Splenectomy ameliorates liver cirrhosis by restoring the gut microbiota balance.

BACKGROUND: Dysbiosis of gut microbiota is frequent in liver cirrhosis (LC) patients, and splenectomy (SP) has been reported to improve LC. Herein, we report the effects of SP on gut microbiota, especially on Veillonella parvula, a Gram-negative coccus of the gastrointestinal tract, in LC mice, and the underlying mechanism. METHODS: LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula. RESULTS: SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1ß, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression. CONCLUSION: SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.

Effects of prospective motion correction on perivascular spaces at 7T MRI evaluated using motion artifact simulation.

PURPOSE: The effectiveness of prospective motion correction (PMC) is often evaluated by comparing artifacts in images acquired with and without PMC (NoPMC). However, such an approach is not applicable in clinical setting due to unavailability of NoPMC images. We aim to develop a simulation approach for demonstrating the ability of fat-navigator-based PMC in improving perivascular space (PVS) visibility in T2-weighted MRI. METHODS: MRI datasets from two earlier studies were used for motion artifact simulation and evaluating PMC, including T2-weighted NoPMC and PMC images. To simulate motion artifacts, k-space data at motion-perturbed positions were calculated from artifact-free images using nonuniform Fourier transform and misplaced onto the Cartesian grid before inverse Fourier transform. The simulation's ability to reproduce motion-induced blurring, ringing, and ghosting artifacts was evaluated using sharpness at lateral ventricle/white matter boundary, ringing artifact magnitude in the Fourier spectrum, and background noise, respectively. PVS volume fraction in white matter was employed to reflect its visibility. RESULTS: In simulation, sharpness, PVS volume fraction, and background noise exhibited significant negative correlations with motion score. Significant correlations were found in sharpness, ringing artifact magnitude, and PVS volume fraction between simulated and real NoPMC images (p ≤ 0.006). In contrast, such correlations were reduced and nonsignificant between simulated and real PMC images (p ≥ 0.48), suggesting reduction of motion effects with PMC. CONCLUSIONS: The proposed simulation approach is an effective tool to study the effects of motion and PMC on PVS visibility. PMC may reduce the systematic bias of PVS volume fraction caused by motion artifacts.

Comprehensive analysis of MAPK cascade genes in sorghum (Sorghum bicolor L.) reveals SbMPK14 as a potential target for drought sensitivity regulation.

The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in regulating many important biological processes in plants. Here, we identified and characterized eight MAPKK and 49 MAPKKK genes in sorghum and analyzed their differential expression under drought treatment; we also characterized 16 sorghum MAPK genes. RNA-seq analysis revealed that 10 MAPK cascade genes were involved in drought stress response at the transcriptome level in sorghum. Overexpression of SbMPK14 in Arabidopsis and maize resulted in hypersensitivity to drought by promoting water loss, indicating that SbMPK14 functions as a negative regulator of the drought response. Subsequent transcriptome analysis and qRT-PCR verification of maize SbMPK14 overexpression lines revealed that SbMPK14 likely increases plant drought sensitivity by suppressing the activity of specific ERF and WRKY transcription factors. This comprehensive study provides valuable insight into the mechanistic basis of MAPK cascade gene function and their responses to drought in sorghum.

Study on Microwave-Assisted Ignition Using a Novel Aero-Engine Combustor.

Microwave plasma can improve the performance of ignition and combustion, as well as reduce pollutant emissions. By designing a novel microwave feeding device, the combustor can be used as a cavity resonator to generate microwave plasma and improve the performance of ignition and combustion. In order to feed the energy of microwave into the combustor as much as possible, and effectively adapt to the change in resonance frequency of combustor during ignition and combustion, the combustor was designed and manufactured by optimizing the size of slot antenna and setting the tuning screws, according to the simulation results of HFSS software (version: 2019 R 3). The relationship between the size, position of metal tip in the combustor and the discharge voltage was studied using HFSS software, as well as the interaction between ignition kernel, flame and microwave. The resonant characteristics of combustor and the discharge of microwave-assisted igniter were subsequently studied via experiments. The results show that the combustor as microwave cavity resonator has a wider resonance curve and can adapt to the change in resonance frequency during ignition and combustion. It is also indicated that microwave can enhance the discharge development of igniter and increase the discharge size. Based on this, the electric and magnetic field effects of microwave are decoupled.

