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Gestational trophoblastic disease (GTD) encompasses a range of trophoblastic disorders from hydatidiform mole (HM), to malignant gestational trophoblastic neoplasia (GTN). The exact molecular mechanisms of GTN remain unknown. Dysregulation and dysfunction of programmed cell death 4 (PDCD4)have been observed in many cancers. The roles of PDCD4 in GTD have not been previously reported.A total of 161 cases of formalin-fixed, paraffin-embedded trophoblast blocks, and 36 cases of fresh trophoblast tissues were collected, including normal first trimester placentas, HM, and invasive HM. Choriocarcinoma cells JAR and JEG-3 were employed. The expressions of PDCD4 and small ubiquitin-like modifier 2/3 (SUMO2/3) were examined by immunohistochemistry, quantitative reverse transcription PCR and Western blotting in trophoblastic tissues and cells. The relationship between SUMOylation and PDCD4 was investigated. The effects of PDCD4 on proliferation, invasion, and migration of choriocarcinoma cells were evaluated by Cell Counting Kit-8 and transwell assays post siRNA transfection. Extracellular MatrixAdhesion Profiler PCR Array was used to screen the downstream molecules of PDCD4.PDCD4 was significantly repressed in HM tissues. Loss of PDCD4 expression was demonstrated in 90% invasive HMs. Choriocarcinoma cells also displayed with suppressed PDCD4 expression. The varied expression of PDCD4 was paralleled by SUMO2/3. Inhibition of SUMOylation reduced the expression of PDCD4. Silencing of PDCD4promoted proliferation/migration/invasion, upregulatedMMP3/MMP8/ITGB2, and downregulated TIMP1/TIMP2 in choriocarcinoma cells.Our results suggest that reduced SUMOylation is one reason for suppressed PDCD4 in GTD. Loss of PDCD4 likely determines the malignant phenotype of GTN by dysregulating some members of the MMPs/TIMPs/integrins complex.

Oxidative stress (OS) induced activation of p38 mitogen-activated kinase (MAPK) and cell fate from p38 signaling was tested using the human fetal membrane’s amnion epithelial cells (AEC). We created p38 KO AEC using the CRISPR/Cas9 approach and tested cell fate in response to OS on an AEC-free fetal membrane extracellular matrix (ECM). Screening using image CyTOF indicated OS causing epithelial–mesenchymal transition (EMT). Further testing revealed p38 deficiency prevented AEC senescence, EMT, cell migration, and inflammation. To functionally validate in vitro findings, fetal membrane-specific conditional KO (cKO) mice were developed by injecting Cre-recombinase encoded exosomes intra-amniotically into p38αloxP/loxP mice. Amnion membranes from p38 cKO mice had reduced senescence, EMT, and increased anti-inflammatory IL-10 compared with WT animals. Our study suggested that overwhelming activation of p38 in response to OS inducing risk exposures can have an adverse impact on cells, cause cell invasion, inflammation, and ECM degradation detrimental to tissue homeostasis.

Supplementary Materials and Methods

Supplementary Figure 1. Time-course analysis of the development of lung tumors induced by urethane in BALB/C mice and MS/MS analysis of destrin identified. Supplementary Figure 2. Validation of targeted proteins chosen by immunohistochemistry analysis. Supplementary Figure 3. Protein expression levels of Prdx5, Ctsd, Ctsh, Ctnna1, and Jup with reference to GAPDH (internal control), examined by immunoblot in the lung tissues of normal control mice and the mice at week 16 and 32 after Urethane treatment. Supplementary Figure 4. The effect of DSTN knockdown or overexpression on colony formation and migration in BEAS-2B cells. Supplementary Figure 5. Representative images of IHC staining using Ki67. Supplementary Figure 6. DSTN knockdown induces G2/M phase arrest in A549 and H1299 cells. Supplementary Figure 7. DSTN knockdown promotes apoptosis in A549 and H1299 cells. Supplementary Figure 8. The effect of DSTN knockdown or overexpression on the migration of A549 and H1299 in vitro. Supplementary figure 9. The effect of DSTN knockdown or overexpression on anchorage-independent growth of A549 and H1299 in vitro. Supplementary figure 10. The effect of DSTN knockdown or overexpression on EMT marker expression. Supplementary Figure 11. The effect of DSTN knockdown or overexpression on the adhesive ability of the A549 and H1299 cells. Supplementary Figure 12. DSTN knockdown or overexpression affects the sub-cellular localization of β-catenin in A549 and H1299 cells. Supplementary figure 13. The interaction between DSTN and β-catenin was assessed by Co-immunoprecipitation.

