Unravelling the Photoelectrochemical Water Splitting of Nanometer-Thick Carbon Nitride Layer.

Matching the thickness of the graphitic carbon nitride (CN) nanolayer with the charge diffusion length is expected to compensate for the poor intrinsic conductivity and charge recombination in CN for photoelectrochemical cells (PEC). Herein, the compact CN nanolayer with tunable thickness is in situ coated on carbon fibers. The compact packing along with good contact with the substrate improves the electron transport and alleviates the charge recombination. The PEC investigation shows CN nanolayer of 93 nm-thick yields an optimum photocurrent of 116 µA cm-2 at 1.23 V versus RHE, comparable to most micrometer-thick CN layers, with a low onset potential of 0.2 V in 1 m KOH under 1 sun illumination. This optimum performance suggests the electron diffusion length matches with the thickness of the CN nanolayer. Further deposition of NiFe-layered double hydroxide enhanced the surface water oxidation kinetics, delivering an improved photocurrent of 210 µA cm-2 with IPCE of 12.8% at 400 nm. The CN nanolayer also shows extended potential in PEC organic synthesis. This work experimentally reveals the PEC behavior of the nanometer-thick CN layer, providing new insights into CN in the application of energy and environment-related fields.

Hydrophobic Carbon Nitride Nanolayer Enables High-Flux Oil/Water Separation with Photocatalytic Antifouling Ability.

Efficient oil/water separation tackles various issues in occasions of oil leakage and oil discharge, such as environmental pollution, recollection of the oil, and saving the water. Herein, a compact superhydrophobic/superoleophilic graphitic carbon nitride nanolayer coated on carbon fiber networks (CNBA/CF) is designed and synthesized for efficient gravity-driven oil/water separation. The CNBA/CF shows excellent oil absorption and an impressive oil/water filtration separation performance. The flux reaches the state-of-art value of 4.29 × 105 L/m2/h for dichloromethane with separation efficiency up to 99%. Successive oil absorption tests, long-term filtration separation, and harsh conditions experiments confirm the remarkable separation and chemical structure stability of the CNBA/CF filter. Besides, the CNBA/CF demonstrates good photocatalytic antifouling ability thanks to the extended visible light absorption and improved charge separation. This work combines the material surface wettability modulation with a photocatalytic self-cleaning property in the fabrication of efficient oil/water separation materials while overcoming the filter fouling issue.

P-Orbital Bismuth Single-Atom Catalyst for Highly Effective Oxygen Electroreduction in Quasi-Solid Zinc-Air Batteries.

P-block metals have gradually been utilized to synthesize non-noble-metal catalysts for oxygen reduction reaction (ORR) due to the easily tunable localized p-orbitals and resulted versatile electronic structures. The high-density single-atom bismuth sites (Bi-NC) anchored onto nitrogen-doped three-dimensional porous carbon are proved to possess significant electrocatalytic ORR performance. Theoretical calculations unveil positively charged bismuth centers prominently improved the adsorption capacity of N-doped carbon to O2 . The p orbitals of Bi sites within Bi-NC easily generate hybrid states with p orbitals of O2 , thus promoting charge transfer and ultimately reducing the energy barrier of ORR. Benefiting from p-orbital electrons regulation of bismuth atoms, Bi-NC exhibit ORR half-wave potential of 0.86 V (vs RHE). Additionally, both liquid and quasi-solid zinc-air batteries with Bi-NC as air-cathodes achieve higher power density and specific capacity than 20 wt% Pt/C, and comparable stability and round-trip efficiency with 20 wt% Pt/C. The discovery sheds light on the theoretical and practical guidance for p-block metallic single-atom catalysts.

TGF-ß-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer.

