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By facile calcination, we successfully prepared CDs@MOF composites via self-carbonization in defect-containing MOFs, achieving photoluminescence fine tuning and effective sensing of picric acid.

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry–based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies. Significance: GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used for treating patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, acquired resistance to osimertinib is inevitable in EGFR-mutant NSCLC. By employing a global mass spectrometry-based phosphoproteomics approach, we identified that the activated p21-activated kinase 2 (PAK2)/β-catenin axis acts as a driver of osimertinib resistance. We found that PAK2 directly phosphorylates β-catenin and increases the nuclear localization of β-catenin, leading to the increased expression and transcriptional activity of β-catenin, which in turn enhances cancer stem-like properties and osimertinib resistance. Moreover, we revealed that HER3 as an upstream regulator of PAK2, drives the activation of PAK2/β-catenin pathways in osimertinib-resistant cells. The clinical relevance of these findings was further confirmed by examining tissue specimens from patients with EGFR-mutant NSCLC. The results demonstrated that the levels of HER3, phospho-PAK2 (p-PAK2) and β-catenin in the tissues from patients with EGFR-mutant NSCLC, that had relapsed after treatment with osimertinib, were elevated compared to those of the corresponding untreated tissues. Additionally, the high levels of HER3, p-PAK2 and β-catenin correlated with shorter progression-free survival (PFS) in patients with EGFR-TKI-treated NSCLC. We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of β-catenin is important for osimertinib resistance and targeting the HER3/PAK2/β-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.

In mammals, DYRK2 increases p53 phosphorylation level by interacting with it and then promotes cell apoptosis. However, the function of fish DYRK2 has not yet been elucidated. In this paper, we cloned and identified the coding sequence (CDS) of a grass carp DYRK2 (CiDYRK2) which is 1773 bp in length and encodes 590 amino acids. SMART predictive analysis showed that CiDYRK2 possesses a serine/threonine kinase domain. Subsequently, we used the dsRNA analog polyinosinic-polycytidylic acid (poly (I:C) and Grass carp reovirus (GCRV) to stimulate grass carp and CIK cells for different times and found that CiDYRK2 mRNA was significantly up-regulated both in fish tissues and cells. To explore the function of CiDYRK2, we carried out overexpression and knockdown experiments of CiDYRK2 in CIK cells. Real-time quantitative PCR (Q-PCR), TdT-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry were used to detect the ratio of BAX/BCL-2 mRNA, the number of TUNEL positive cells, the proportion of Annexin V-positive cells respectively. The results showed that CiDYRK2 significantly up-regulated BAX/Bcl-2 mRNA ratio and increased the number of TUNEL-positive cells, as well as the proportion of Annexin V-positive cells. On the contrary, knock-down of CiDYRK2 significantly down-regulated BAX/Bcl-2 mRNA ratio in the cells. Therefore, CiDYRK2 promoted cell apoptosis. To study the molecular mechanism by which CiDYRK2 promoting cell apoptosis, subcellular localization and immunoprecipitation experiments were used to study the relationship between grass carp DYRK2 and the pro-apoptotic protein p53. The results showed that CiDYRK2 and Cip53 were located and co-localized in the nucleus. Co-immunoprecipitation experiment also showed that CiDYRK2 and Cip53 can bind with each other. We further found that DYRK2 can increase the phosphorylation level of p53. In a word, our results showed that grass carp DYRK2 induces cell apoptosis by increasing the phosphorylation level of p53.

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry–based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies.Significance:GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer.

Supplementary Data from ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer

Aims. Short-wavelength blue light damaged retina by the oxidative stress in the retinal pigment epithelial (RPE) cells. Filtering blue light from screen could reduce blue hazard, whereas it inevitably altered color-gamut coverage and color-deviation level. Although abnormal fundus-vascular density (FVD) sometimes indicated fundus disease, few researchers noticed its responses to the variation of color-gamut coverage and color-deviation level. Methods. In this study, we performed cellular experiments and analyzed the RPE cell viabilities (CVs) in spectrums with different blue (455-475 nm) ratios to describe the corresponding oxidative-stress levels. Further, we investigated the effects of color-gamut and deviation on FVD variations during the screen-watching task using human factor experiments with 30 participants (university students, including 17 males and 13 females, 21 to 30 years old). Results. RPE CVs were similar in different spectrums, implying that non-oxidative blue filtering hardly contributed to CV improvement. Color-deviation level seems to induce more significant effects on the visual function compared to color-gamut coverage, and MTF and FVD presents similar variation trends during the visual task. Conclusion. Oxidative-free blue filtering contributed little to decrease retinal oxidative stress yet caused color-deviation increase, which caused significant FVD reduction.