Supplementary Table 1. The differentially expressed proteins of normal and early - stage lung cancer tissues identified by LC-MS/MS analysis (N: normal; T: tumor).

Supplementary Table 2.Proteins chosen for immunohistochemistry and Western blot validation. Supplementary Table 3. Correlations between clinicopathologic factors and destrin expression. Supplementary Table 4. Multivariate Cox regression analysis of survival rate in 86 lung. Supplementary Table 5. The primers used in this study for plasmid construction. Supplementary Table 6. The primers used in this study for reverse transcription-quantitative polymerasechain reaction analysis.

Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of β-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma.Implications:This finding indicates that DSTN facilitates β-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.

To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older.This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression.Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P0.001] and a significantly lower probability of survival (P0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19.The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.

Introduction In this study we examined the hypothesis that a hypoxic intrauterine environment causes mitochondrial dysfunction of trophoblasts in fetal growth restriction (FGR). Methods The mtDNA content, mRNA levels of mitochondrial encoded genes (ND6, COX I), mitochondrial membrane proteins (COX I, COX IV and VDAC), HIF-1α and BINP3 (mitophagy receptor) protein levels were examined in FGR placentas and normal placentas. The mitochondrial function (ATP production and mitochondrial membrane potential-ΔΨm) and above related proteins were further examined in hypoxic HTR-8/SVneo cells induced by cobalt chloride (CoCl2). Mitophagy and its regulating mechanism under hypoxia in FGR was also investigated. Results Compared with normal controls, both FGR placentas and CoCl2-treated trophoblast cells demonstrated statistically lower mtDNA content, reduced mRNAs of mitochondrial encoding genes, and decreased mitochondrial membrane proteins, accompanied by increased HIF-1α. Mitochondrial functions were impaired as demonstrated by decreased ATP production, and, reduced ΔΨm in CoCl2-treated cells. Meanwhile, mitophagy was markedly enhanced as indicated by increased LC3 fluorescent puncta in mitochondria of hypoxic trophoblastic cells. The upregulated BINP3 expression was demonstrated in FGR placentas as well as in hypoxic trophoblastic cells. Discussion We demonstrated that hypoxic conditions lead to impaired mitochondrial function in trophoblasts in FGR. Reduced mtDNA may be associated with enhanced mitophagy via activating HIF-1α/BINP3 signalling pathway, that may, in turn, affect nutrition and energy transfer to the growth-restricted fetus.

The warning of membrane fouling is of great important to maintain the stable operation of membrane bioreactor (MBR). However, traditional methods are so error-prone that probably do not acquire reliable solutions of membrane fouling due to its uncertainties. To overcome this problem, an intelligent warning method is proposed to monitor the status of MBR in this paper. The main advantages in this paper are as follows. First, an identification method, based on robust deep neural network (RDNN), is developed to diagnose the different types of membrane fouling. Second, a decision-making method, based on the restricted Boltzmann machine (RBM), is designed to distinguish the operational suggestion. Third, an intelligent warning system, based on the above two methods and some sensors, is developed to mitigate the membrane fouling in real wastewater treatment plants. Finally, the simulation and experimental results demonstrate the proposed warning method can obtain the higher identification accuracy of membrane fouling than other methods.