Influences of Total Alkaloids in Caulis Mahoniae on Proliferation and Apoptosis of Cervical Cancer Cells and the Caspase-3 Expression.

The study aimed to investigate the influences of the active ingredient in Caulis Mahoniae, total alkaloids, on the proliferation and apoptosis of cervical cancer cells and the caspase-3 expression. The total alkaloids were extracted in vitro from Caulis Mahoniae, and cervical cancer HeLa cell lines were used as experimental objects. The half inhibitory concentration (IC50) of total alkaloids on HeLa cell lines was detected via the preliminary experiment, the influences of total alkaloids at different concentrations on the proliferation of HeLa cell lines were detected via methyl thiazolyl tetrazolium (MTT) assay, and the cell growth curve was plotted. Moreover, the cell cycle and apoptosis after treatment with total alkaloids at different concentrations were detected via flow cytometry, and the caspase-3 gene and protein expressions were detected via reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The IC50 of total alkaloids in Caulis Mahoniaeon HeLa cell lines was 12.5 µg/mL. With the gradual increase of concentration of total alkaloids in the treatment of cervical cancer cells, the inhibitory rate on cancer cells was gradually increased, and the proportion of cells in the G0/G1 phase was gradually decreased, while that in S and G2/M phases was gradually increased. Besides, with the increase in the concentration of total alkaloids, the apoptotic rate of cervical cancer cells was gradually increased, and both caspase-3 gene and protein expressions were also gradually increased. The total alkaloids extracted from Caulis Mahoniae can effectively inhibit the proliferation and promote the apoptosis of cervical cancer HeLa cells, which may be realized by promoting the expression of apoptosis-related factor caspase-3.

The B-Type Cyclin CYCB1-1 Regulates Embryonic Development and Seed Size in Maize.

Progress through the cell cycle is a critical process during plant embryo and seed development and its progression is regulated by cyclins. Despite extensive study of cyclins in other systems, their role in embryo and seed development of maize is unclear. In this study, we demonstrate that ZmCYCB1-1 overexpression significantly accelerated embryo growth and increased seed size. In situ hybridization and toluidine blue staining indicated that ZmCYCB1-1 was highly expressed in the plumule of embryos, and the cells of the plumule were smaller, denser, and more regularly arranged in ZmCYCB1-1 overexpression plants. Overexpression of ZmCYCB1-1 in maize also resulted in an increased ear length and enhanced kernel weight by increasing kernel width. Transcriptome analysis indicated that the overexpression of ZmCYCB1-1 affected several different metabolic pathways, including photosynthesis in embryos and leaves, and lipid metabolism in leaves. Conversely, knocking out ZmCYCB1-1 resulted in plants with slow growth. Our results suggest that ZmCYCB1-1 regulates embryo growth and seed size, making it an ideal target for efforts aimed at maize yield improvement.

Mutation of OsSAC3, Encoding the Xanthine Dehydrogenase, Caused Early Senescence in Rice.

In both animals and higher plants, xanthine dehydrogenase is a highly conserved housekeeping enzyme in purine degradation where it oxidizes hypoxanthine to xanthine and xanthine to uric acid. Previous reports demonstrated that xanthine dehydrogenase played a vital role in N metabolism and stress response. Is xanthine dehydrogenase involved in regulating leaf senescence? A recessive early senescence mutant with excess sugar accumulation, ossac3, was isolated previously by screening the EMS-induced mutant library. Here, we show that xanthine dehydrogenase not only plays a role in N metabolism but also involved in regulating carbon metabolism in rice. Based on map-based cloning, OsSAC3 was identified, which encodes the xanthine dehydrogenase. OsSAC3 was constitutively expressed in all examined tissues and the OsSAC3 protein located in the cytoplasm. Transcriptional analysis revealed purine metabolism, chlorophyll metabolism, photosynthesis, sugar metabolism and redox balance were affected in the ossac3 mutant. Moreover, carbohydrate distribution was changed, leading to the accumulation of sucrose and starch in the leaves containing ossac3 on account of decreased expression of OsSWEET3a, OsSWEET6a and OsSWEET14 and oxidized inactivation of starch degradation enzymes in ossac3. These results indicated that OsSAC3 played a vital role in leaf senescence by regulating carbon metabolism in rice.