Through this study, we aimed to evaluate the effects of different types of placenta previa (PP) on maternal and neonatal outcomes. This study was conducted in The Third Affiliated Hospital of Guangzhou Medical University and Tongji Hospital between January 2009 and 2019. PP was traditionally classified into four types, namely low-lying placenta, marginal, partial, and complete PP. Previous studies have classified PP into two types, namely low-lying placenta and PP. Based on our clinical experience, we proposed the classification of PP into three types, for the first time, which included low-lying placenta, “marpartial” (marginal and partial) PP, and complete PP. Multivariate logistic regression analysis was performed to determine the effects of different types of PP on maternal and neonatal outcomes. In total, 4490 singleton pregnancies were complicated with PP. In the four-classification method, compared with women with low-lying placenta, women with complete PP had a risk of placenta accrete spectrum disorders, postpartum hemorrhage (PPH), hemorrhagic shock, severe PPH, blood transfusion, hysterectomy, puerperal infection, preterm labor, NICU admission, and low birth weight. There was no difference in maternal and neonatal outcomes between marginal and partial PP, except for increased chances of preterm labor and low birth weight in partial PP. In the two-classification method, PP was the risk factor for most of the adverse maternal and neonatal outcomes, compared with low-lying placenta. Complete PP and low-lying placenta were associated with the highest and lowest risks of adverse pregnancy outcomes, respectively, whereas clinically similar outcomes were observed between marginal and partial PP. The three-classification of PP may be practical from the clinical perspective.

Capacitive deionization (CDI) is a robust water treatment technique due to its energy-efficient, low cost, and environmentally safe features. Recently, the utilization of faradaic electrode materials to construct hybrid capacitive deionization (HCDI) is considered to be one of the effective ways to address the drawbacks of the inferior desalination capacity of conventional CDI. Here, for the first time, a Na3MnTi(PO4)3/C (NTMP/C) composite was prepared via a sol–gel-calcination method and used as a faradaic electrode in HCDI. The NTMP nanoparticles were encapsulated in a carbon matrix, which could reduce the ion diffusion distance as well as ensure rapid ion transmission. In addition, taking the advantage of the high ratio of pseudo-capacitive performance and the two-species redox reaction of Ti4+/Ti3+ and Mn3+/Mn2+ couples, the obtained NTMP/C composite displayed a large ion removal capacity (72.2 mg g−1) (IRC), ultrafast ion removal rate (IRR) (21.6 mg g−1 min−1) and excellent cycle stability. Moreover, the mechanism of the Na+ removal of NTMP/C in the desalination process was investigated via electrochemical and ex situ structural characterization. This study indicates that NTMP/C can be an alternative faradaic electrode material towards CDI applications.

Blue crest between the wavelength of 460 nm and 480 nm was reported to present melatonin suppression effects, whereas effects of red light on circadian rhythm regulation remain unclear. Spectrum plays an important role in circadian rhythm regulation, yet a lot of researches focused on the correlated color temperature, although a correlated color temperature value corresponds to various possible spectrums. Here, we performed human factor experiments with 3 lamps on 17 participants, comprising 9 males and 8 females. Our results showed that spectrums with high blue intensity tended to cause abnormal regulations of melatonin and cortisol, while the abnormalities were likely to be compensated by the 606-635-nm red light, which was indispensable for the photo-biological effects concerning circadian rhythm regulation. Abnormal circadian rhythm regulation was also found to be influenced by the illuminance, as abnormalities were significant in 500 lux whereas they were likely to disappear in 250 lux, implying the existence of threshold doses to trigger abnormities concerning circadian rhythm regulation. Furthermore, circadian rhythm responses were distinct between males and females. Our work may have implications for the development of light source, as we suggest that lighting source designers should increase the 606-635-nm intensity for bed room luminaires to decrease melatonin suppression effects.