Developing effective non-precious metal electrocatalysts for oxygen reduction reaction (ORR) with a simple synthesis procedure is of great importance in a wide range of clean energy conversion syst...

Liver fibrosis is a global health problem caused by a number of diseases related to liver damage. 6-Shogaol is a biologically active substance derived from the rhizome of Zingiber officinale Roscoe with anti-tumor, anti-inflammatory, and antioxidant properties. To explore the effects of 6-Shogaol on liver fibrosis, we used a mouse model of the condition in which mice were injected intraperitoneally with carbon tetrachloride (CCl4) at a dose of 2 mL/kg three times per week for a period of 4 weeks. 6-Shogaol was administered orally at two different doses (5 mg/kg, 20 mg/kg) 30 min before CCl4 injection. CCl4 induced severe liver injury and fibrosis, as indicated by significant inflammatory cell infiltration, disordered liver structure, increased activities of aspartate aminotransferase and alanine aminotransferase (liver damage markers) in serum, elevated collagen deposition, and overexpressed alpha-smooth muscle actin (α-SMA, marker of hepatic stellate cells activation) in liver tissues, whereas 6-Shogaol administration rescued those alterations dose-dependently. We found that 6-Shogaol suppressed CCl4-induced inflammatory response by inhibiting macrophage recruitment, release of pro-inflammatory factors, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in liver tissues. Additionally, we demonstrated that 6-Shogaol blocked CCl4-induced activation of the nuclear factor-kappa B (NF-κB) pathway, which is a vital transcriptional regulator of the inflammatory response. Altogether, this study demonstrates that 6-Shogaol can prevent CCl4-induced liver fibrosis by suppressing inflammatory response through the NF-κB pathway and suggests that 6-Shogaol can be used for liver fibrosis prevention.

Developing effective earth aboundant non-precious metal electrocatalysts for oxygen reduction reaction (ORR) is highly demanded in clean energy conversion systems, such as fuel cells. In this work, we demonstrate N,F dual-doped carbon embedded with Co&CoN paragenetic structure (N,F–Co&CoN@C) as an effective ORR electrocatalyst through directly pyrolyzing the solid mixture of cobalt chloride hexahydrate, melamine hydrogen fluoride and carbon black in an N2 atmosphere. N,F–Co&CoN@C prepared at 700 °C (N,F–Co&CoN@C700) exhibits an excellent electrocatalytic performance with the ORR peak potential (Ep) at 0.875 V, the half wave potential (E1/2) at 0.871 V and a nearly four-electron reaction path in 0.1 M KOH. It also displays a better stability and methanol-tolerance than that of the commercial 40 wt% Pt/C. Origin of this outstanding performance of the prepared N,F–Co&CoN@C700 comes from the synergistic effect of Co&CoN and N,F–C in the hybrid materials. TEM images, STEM-mapping images, XRD and XPS results verify that N,F–Co&CoN@C700 has a core@shell structure with Co&CoN paragenetic structure embedded in N, F dual-doped carbon. Its specific surface area is calculated to be 1018 m2/g with a high defect degree of the ID/IG at 1.31.

Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (Rb) pathway is an effective therapeutic strategy against cancer. Here, we report a novel CDK4/6 inhibitor, BPI-16350, identified from comprehensive screening of a large panel of kinases. A series of investigations to evaluate anti-tumor activity show that BPI-16350 exhibits potent antiproliferative activities by inducing G1 arrest in a wide range of human Rb-positive tumor cells. Multiple carcinoma xenografts reveal that BPI-16350 has equivalent or improved anti-tumor efficacy compared with palbociclib or abemaciclib, and achieves obvious tumor regression without body weight loss in experimental animals, where pharmacokinetic study in SD rats indicates a longer half-life of BPI-16350 with once daily. Furthermore, BPI-16350 achieves excellent brain penetration with a nearly sixfold brain-to-plasma ratio in mice, suggesting the potential of treating tumor brain metastasis. Taken together, our findings indicate that BPI-16350 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties as an anti-cancer agent.