The impact of different iron metabolism processes (DIMP) on ovarian cancer remains unclear. In this study, we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer. cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer. Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer. By analyzing 1669 serous ovarian cancer cases, we identified a range of mutations in iron metabolism genes, notably in those coding for the transferrin receptor (19%), melanotransferrin (19%), and ceruloplasmin (10%) in the iron import process, and glucose-6-phosphate isomerase (9%), hepcidin antimicrobial peptide (9%), metal regulatory transcription factor 1 (8%), and bone morphogenetic protein 6 (8%) in the iron regulation process. Compared to the unaltered group, the group with gene alterations exhibited a higher tumor mutation burden count (43 vs. 54) and more advanced histologic grade (78.19% vs. 87.90%). Compared to the normal ovarian counterparts, a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer; in contrast, an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer. Furthermore, in cisplatin-resistant cells compared to cisplatin-sensitive ones, the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased, while that of 8 out of the 10 genes in iron utilization was increased. In addition, survival curve analysis indicated that a higher expression in the majority of genes in the iron import process (12/21), or a reduced expression in most genes in the iron export process (4/5) correlated with poor progression-free survival. Additionally, TGF-ß could regulate the expression of most iron metabolism-associated genes; particularly, expression of genes involved in the iron storage process (2/2) was inhibited after TGF-ß1 or TGF-ß2 treatment. In conclusion, DIMP plays multifaceted roles in the initiation, chemo-resistance, and prognosis of ovarian cancer. Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.

A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation.

Plasma cells (PC) are antibody-secreting cells and terminal effectors in humoral responses. PCs differentiate directly from activated B cells in response to T cell-independent (TI) antigens or from germinal center B (GCB) cells in T cell-dependent (TD) antigen-induced humoral responses, both of which pathways are essentially regulated by the transcription factor BLIMP1. The p38 mitogen-activated protein kinase isoforms have already been implicated in B cell development, but the precise role of p38α in B cell differentiation is still largely unknown. Here we show that PC differentiation and antibody responses are severely impaired in mice with B cell-specific deletion of p38α, while B cell development and the GCB cell response are spared. By utilizing a Blimp1 reporter mouse model, we show that p38α-deficiency results in decreased BLIMP1 expression. p38α-driven BLIMP1 up-regulation is required for both TI and TD PCs differentiation. By combining CRISPR/Cas9 screening and other approaches, we identify TCF3, TCF4 and IRF4 as downstream effectors of p38α to control PC differentiation via Blimp1 transcription. This study thus identifies an important signalling pathway underpinning PC differentiation upstream of BLIMP1, and points to a highly specialized and non-redundant role for p38α among p38 isoforms.

ASP-Det: Toward Appearance-Similar Light-Trap Agricultural Pest Detection and Recognition.

Automatic pest detection and recognition using computer vision techniques are a hot topic in modern intelligent agriculture but suffer from a serious challenge: difficulty distinguishing the targets of similar pests in 2D images. The appearance-similarity problem could be summarized into two aspects: texture similarity and scale similarity. In this paper, we re-consider the pest similarity problem and state a new task for the specific agricultural pest detection, namely Appearance Similarity Pest Detection (ASPD) task. Specifically, we propose two novel metrics to define the texture-similarity and scale-similarity problems quantitatively, namely Multi-Texton Histogram (MTH) and Object Relative Size (ORS). Following the new definition of ASPD, we build a task-specific dataset named PestNet-AS that is collected and re-annotated from PestNet dataset and also present a corresponding method ASP-Det. In detail, our ASP-Det is designed to solve the texture-similarity by proposing a Pairwise Self-Attention (PSA) mechanism and Non-Local Modules to construct a domain adaptive balanced feature module that could provide high-quality feature descriptors for accurate pest classification. We also present a Skip-Calibrated Convolution (SCC) module that can balance the scale variation among the pest objects and re-calibrate the feature maps into the sizing equivalent of pests. Finally, ASP-Det integrates the PSA-Non Local and SCC modules into a one-stage anchor-free detection framework with a center-ness localization mechanism. Experiments on PestNet-AS show that our ASP-Det could serve as a strong baseline for the ASPD task.

Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer.

Ferroptosis, a new way of cell death, is involved in many cancers. A growing number of studies have focused on the unique role of ferroptosis on endometrial cancer. In this study, we made a comprehensive review of the relevant articles published to get deep insights in the association of ferroptosis with endometrial cancer and to present a summary of the roles of different ferroptosis-associated genes. Accordingly, we made an evaluation of the relationships between the ferroptosis-associated genes and TNM stage, tumor grade, histological type, primary therapy outcome, invasion and recurrence of tumor, and accessing the different prognosis molecular typing based on ferroptosis-associated genes. In addition, we presented an introduction of the common drugs, which targeted ferroptosis in endometrial cancer. In so doing, we clarified the opportunities and challenges of ferroptosis activator application in treating endometrial cancer, with a view to provide a novel approach to the disease.

Association between common vaginal and HPV infections and results of cytology test in the Zhoupu District, Shanghai City, China, from 2014 to 2019.