Background: Post-stroke spasticity (PSS) is a major cause of disability, leading to severely impaired upper-limb flexibility and ability to walk and move, significantly affecting the quality of life of cerebral infarction patients. There is currently no recognized effective therapy. Alternatively, Chinese traditional medicine has shown promise for PSS treatment. In this regard, the BSLSF has been reported to be effective; however, its underlying mechanism remains unclear. Objective: The objective of this study is to clarify the main targets and pathways of Baishao Luoshi Formula (BSLSF) during PSS treatment, laying the foundation for further research on its pharmacological effects. Method: In this study, network pharmacology and experimental verification were conducted to explore the potential mechanism of BSLSF systematically. After obtaining active ingredients of BSLSF from the TCMSP database, SwissTarget-Prediction and PharMapper were used to uncover BSLSF targets. PSS-related targets were gathered with GeneCards and Online Mendelian Inheritance in Man. The differentially expressed genes between BSLSF and PSS were identified by a Venn plot. The drug-active ingredient-target interaction network and Protein-protein interaction (PPI) were constructed using Cytoscape and further analyzed using the MCC algorithm of Cyto- Hubba plugin. Then, Pathway enrichment and GO biological process enrichment analyses were performed. Subsequently, a mice model of middle cerebral artery occlusion (MCAO) was established for the in vivo experiments. Result: We found that AKT1, TNF, CASP3, VEGFA, and CREB1 were potential targets during PSS treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that the mechanism of PSS was closely related to synaptic plasticity. And the immunohistochemical staining showed that BSLSF protected against ischemic stroke via the CCR5/CREB signaling pathway and probably affected synaptic plasticity. Conclusion: our study validated that treatment with BSLSF protected against ischemic stroke via the CCR5/CREB signaling pathway and could affect synaptic plasticity. In a sense, this study provides the basis for further extensive and in-depth analysis of BSLSF, enabling the quest for new drug targets at the same time.

Defective decidual function contributes to the pathogenesis of preeclampsia. However, the precise mechanism of defective decidua during preeclampsia has not been characterized. During decidualization, endometrial stromal cells undergo phenotypic changes that are consistent with mesenchymal-epithelial transition (MET). cGMP-dependent kinase protein I (PKGI)/VASP signaling is important in cell motility proliferation, differentiation and cell adhesion. To investigate this aim, we analyzed PKGI levels, phosphorylated VASP protein levels, and eNOS and sGC protein expression levels during pregnancy complicated by preeclampsia, which indicated that PKGI/VASP signaling function is decreased by the condition. Moreover, we evaluated the differential expression of genes that regulate MET in the decidua resulting from preeclampsia and healthy pregnancies. We discovered that vimentin mRNA levels are decreased in the decidua of preeclampsia, which indicates that excessive MET occurs in the decidua of preeclampsia pregnancies. A fundamental developmental MET program occurred in response to signaling pathways. These results suggest the important role of decreased PKGI/VASP signaling during excessive MET in the pathogenesis of preeclampsia.

Resistance to platinum-based chemotherapy becomes a major obstacle in non-small-cell lung cancer (NSCLC) treatment. Overexpression of the excision repair cross-complementing 1 (ERCC1) gene is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. In this study, we confirm that high ERCC1 expression correlates with cisplatin resistance in NSCLC cells. Importantly, histone deacetylase inhibitors (HDACis) re-sensitize ERCC1-high NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, the HDACi induces the expression of miR-149 by acetylation and activation of E2F1, which directly targets ERCC1 and inhibits ERCC1 expression. Inhibition of miR-149 reverses the promotion effect of HDACis on cisplatin-induced DNA damage and cell apoptosis in ERCC1-high NSCLC cells. In conclusion, this study reveals a novel mechanism by which HDACis re-sensitizes ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and we propose that combination of HDACis and cisplatin might hold promise to be a more effective therapeutic paradigm for ERCC1-high NSCLCs., Graphical Abstract, Overexpression of ERCC1 is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. Liu and colleagues demonstrate that HDACis could re-sensitize ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and they propose that the combination of HDACis and cisplatin might hold promise to be a more effective therapeutic strategy for ERCC1-high NSCLCs.

The impacts of the current COVID-19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS-CoV-2 infection at early-to-mid gestation on maternal and foetal health remains unclear.Here, we report the follow-up study of a pregnant woman of her whole infective course of SARS-CoV-2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single-cell RNA sequencing (scRNA-seq) for the placenta were performed.Compared with the gestational age-matched control placentas, the placenta from this COVID-19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast-related genes. The scRNA-seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over-activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood.These findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal-foetal interface that may be attributed to SARS-CoV-2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID-19.