Due to the emergence of various new technologies, Internet of things (IoT) is gradually becoming one of the most valued technologies at present. The IoT makes our life more and more convenient through the interconnection of everything, but the IoT brings many advantages and also raises some security issues, such as the IoT perception layer as the main means of sensing data delivery, due to the limited resources of sensing nodes and their vulnerability, the diversity of sensing data, and the heterogeneity of the sensing network, making the IoT perception layer more vulnerable to various malicious attacks. Therefore, guaranteeing the trustworthy source of sensing data is the cornerstone to guarantee the secure operation of the sensing layer. In this paper, we investigate the remote proof scheme applicable to the IoT perception layer and propose a remote attestation mechanism using a threshold ring signature for a perception layer of distributed networking, which realizes the trusted proof of a data source and thus can effectively discern the trusted status of the data source, and prove that the proposed scheme in this paper outperforms other remote proof schemes through efficiency analysis and verify the correctness as well as the effectiveness of the scheme in this paper.

Deep neural network (DNN) has been applied in many fields and achieved great successes. However, DNN suffers from poor robustness for uncertainties because of its characteristic of the deterministic representation. To overcome this problem, a novel robust DNN (RDNN) is designed in this paper. First, a fuzzy denoising autoencoder (FDA) is developed to replace the general base-building unit in DNN. Then, the proposed RDNN is able to extract the robust representations to weaken the uncertainties. Second, a compact parameter strategy (CPS) is designed to reconstruct the parameters of FDA. Then, the computational burden of FDA can be alleviated to speed up the learning process. Third, an adaptive back-propagation (ABP) algorithm, with an adaptive learning rate strategy, is proposed to update the parameters of RDNN. Then, the performance of RDNN can be improved. Finally, the results on the benchmark problems and real applications demonstrate the effectiveness of RDNN.

C3H-type zinc finger genes play diverse roles in plant growth, development, and stress responses. In our present study, a C3H-type gene namely BoC3H4 was isolated from broccoli. BoC3H4 was 1629 bp in length encoding 542 amino acid residues. The deduced protein sequence contained two ankyrin repeats and two CCCH zinc finger motifs, and those motifs shared high identities with homologous sequences from other Cruciferae plants. The expression levels of BoC3H4 elevated when subjected to both salt stress and Sclerotinia sclerotiorum infection. Broccoli plants with constitutive expression of BoC3H4 demonstrated increased tolerance toward salinity stress, accompanied by a prominent accumulation of proline, and a remarkable decrease of chlorophyll loss, MDA, REC, as well as H2O2 accumulation compared to WT plants. Moreover, over-expression of BoC3H4 in broccoli lines decreased resistance to S. sclerotiorum, and it could not induce the expression of BoPDF1.2 gene, the marker gene for JA/ET signaling pathway. Our study proposes that BoC3H4 acts as a positive regulator of plant tolerance to salinity stress and a negative regulator of resistance to necrotrophic pathogen S. sclerotiorum.

Background The purpose of this phase II study was to evaluate the feasibility of hypofractionated radiotherapy (HFRT) with a dose of 36.5 Gy in 10 fractions in postmastectomy patients. Methods From March 2014 to December 2015, 85 patients with locally advanced breast cancer were eligible to participate in this study with a schedule of 36.5 Gy in 10 fractions. Intensity-modulated radiation therapy (IMRT) was delivered to the chest wall with or without the supraclavicular region. The primary endpoint was radiation-related toxicities. The secondary endpoints were locoregional failure-free survival (LRFFS), disease-free survival (DFS) and overall survival (OS). And the outcomes were compared with our retrospective study of 72 patients with 42.5 Gy in 16 fractions. Results The median follow-up was 69.0 (range 66.5-71.5) months in the 36.5 Gy group and 93.0 (range 91.9-94.1) months in the 42.5 Gy group, respectively. Radiation-related toxicities were mainly grade 1, although a few patients had grade 2 plexopathy (1.2%) and acute skin toxicity (1.2%) in the 36.5 Gy group, and grade 2 acute skin toxicity (5.6%) and lymphedema (4.2%) in the 42.5 Gy group. There were no significant differences between the groups in acute and late toxicities. For all the patients, the 5-year LRFFS, DFS and OS were 97.7 and 100.0%, 93.1 and 90.3%, 98.8 and 97.2%, respectively, without significant differences between the groups. Conclusion Postmastectomy HFRT with a schedule of 36.5 Gy in 10 fractions was feasible, with mild toxicities and excellent 5-year clinical outcome. Trial registration Trial registration number: ChiCTR-ONRC-14004391. Date of registration: 9/3/2014.