Dopamine receptor D2 inhibition alleviates diabetic hepatic stellate cells fibrosis by regulating the TGF-ß1/Smads and NFκB pathways.

Diabetic hepatic fibrosis (DHF) is a progressive liver disease and a chronic complication of diabetes mellitus. The main cause of DHF is the activation of quiescent hepatic stellate cells (HSCs) by high glucose stimulation. Dopamine receptor D2 (DRD2)-mediated dopamine signalling can be involved in the regulation of diabetic liver disease, but the exact role of DRD2 in DHF is still poorly understood. This study aimed to investigate the protective effect of DRD2 inhibition on diabetic liver fibrosis and the potential mechanism. We established both streptozotocin (STZ)-induced type 1 diabetes (T1D, fed for 20 weeks) rat model and high glucose (HG, 40 mmol/L)-stimulated HSCs model. The results from both the rats with STZ and the HSCs treated with HG showed increased expression of DRD2, NOX-5, inflammation-related proteins (IL-6 and TNFα) and fibrosis-related proteins (TGF-ß1, CO-Ⅰ/Ⅲ/ IV, MMP-2/9 and fibronectin). In vivo, the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total antioxidant capacity (T-AOC) levels were significantly increased, and hematoxylin-eosin (HE) staining, Masson staining, and electron microscopy revealed liver lesions and hepatocyte injury. In addition, HG-treated HSCs exhibited altered oxidative stress - related indexes, including superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS), changed and abnormally proliferated in vitro. TGF-ß1, the phosphorylated Smad2, nuclear NFκB-p65, phosphorylated NFκB-p65 and phosphorylated IκBα were also increased. Interestingly, haloperidol (DRD2 inhibitor) and n-acetyl-L-cysteine (NAC, an active oxygen scavenger) reduced the above-mentioned changes. In conclusion, DRD2 inhibition can reduce diabetic HSCs oxidative damage and fibrotic proliferation partly via the TGF-ß1/Smads and NFκB pathways.

Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway.

Myocardial fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Spermine (SPM), a product of polyamine metabolism, plays an important role in many cardiac diseases including hypertrophy, ischemia, and infarction, but its role in diabetic myocardial fibrosis has not been clarified. This study aimed to investigate the role of polyamine metabolism, specifically SPM, in diabetic myocardial fibrosis and to explore the related mechanisms. We used intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) in Wistar rats and high glucose (HG, 40 mM) stimulated cardiac fibroblasts (CFs) to established a type 1 diabetes (T1D) model in vivo and in vitro, which were pretreated with exogenous SPM (5 mg/kg per day and 5 µM). The results showed that hyperglycemia induced the expression of the key polyamine synthesis enzyme ornithine decarboxylase (ODC) decreased and the key catabolic enzyme spermidine/spermine N1 -acetyltransferase (SSAT) increased compared with those in the control group. The body weight, blood insulin level, and cardiac ejection function were decreased, while blood glucose, heart weight, the ratio of heart weight to body weight, myocardial interstitial collagen deposition, and endoplasmic reticulum stress (ERS)-related protein (glucose-regulated protein-78, glucose-regulated protein-94, activating transcription factor-4, and C/EBP homology protein) expression in the T1D group were all significantly increased. HG also caused an increased expression of Wnt3, ß-catenin (in cytoplasm and nucleus), while Axin2 and phosphorylated ß-catenin decreased. Exogenous SPM improved the above changes caused by polyamine metabolic disorders. In conclusion, polyamine metabolism disorder occurs in the myocardial tissue of diabetic rats, causing myocardial fibrosis and ERS. Exogenous SPM plays a myocardial protective role via inhibiting of ERS and the canonical Wnt/ß-catenin signaling pathway.

A leucine-rich repeat-receptor-like kinase gene SbER2-1 from sorghum (Sorghum bicolor L.) confers drought tolerance in maize.