Defects in decidual response are associated with adverse pregnancy outcomes which includes recurrent pregnancy loss (RPL). It is reported that cellular senescence happens during decidualization and pro-senescent decidual response in the luteal phase endometrium is related to RPL. However, the underlying mechanisms of how excessive decidual senescence takes place in RPL decidua cells remain largely unexplored. The senescent phenotype of RPL decidua and tumor necrosis factor receptor 1(TNFR1) expression were analyzed by using our previously published single-cell sequencing dataset of decidua cells from 6 RPL and 5 matched normal decidua, which were further verified by PCR and WB in decidual tissues. Effects of TNFα on the decidual stromal cells (DSCs) senescence and underlying molecular pathways were analyzed using the in vitro decidualization model of human endometrial stromal cells (HESCs). We showed that decidual stroma cells from RPL patients exhibited transcriptomic features of cellular senescence by analysis of single-cell datasets. The TNFα level and TNFR1 expression were increased in RPL decidua tissues. Furthermore, in vitro cell model demonstrated that increased TNFα induced excessive senescence during decidualization and TNFR1/p53/p16 pathway mediates TNFα-induced stromal senescence. In addition, we also found that the expression of IGFBP1 was regulated by TNFα-TNFR1 interaction during decidualization. Taken together, the present findings suggest that the increased secretion of TNFα induced stromal cell excessive senescence in RPL decidua, which is mediated via TNFR1, and thus provide a possible therapeutic target for the treatment of RPL.

Background Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. Methods Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. Results Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C–C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties. Conclusions This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC.

Objectives Successful pregnancy involves the homeostasis between maternal decidua and fetoplacental units, whose disruption contributes to compromised pregnancy outcomes, including recurrent spontaneous abortion (RSA). The role of cell heterogeneity of maternal decidua in RSA is yet to be illustrated. Materials and methods A total of 66,078 single cells from decidua samples isolated from patients with RSA and healthy controls were analysed by unbiased single‐cell RNA sequencing (scRNA‐seq). Results Our scRNA‐seq results revealed that stromal cells are the most abundant cell type in decidua during early pregnancy. RSA samples are accompanied by aberrant decidualization and obviously obstructed communication between stromal cells and other cell types, such as abnormal activation of macrophages and NK cells. In addition, the over‐activated TNF superfamily member 12 (TNFSF12, TWEAK) and FASLG in RSA are closely related to stromal cell demise and pregnancy failure. Conclusions Our research reveals that the cell composition and communications in normal and RSA decidua at early pregnancy and provides insightful information for the pathology of RSA and will pave the way for pregnancy loss prevention., Recurrent spontaneous abortion (RSA), characterized by pregnancy loss before 20 weeks of gestation more than twice, is an intricated pregnancy complication with enigmatic underlying mechanism ascribes to its complex pathogenesis. The homeostasis between the developing foetus and maternal decidua is critical for pregnancy maintenance. By exploring the cell heterogeneity in normal and RSA decidua utilizing scRNA‐Seq, we unravel the discrepancies in cell composition and communications in these two distinct deciduae. Our investigations uncover that stromal cells are the most abundant cell populations in the decidua, with three different subpopulations at various decidualization stages and two fibroblasts. There are two separated trajectories of stromal cell decidualization marked by PLA2G2A and WNT4. As the most abundant cell population in the decidua, the stromal cells dominate the communications with other cell types, including endothelial cells, macrophages, uNK cells and perivascular cells. Compared with normal decidua, decidualized stromal cells are overtly decreased in RSA decidua with augmented macrophages. In addition, we present some previously unappreciated signaling pathways among different cells types in decidua and also depict the remarkably changed communications between normal and RSA decidual. The aberrant activated TWEAK and FASLG in RSA are considered to be potential reasons for stromal cells demise and pregnancy failure. Our research reveals the cell composition and communications in normal and RSA decidua at early pregnancy and provides insightful information for the pathology of RSA and will pave the way for pregnancy loss prevention.