BACKGROUND: HPV (human papillomavirus) is an important cause of cervical cancer. Cervical-vaginal infection with pathogens, such as herpes simplex virus (HSV), bacterial vaginosis Trichomonas vaginalis and vaginal candidiasis could be a cofactor. This study aimed to assess the relationship between vaginal infection with HPV genotype and cytology test results and analyze the relationship between vaginal and HPV infections and cervical cancer. METHODS: We performed a district-based study to elucidate the relationship among the vaginal and HPV infections and cervical cancer. We collected the cervical exfoliation data of 23,724 women admitted to the Shanghai Zhoupu Hospital and received ThinPrep cytology test (TCT) and HPV detection between 2014 and 2019. RESULTS: Total vaginal infection rate was 5.3%, and the HPV-positive group had a slightly higher vaginal infection rate than the HPV-negative group (P < 0.01). The incidence rate of cervical intraepithelial neoplasia or cervical cancer with vaginal infection was higher than without vaginal infection (P < 0.001). CONCLUSION: HPV/vaginal infection-positive women tended to have abnormal results of TCT. Women with vaginal infection were more likely to develop HPV infection. HSV combined with HPV infection was noted as a causal factor for HSIL.

CRNDE inducing cisplatin resistance through SRSF1/TIA1 signaling pathway in ovarian cancer.

BACKGROUND: CRNDE is known to be an important predictive factor of prognosis in many tumors; however, its role in cisplatin resistance is still unknown in ovarian cancer. The aim of the current research was to investigate the association between CRNDE and cisplatin resistance. MATERIALS AND METHODS: QRT-PCR and in situ hybridization assay were employed to detect the expression of CRNDE in ovarian cancer cells and tissues; CCK8 assay, AnnexinV-FITC apoptosis assay and Trans-well assay, to determine the cell proliferation, apoptosis and invasion; and RNA-pull down assay, mass spectrometry analysis, gene microarray to search the targeted gene of CRNDE and SRSF1. Association of CRNDE with SRSF1 was determined in ovarian cancer cells and nude mice. RESULTS: It was found that CRNDE and SRSF1 expression were higher in the cisplatin resistant ovarian cancer cells than their control cells. High expression of CRNDE and SRSF1 led to cisplatin resistance. While inhibition of CRNDE or SRSF1 sensitized ovarian cancer to cisplatin in vitro and in vivo. Moreover, as indicated in RIP assay, SRSF1 was potentially the targeted gene of CRNDE, and CRNDE promoting SRSF1 expression to induce cisplatin resistance; as indicated in gene microassay, there was significantly positive correlation between SRSF1 and TIA1, and SRSF1 promoting TIA1 expression. CONCLUSION: In conclusion, CRNDE induced cisplatin resistance in ovarian cancer through SRSF1/TIA1 signaling pathway; thus, CRNDE inhibitor or SRSF1 inhibitor combined with cisplatin might act as a novel promising approach to ovarian cancer.

Antinuclear antibodies in follicular fluid may be a risk factor in vitro fertilization and embryo transfer.

OBJECTIVE: To explore the effect of anti-nuclear antibodies (ANAs) on the outcome of in vitro fertilization-embryo transplantation (IVF-ET) and to study the effect of ANAs in follicular fluid (FF) on embryonic development. METHODS: The expression of ANAs in FF of patients treated with IVF-ET and healthy group. The patients were divided into ANAs-positive group and ANA-negative group. The age, duration of infertility, body mass index (BMI), basic follicle stimulating hormone (bFSH), anti-Mullerian hormone (AMH), number of retrieved oocytes, portion of metaphase II oocytes (MII), number of embryos in the cleavage stage, bipronuclear (2PN), number of embryos, number of high-quality embryos and the outcome of IVF-ET were compared between the two groups. In vitro, HTR8/SVneo trophoblast cells were cultivated and divided into ANAs-negative group (control group) and ANAs-positive group (ANAs-positive FF was added to cytotrophoblasts). The ANAs titer in the serum and FF of patients who treated with IVF-ET was detected using ELSIA method. CCK-8 assay and flow cytometry (at 24 h and at 48 h) were used to detect the cell proliferation and apoptosis frequency of the two groups, respectively. RESULTS: Among those who underwent IVF-ET treatment, the number of retrieved oocytes, the number of fertilization and the portion of MII oocytes in the FF-positive group were significantly lower than those in the FF-negative group. Furthermore, the implantation rate and the clinical pregnancy rate were decreased, and early miscarriage rate was increased in the FF-positive patients than those in the FF-negative patients. In vitro, the cytotrophoblasts proliferation activity in the ANAs group was significantly lower than that in the control group. Moreover, the cytotrophoblasts apoptosis rate in the ANAs group was significantly higher than that in the control group. CONCLUSIONS: Our data suggested that ANAs in FF might become an obstacle to embryonic development through promoting trophoblast apoptosis and inhibiting trophoblast proliferation. ANAs in FF might be an unfavorable factor for the outcome of those who undergo IVF-ET treatment.