BACKGROUND: ERECTA (ER) is a leucine-rich repeat-receptor-like kinase gene (LRR-RLK) encoding a protein isolated from Arabidopsis. Although the regulatory functions of ER genes have been widely explored in plant development and disease resistance, their roles in drought stress responses remain to be clarified. RESULTS: In this study, we cloned and characterized two ER genes, SbER1-1 and SbER2-1, from the drought-tolerant model plant sorghum (Sorghum bicolor L.). Under drought stress, the two genes were expressed in the leaves and stems but not in the roots, and SbER2-1 transcript accumulation in the stem was increased. SbER2-1 was localized both on the plasma membrane and in the chloroplast. Moreover, SbER2-1 expression in Arabidopsis and maize conferred increased drought tolerance, especially in regard to water-use efficiency, increasing the net photosynthetic rate in maize under drought stress. Based on RNA-Seq analysis together with the physiological data, we conclude that the transgenic maize plants have upregulated phenylpropanoid metabolism and increased lignin accumulation under drought stress. CONCLUSIONS: Our results demonstrate that SbER2-1 plays an important role in response to drought stress. Furthermore, photosynthetic systems and phenylpropanoid metabolism are implicated in SbER2-1-mediated drought stress tolerance mechanisms. The use of genetic engineering to regulate SbER2-1 expression in plants and to breed new varieties tolerant to drought is a research field full of potential.

Microarray-based identification of genes associated with prognosis and drug resistance in ovarian cancer.

The outcome for patients with ovarian cancer (OC) is poor because of drug resistance. Therefore, identification of factors that affect drug resistance and prognosis in OC is needed. In the present study, we identified 131 genes significantly dysregulated in 90 platinum-resistant OC tissues compared with 197 sensitive tissues, of which 30 were significantly associated with disease-free survival (DFS; n = 16), overall survival (OS; n = 6), or both (n = 8) in 489 OC patients of the The Cancer Genome Atlas cohort. Of these 30 genes, 17 were significantly upregulated and 13 were downregulated in the 90 resistant tissues, and with one exception, all of the up-/downregulated genes in resistant tissues were predictors of shorter DFS or/and OS. LAX1, MECOM, and PDIA4 were independent risk factors for DFS, and KLF1, SLC7A11, and PDIA4 for OS; combining these genes provided more accurate predictions for DFS and OS than any of the genes used individually. We further verified downregulation of PDIA4 protein in 51 specimens of patients with OC (24 drug resistant's and 27 sensitive's), which confirmed that downregulated PDIA4 predicted DFS and OS. PDIA4 also consistently predicted OS in a larger sample of 1656 patients with OC. These 30 genes, particularly the PDIA4, could be therapeutic targets or biomarkers for managing OC.

Retracted: EBF1 gene promotes the proliferation and inhibits the apoptosis of bone marrow CD34+ cells in patients with myelodysplastic syndrome through negative regulation of mitogen-activated protein kinase axis.

The transcription factor, early B cell factor 1 (EBF1), plays a vital role in the lineage specification involving early B cell development and the onset of myelodysplastic syndrome (MDS). Therefore, to investigate whether or not EBF1 affects MDS as well as the transcription factor's underlying mechanism, we used CD34+ hematopoietic stem cells in bone marrow from patients with MDS. The extracted cells were then transfected with a series of EBF1, short hairpin RNA against EBF1 (shEBF1), and SB203580 (a specific mitogen-activated protein kinase [MAPK] axis inhibitor). The effects EBF1 gene and MAPK axis had on cell proliferation, apoptosis, and migration were determined by in vitro cell culturing. We made observations that involved EBF1 inhibiting the messenger RNA (mRNA) level of p38 MAPK, increasing the mRNA levels of extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase 5 (ERK5), decreasing the protein expression of Bcl-2-associated X protein (Bax), and finally elevating the protein levels of B cell lymphoma/leukemia-2 (Bcl-2), stem cell factor (SCF), erythropoietin receptor (EpoR), p-ERK, p-JNK, p-ERK5, cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), and CDK6, implying that EBF1 may very well have an inhibitory role in the MAPK axis. Another discovery found that EBF1 had a positive effect on the promotion of bone marrow CD34+ cell proliferation as well as its migration, but inhibited the apoptosis of cells. The results we obtained from this study indicated that the EBF1 gene suppresses the activation of the MAPK axis, thereby promoting both the proliferation and migration of bone marrow CD34+ cells as well as inhibiting the associating apoptosis. The effects of the EBF1 gene are likely to present a new therapeutic target in preventing the progression of MDS.

