol/L groups at 96 h post-fertilization (hpf). Thus, ZnSe/ZnS QDs damaged the reproductive system of the rare minnow, and this effect continued to the F1 generation.

Smad7 attenuates TGF-ß-mediated aging-related hypofunction of submandibular glands.

Submandibular glands have essential functions in taste, mastication, swallowing, and digestion. Submandibular gland hypofunction is prevalent in the elderly, impairing the patients' quality of life. Current clinical treatment strategies have not decelerated or reversed the pathological process of submandibular gland hypofunction. Therefore, novel restoration strategies should be explored. However, studies on the mechanism of aging-related submandibular gland hypofunction remain very limited. The role of the TGF-ß/Smad pathway in fibrosis has been studied in other organs. Therefore, this study aimed to elucidate the role of TGF-ß/Smad signaling in the aging-related submandibular gland hypofunction. The results showed that Smad7 knockout in mice decreased the salivary flow rate. H&E, Masson trichrome, and immunohistochemistry staining of MCP-1 and α-SMA showed that Smad7 knockout in mice resulted in lymphocytic infiltration, acinar cell atrophy, and interstitial fibrosis. The Western blotting of collagen I and III also confirmed extensive fibrosis. We then found that Smad7 depletion resulted in the TGF-ß-mediated fibrosis via mir-21, mir-29, and np_5318, and NFκB-driven inflammation activation. This study confirmed the inhibitory role of Smad7 in the aging-related submandibular gland hypofunction. Therefore, it provided a promising treatment target for aging-related dysfunction and sialadenitis of submandibular gland.

NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development.

Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. The elevated pre-rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T-cell activation can be significantly suppressed by inhibiting NF45/NF90-dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription-specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off-target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90-mediated rDNA transcription as a novel signaling pathway essential for T-cell activation and as a new target for the development of safe and effective immunosuppressants.