Epidemiological analysis of hydrometra and its predictive value in gynecological tumors.

Introduction: Hydrometra is a common gynecological disease, especially in postmenopausal women. However, its epidemiology, harmfulness, and value in predicting gynecological tumors have not been clearly elucidated. Methods: In this study, the prevalence rate of and risk factors for hydrometra were investigated in 3,903 women who underwent screening for gynecological diseases at Zhoupu Hospital in Shanghai from 1 January to 31 December 2021. In addition, pathological distribution of hydrometra and its predictive value in gynecological tumors were studied in another 186 patients in whom hydrometra was diagnosed sonographically at Zhoupu Hospital, from 1 January 2020 to 31 December 2021, and who underwent hysteroscopy and postoperative pathological examination. Results: The observed prevalence rate of hydrometra was 10.86%, which was higher than the prevalence of other gynecological diseases. Univariate and multivariate analysis indicated that advanced age (OR 1.11) and vaginitis (OR 3.18) were independent risk factors for hydrometra. Among 186 patients with a sonographic diagnosis of uterine fluid, simple hydrometra accounted for 34.41% of cases, inflammation accounted for 16.23%, and hematometra accounted for 2.15%, while gynecological tumors accounted for 5.91%. Moreover, univariate and multivariate analysis indicated that a higher body mass index (>23.92 kg/m2), greater hydrometra volume (i.e., distance between the two layers of endometrium>4.75 mm), and abnormal vaginal bleeding were high-risk predictive factors for gynecological tumors. Discussion: In conclusion, hydrometra is a common disease, and is a risk factor for endometrial cancer and cervical cancer, especially in patients with higher hydrometra volume, higher BMI, and abnormal vaginal bleeding. It is necessary to pay more attention to hydrometra.

Diagnosis of TCM symptoms and analysis of risk factors of mild cognitive impairment in patients with type 2 diabetes mellitus.

OBJECTIVE: To explore the diagnosis of traditional Chinese medicine (TCM) syndrome and analyze the risk factors of mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM). METHODS: 141 T2DM patients, who were hospitalized in department of endocrinology of our hospital from February 2020 to December 2020, were chosen as research subjects. The patients were divided into an observation group (n=65, T2DM with MCI) and a control group (n=76, T2DM with normal cognitive function) according to the Montreal Cognitive Assessment (MoCA) score and diagnostic criteria of MCI. Pearson correlation analysis was used to study the correlation between MoCA score and influencing factors, and multiple logistic regression analyses were applied to analyze the risk factors of T2DM patients. RESULTS: Deficiency of kidney essence (34/65, 52.31%) and phlegm obstructing orifices (16/65, 2.62%) were common in T2DM patients with MCI. The observation group had apparently lower MoCA scores than the control group (23.46±3.12 points vs. 27.39±2.56 points, t=8.2150, P=0.0000). According to the results of multivariate logistic regression analysis, age, course of diabetes, homocysteine (HCY) and glycosylated hemoglobin (HbAlc) were the independent risk factors of MCI, and the education level was a protective factor. CONCLUSION: Mental deficiency and phlegm obstruction are common in T2DM patients complicated with MCI. The factors such as age, diabetes course, education degree, HCY and HbAlc are closely related to MCI. The occurrence of MCI in T2DM patients can be prevented by improving the education degree of patients, effective control of blood glucose and reduction of HCY level.

Glycogen synthase kinase 3 drives thymocyte egress by suppressing ß-catenin activation of Akt.

Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell­specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, ß-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P1 expression, thereby preventing emigration of thymocytes. A cytoplasmic membrane-localized ß-catenin excluded from the nucleus promoted Akt activation, suggesting a new function of ß-catenin independent of its role as a transcriptional activator. Furthermore, genetic ablation of ß-catenin, retroviral expression of a dominant negative Akt mutant, and transgenic expression of a constitutively active Foxo1 restored emigration of GSK3-deficient thymocytes. Our findings establish an essential role for GSK3 in thymocyte egress and reveal a previously unidentified signaling function of ß-catenin in the cytoplasm.

A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.

Tumor necrosis factor receptor-1 (TNFR1) signaling, apart from its pleiotropic functions in inflammation, plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice. Caspase-8 noncleavable receptor interacting serine/threonine kinase 1 (RIPK1) mutations occur naturally in humans, and the corresponding D325A mutation in murine RIPK1 leads to death at early midgestation. It is known that both the demise of Ripk1D325A/D325A embryos and the death of Casp8-/- mice are initiated by TNFR1, but they are mediated by apoptosis and necroptosis, respectively. Here, we show that the defects in Ripk1D325A/D325A embryos occur at embryonic day 10.5 (E10.5), earlier than that caused by Casp8 knockout. By analyzing a series of genetically mutated mice, we elucidated a mechanism that leads to the lethality of Ripk1D325A/D325A embryos and compared it with that underlies Casp8 deletion-mediated lethality. We revealed that the apoptosis in Ripk1D325A/D325A embryos requires a scaffold function of RIPK3 and enzymatically active caspase-8. Unexpectedly, caspase-1 and caspase-11 are downstream of activated caspase-8, and concurrent depletion of Casp1 and Casp11 postpones the E10.5 lethality to embryonic day 13.5 (E13.5). Moreover, caspase-3 is an executioner of apoptosis at E10.5 in Ripk1D325A/D325A mice as its deletion extends life of Ripk1D325A/D325A mice to embryonic day 11.5 (E11.5). Hence, an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5.

Characteristics of human papillomavirus infection among women with cervical cytological abnormalities in the Zhoupu District, Shanghai City, China, 2014-2019.

BACKGROUND: Human papillomavirus (HPV) infection is currently the main cause of cervical cancer and precancerous lesions in female patients. By analyzing 6-year patient data from Shanghai Zhoupu Hospital in China, we retrospectively analyzed the epidemiological characteristics of women to determine the relationship between HPV genotype and cytological test results. METHODS: From 2014 to 2019, 23,724 cases of cervical shedding were collected from Zhoupu Hospital in Shanghai, China. By comparing the results of HPV and ThinPrep cytology test (TCT), the HPV infection rate of patients was retrospectively analyzed. HPV genotyping using commercial kits can detect 21 HPV subtypes (15 high-risk and 6 low-risk). According to the definition of the Bethesda system, seven types of cervical cytology results were involved. RESULTS: 3816 among 23,724 women, nearly 16.08%, were infected with HPV. The top three highest HPV prevalence rates were high-risk type infection, including HPV52 (3.19%), 58 (2.47%) and 16 (2.34%). The number of single-type HPV infections (3480 (91.20%)) was much larger than the number of multi-type ones (336 (8.8%)). Single-type infections were mainly in women aged 50-60 (16.63%) and women under 30 (15.37%), while multi-type infections were more common in women over 60 (2.67%). By analyzing the long-term trends, between 2014 and 2019, HPV52, 58, and 16 subtypes changed significantly, and the HPV positive rate also changed significantly during this period. Among 4502 TCT positive women, 15 (4.04%), 125 (2.64%),159 (1.54%), 4202 (17.71%) and 1 (0.004%) had atypical glandular cells (AGC), high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL), atypical squamous cells (ASC)and cervical adenocarcinoma, respectively. The HPV infection rates were 66.08%, 63.99%, 115.20%, 119.50%, and 31.72% for NILM, AGCs, HSILs LSILs and ASCs, respectively. CONCLUSIONS: HPV and TCT screening were very important steps in the secondary prevention of cervical cancer. Through the tracking and analysis of HPV and TCT results in this study, it can provide valuable information for Shanghai's HPV screening and prevention strategies, and provide references for clinical decision-making in the treatment of cervical cancer and precancerous lesions.

Changes in clinical trials of endocrine disorder and metabolism and nutrition disorder drugs in mainland China over 2010-2019.

With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self-evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.

Interleukin-33 promotes proliferation and inhibits apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis.