LncRNA PRAL is closely related to clinical prognosis of multiple myeloma and the bortezomib sensitivity.

Chromosome 17p deletions (del(17p)) are present in about 11% of newly diagnosed multiple myeloma (MM) patients and related to inferior prognosis. Bortezomib (BTZ), the first proteasome inhibitor anticancer drug, has a good therapeutic effect for newly diagnosed, relapsed or refractory MM, but is unable to improve the outcome of MM patients with del(17p). Long noncoding RNA (lncRNA) PRAL is located on chromosome 17p, and is associated with the progression and prognosis of different types of cancers. However, little is known about its role in MM. Here, we found that PRAL was downregulated in primary MM cells and cell lines, especially in MM cells with del(17p), and was associated with ISS (international staging system) stage and Durie-Salmon stage in MM patients. Survival curves showed that MM patients with low PRAL expression had a significantly shorter disease-free survival (DFS) and overall survival (OS) than the patients with high PRAL expression. Multivariate Cox regression analysis showed that PRAL expression was an independent predictor for DFS and OS. Then cell proliferation, viability, Ki67 expression, and caspase-3 activity detection showed that PRAL promoted MM cell growth inhibition and apoptosis, and potentiated the anti-MM effect of BTZ in vitro. We further identified and confirmed that miR-210 was the target of PRAL, and miR-210 overexpression overturned the potentiation effect of PRAL on BTZ efficacy. Subsequently, bone morphogenetic protein 2 (BMP2) was confirmed to be the target of miR-210, and PRAL positively regulated the derepression of BMP2 by sponging miR-210. Overexpression of BMP2 potentiated the anti-MM effect of BTZ in vitro. In addition, animal experiments further confirmed that PRAL potentiated BTZ efficacy in vivo. Collectively, our study first revealed a critical role of PRAL-miR-210-BMP2 axis in MM progression, prognosis and treatment with BTZ, and PRAL could become a novel diagnostic, prognostic and therapeutic candidate for MM patients especially for the MM patients harboring del(17p) in the future.

Calhex231 Alleviates High Glucose-Induced Myocardial Fibrosis via Inhibiting Itch-Ubiquitin Proteasome Pathway in Vitro.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and features myocardial fibrosis as its main pathological feature. Calcium sensing receptor (CaSR) is a G protein-coupled receptor, which involves in myocardial fibrosis by regulation of calcium homeostasis. Calhex231, the CaSR inhibitor, is not clear whether it regulates myocardial fibrosis in DCM. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts were used to observe the role of Calhex231. In vivo experiments showed that in the T1D group, contractile dysfunction and the deposition of collagen I and III were obvious after 12 weeks. In vitro experiments, we found that high glucose (HG) could increase the expression of CaSR, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) collagen I/III, matrix metalloproteinase-2 (MMP-2), MMP9, along with cardiac fibroblast migration and proliferation. We further demonstrated that CaSR activation increased intracellular Ca2+ concentration and upregulated the expression of Itch (atrophin-1 interacting protein 4), which resulted in increasing the ubiquitination levels of Smad7 and upregulating the expression of p-Smad2, p-Smad3. However, treatment with Calhex231 clearly inhibited the above-mentioned changes. Collectively these results suggest that Calhex231 could inhibit Itch-ubiquitin proteasome and TGF-ß1/Smads pathways, and then depress the proliferation of cardiac fibroblasts, along with the reduction deposition of collagen, alleviate glucose-induced myocardial fibrosis. Our findings indicate an important new mechanism for myocardial fibrosis, and suggest Calhex231 would be a new therapeutic agent for the treatment of DCM.

Microstructural Characterization and Phase Diagram Calculation of a Less Known Al-Fe-Mn-Si Phase in a SiCp/2014Al Composite.