In this study, a class of non-precious metal catalyst for oxygen reduction reaction (ORR), namely N-doped porous carbon accompanied with Fe2O3 (herein named as AC-4), is synthesized from one-step pyrolyzing the precursors of KOH, coal, Fe salt and melamine, followed by acid-leaching. Several catalysts, AC-1 from KOH + coal, AC-2 from KOH + coal + melamine and AC-3 from KOH + coal + Fe salt, are also shown for comparison. As a result, AC-4 provides the best ORR catalytic activity with the ORR peak potential (Ep) of 818 mV, followed by the order of AC-2 (783 mV) > AC-3 (775 mV) > AC-1(771 mV), meaning that the N-doping strategy plays more effect than the Fe2O3-doping method, and AC-4 has the synergetic effect of these two ways. Furthermore, the ORR mechanism on AC-4 is near a four-electron transfer pathway with the electron transfer number around 3.7–3.9. It also has a good stability and methanol-resistance. Structure measurements display that introduction of N heteroatom and/or metal can increase the disorder degree of AC, and AC-4 has a structure of N-doped porous carbon (the special surface area of 1193 m2 g−1) accompanied with Fe2O3.

Neural indicators of pain discriminability have far-reaching theoretical and clinical implications but have been largely overlooked previously. Here, to directly identify the neural basis of pain discriminability, we apply signal detection theory to three EEG (Datasets 1-3, total N = 366) and two fMRI (Datasets 4-5, total N = 399) datasets where participants receive transient stimuli of four sensory modalities (pain, touch, audition, and vision) and two intensities (high and low) and report perceptual ratings. Datasets 1 and 4 are used for exploration and others for validation. We find that most pain-evoked EEG and fMRI brain responses robustly encode pain discriminability, which is well replicated in validation datasets. The neural indicators are also pain selective since they cannot track tactile, auditory, or visual discriminability, even though perceptual ratings and sensory discriminability are well matched between modalities. Overall, we provide compelling evidence that pain-evoked brain responses can serve as replicable and selective neural indicators of pain discriminability.

N6-methyladenosine (m6A) is the most prevalent type of RNA modification, and we hypothesized that patterns of m6A-related genes may be useful for estimating risk of lung adenocarcinoma (LUAD). An m6A-related gene set variation score (m6A-GSVS) was generated using RNA-sequencing data from LUAD patients in The Cancer Genome Atlas (TCGA). We investigated the association of m6A-GSVS with stemness, tumor mutational burden (TMB), expression of three immune checkpoints, levels of tumor-infiltrating lymphocytes (TILs), and patient prognosis. We found that m6A-GSVS was higher in LUAD than in healthy lung tissue, and it strongly correlated with stemness and TMB. Activated CD4 + T cells were more numerous in LUAD samples that had higher m6A-GSVS than in those with lower scores. Biological processes and pathways, including “Cell cycle,” “DNA replication,” and “RNA degradation,” were significantly enriched in samples with high scores. Furthermore, m6A-GSVS was an independent prognostic indicator in LUAD. In conclusion, we proposed an m6A-GSVS in LUAD. It is a putative indicator for evaluating the ability to RNA m6A, an independent prognostic indicator and associated with tumor stemness.