OBJECTIVES: The aim of our study was to determine the effect of interleukin (IL)-33 on the proliferation, apoptosis, and secretion of inflammatory cytokines by fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) and to investigate the underlying mechanisms. METHODS: Cultured RA FLSs and osteoarthritis (OA) FLSs were cocultured with different concentrations of IL-33. TUNEL assay and flow cytometry were used to detect apoptosis. Western blotting and Real-time (RT)-PCR were used to detect the expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), while the Cell Counting Kit-8 was used to determine cell proliferation in each cocultured group. Enzyme-linked immunosorbent assay was used to detect the expression levels of tumour necrosis factor (TNF)-α and IL-6 in the supernatant from each cell culture. Western blot analysis was used to determine the phosphorylated expression levels of the nuclear factor-kappa light chain enhancer of the activated B cells (NF-κB) pathway in each group. RESULTS: IL-33 inhibited RA FLS apoptosis, promoted FLS proliferation, increased Bcl-2 protein expression levels, and decreased Bax protein expression levels. It also increased the expression levels of inflammatory cytokines TNF-α and IL-6 and increased the expression levels of P-NF-κ B in FLSs. CONCLUSIONS: IL-33 inhibited apoptosis and promoted proliferation of FLSs; in addition, IL-33 increased the serum levels of inflammatory cytokines. The effect of IL-33 on RA FLSs was likely mediated via the NF-κB pathway.

miR-194-5p inhibits SLC40A1 expression to induce cisplatin resistance in ovarian cancer.

BACKGROUND: miR-194-5p has been associated with drug resistance in many cancers. However, the role of miR-194-5p in cisplatin resistance in ovarian cancer is still unclear. MATERIALS AND METHODS: To study the role and mechanism of miR-194-5p in cisplatin resistance, qRT-PCR was performed to determine the expression of miR-194-5p and SLC40A1 in ovarian cancer. Cell Counting Kit-8 (CCK8) assay was used to analyse cell viability after cisplatin treatment. Dual-luciferase reporter gene assay was performed to examine the relationship between miR-194-5p and SLC40A1. The genes downstream of SLC40A1 were investigated through bioinformatics analysis. RESULTS: Compared to cisplatin-sensitive ovarian cancer cells, higher miR-194-5p expression and lower SLC40A1 expression were found in cisplatin-resistant ovarian cancer cells. Moreover, this study demonstrated that over-expression of miR-194-5p inhibited SLC40A1 expression, and knockdown of miR-194-5p promoted SLC40A1 expression. In addition, dual-luciferase reporter gene assay further confirmed the negative correlation between miR-194-5p and SLC40A1. Furthermore, we found that over-expression of miR-194-5p resulted in cisplatin resistance. When miR-194-5p and SLC40A1 were simultaneously up-regulated, cisplatin sensitivity increased, while down-regulation of miR-194-5p sensitised ovarian cancer cells to cisplatin. However, when miR-194-5p and SLC40A1 were simultaneously down-regulated, cisplatin sensitivity was decreased. These data suggested that miR-194-5p inhibited SLC40A1 expression to induce cisplatin resistance. In addition, bioinformatics analysis indicated a positive correlation of SLC40A1 with hephaestin (HEPH), and homeostatic iron regulator (HFE). However, we found that HEPH and HFE were associated with cisplatin resistance, suggesting that their role in drug resistance is induced by miR-194-5p/SLC40A1. CONCLUSION: In conclusion, we found that miR-194-5p inhibited SLC40A1 expression to induce cisplatin resistance in ovarian cancer. This study suggests that miR-194-5p could be a potential therapeutic target and a prognostic biomarker for ovarian cancer, with important implications for future research.

ZBP1 mediates interferon-induced necroptosis.

Interferons (IFNs) play an important role in immunomodulatory and antiviral functions. IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1 (RIPK1), Fas-associated protein with death domain (FADD), or caspase-8, but the mechanism is largely unknown. Here, we report that the DNA-dependent activator of IFN regulatory factors (ZBP1, also known as DAI) is required for both type I (ß) and type II (γ) IFN-induced necroptosis. We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1, FADD, or Caspase-8 was genetically deleted, confirming the antinecroptotic role of these proteins in IFN signaling. We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1, an IFN-stimulated gene (ISG) product, as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells. The N-terminal domain (ND) of ZBP1 is important for ZBP1-ZBP1 homointeraction, and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis. The antinecroptotic function of RIPK1, FADD, and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3, since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated. ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant, as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome (SIRS) induced by TNF + IFN-γ.