Protein inhibitor of activated signal transducer and activator of transcription (PIAS) family protein involved in gene transcriptional regulation acts as negative regulator in Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. But until now, the roles of PIAS in fish are not clear. In this study, we identified the two mammalian PIAS1 orthologs from Ctenopharyngodon idellus, namely CiPIAS1a and CiPIAS1b, respectively. They can respond to the stimulation from Polyribocytidylic acid (Poly I:C), Grass Carp Reovirus (GCRV) and Lipopolysaccharides (LPS) respectively, so we suggested that they could participate in interferon (IFN)-mediated antiviral and antibacterial immune response. The subcellular localization and nuclear cytoplasm extraction showed that CiPIAS1a and CiPIAS1b were mainly distributed in the nucleus. In addition, Co-IP showed that they separately inhibited the phosphorylation of STAT1 via interacting with it, which leads to the reduction of IFN1 expression.

Breast cancer stem cells (BCSCs) are tumor initiating cells that can self-renew and are highly tumorigenic and chemoresistant. Therefore, the identification of factors critical for BCSC function is vital for the development of therapies. Here, we report that DNMT1-mediated FOXO3a promoter hypermethylation leads to downregulation of FOXO3a expression in breast cancer. FOXO3a is functionally related to the inhibition of FOXM1/SOX2 signaling and to the consequent suppression of BCSCs properties and tumorigenicity. Moreover, we found that SOX2 directly transactivates DNMT1 expression and thereby alters the methylation landscape, which in turn feedback inhibits FOXO3a expression. Inhibition of DNMT activity suppressed tumor growth via regulation of FOXO3a/FOXM1/SOX2 signaling in breast cancer. Clinically, we observed a significant inverse correlation between FOXO3a and FOXM1/SOX2/DNMT1 expression levels, and loss of FOXO3a expression or increased expression of FOXM1, SOX2, and DNMT1 predicted poor prognosis in breast cancer. Collectively, our findings suggest an important role of the DNMT1/FOXO3a/FOXM1/SOX2 pathway in regulating BCSCs properties, suggesting potential therapeutic targets for breast cancer.

In this work, UiO-66-based metal–organic frameworks are investigated as an oxygen reduction reaction (ORR) catalyst for the first time. UiO-66-NO2 is solvothermally grown on the surface of cobalt p...

The illuminance index has been widely used in the field of photometry, although the luminance contains more information on not only light intensity but also light direction. In this study, we clarify which photometric index is more competent to describe the influence of lighting environment on human eye. In this study, we propose a novel methodology to investigate the photo-biological effect of the lighting environment by human factor experiment. With the human factor experiments performed on 20 participants, we compare the variations of ocular responses during the Landolt-rings-counting visual task in lighting environments with similar illuminance while distinct luminance changes. With the same Correlated Color Temperature (CCT) and Spectral Power Distribution (SPD), optical performances with similar illuminance values present quite different influences on ocular responses, and the response variations are found to vary with luminance values. It is implied that the regularity of luminance influence on the ocular responses to lighting environment is likely to be dependent on luminance value instead of illuminance, and the photometric index luminance seems more appropriate to be used to assess the lighting quality in standards.

PKR plays a significant role in IFN antiviral responses and in mediating apoptosis. Its activity is crucial for cellular antiviral and subsequent recovery. In mammalian cells, Protein Activator of the Interferon-induced Protein Kinase (PACT) and Trans-Activation-Responsive RNA-Binding Protein 2 (TARBP2) have the opposite effect on PKR activity in a dsRNA independent manner. There are some corresponding regulators of PKR in fish, too. In previous studies, we found that grass carp PACT can activate PKR in dsRNA independent manner. In this study, we tried to find out the effect of grass carp TARBP2 on PKR regulation. Grass carp TARBP2 expression is significantly increased at 6h post-poly I:C stimulation in CIK cells and grass carp tissues, indicating that it may play a role in poly I:C-mediated immune response. Then, we found that CiTARBP2 interacts with CiPKR and CiPACT, suggesting that it may regulate PKR activity by direct interaction with PKR or its regulators. Further, poly I:C promotes the phosphorylation of CiTARBP2 and enhances the interaction of CiTARBP2 and CiPKR. Finally, over-expression of CiTARBP2 decreases CiPKR phosphorylation and inhibits PKR-induced apoptosis. Therefore, our study reveals that CiTARBP2 can bind to CiPKR, CiPACT and CiTARBP2. The phosphorylated TARBP2 has stronger affinity to PKR, which results in the decrease of PKR phosphorylation and inhibition of cell apoptosis.