A systematic characterization of a less known Al, Fe, Mn, and Si phase in a SiC particulate-reinforced 2014Al composite (SiCp/2014Al) was performed. In addition to the expected CuAl2 phase, the Al, Fe, Mn, and Si phase was formed as either an adhesion (>1 µm) onto SiC in the as-cast composite, or as a precipitate (<100 nm) in the matrix after hot extrusion. The structure of the phase was identified as cubic by both X-ray diffraction and selected area electron diffraction (SAED). The SAED pattern also indicated that the structure belongs to the Pm space group instead of Im. The thermodynamic phase diagram was calculated, confirming the presence of an α-AlFeMn or α-AlFeSi phase in the Al-Fe-Mn and Al-Fe-Si ternary systems, respectively, within the Fe, Mn, and Si content range corresponding to 2014Al. Wavelength-dispersive spectroscopy analysis indicated that the composition of the phase is close to Al12(Fe, Mn)3Si2, in which the Mn/Fe ratio is in the range of 0.6-1.4. The determined Mn/Fe ratio corresponds to the nominal composition of Mn and Fe in the alloy.

Relationship between inter-α-trypsin inhibitor heavy chain 4 and ovarian cancer.

OBJECTIVE: The inter-α-trypsin inhibitor heavy chain 4 (ITIH4) protein is involved in the development of tumors. However, the relationship between ITIH4 and ovarian cancer (OC) has not been extensively examined. This study aimed to explore the effect of ITIH4 on OC and to identify its underlying mechanism. METHODS: Expressions of ITIH4 in OC tissues and cells were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blots. The function of ITIH4 in the OC cell line HO8910pm was tested via ITIH4 knockdown. The cell growth rate was measured using MTT and colony formation assays. Flow cytometry was performed to evaluate cell cycle progression. Cell migration and invasion abilities were observed using the transwell migration assay. RESULTS: ITIH4 was downregulated in OC tissues and cells. ITIH4 knockdown promoted cell growth and cell cycle progression. Consistent with these results, inhibition of ITIH4 in OC cells significantly increased cell migration and invasion abilities. Cox regression analysis suggests that ITIH4 expression alone is not a good predictor of the prognosis of malignant ovarian tumors in patients. CONCLUSIONS: ITIH4 inhibits the progression of OC, suggesting that ITIH4 may be a useful biomarker for OC. This study may provide a potential novel target for the treatment of OC.

Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents.

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-ß, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.

Design, Synthesis and Biological Evaluation of Novel Phenylsulfonylurea Derivatives as PI3K/mTOR Dual Inhibitors.

Five series of novel phenylsulfonylurea derivatives, 19a⁻d, 20a⁻d, 21a⁻d, 22a⁻d and 23a⁻d, bearing 4-phenylaminoquinoline scaffold were designed, synthesized and their IC50 values against four cancer cell lines (HepG-2, A549, PC-3 and MCF-7) were evaluated. Most compounds showed moderate cytotoxicity activity against the cancer cell lines. Structure⁻activity relationships (SARs) and pharmacological results indicated that introduction of 4-aminoquinoline scaffold and phenylsulfonylurea scaffold were beneficial for anti-tumor activity. Moreover, para-methoxyl substitution of 4-anilino moiety and para-halogen substitution of phenylsulfonylurea have different impacts on different series of compounds. Furthermore, the micromolecule group substitution in the 6-position of the quinoline ring have a slight impact on the cellular activity of the target compounds.

Avian Influenza (H7N9) Viruses Co-circulating among Chickens, Southern China.

In April 2017, three avian influenza (H7N9) viruses were isolated from chickens in southern China. Each virus had different insertion points in the cleavage site of the hemagglutinin protein compared to the first identified H7N9 virus. We determined that these viruses were double or triple reassortant viruses.

Identification of PDZD11 as a Potential Biomarker Associated with Immune Infiltration for Diagnosis and Prognosis in Epithelial Ovarian Cancer.

Purpose: Evidence has indicated that PDZD11 is involved in regulating adherens junction. However, the distinct effect of its aberrant expression on epithelial ovarian cancer (EOC) awaits clarification. Methods: In this study, public databases (Gene Expression Omnibus, The Cancer Genome Atlas, and The Genotype-Tissue Expression), online analysis tools (Kaplan-Meier plotter and TIMER), and data analysis methods (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and the CIBERSORT algorithm) were fully utilized to analyze the differential expression, diagnostic efficiency, prognostic significance, potential function, and correlation with immune infiltration of PDZD11. The differential expression of PDZD11 was tested by immunohistochemistry in EOC tissues (78 cases) and control tissues (37 cases). Results: Our results indicate that PDZD11 was remarkably overexpressed in EOC, which was associated with advanced cancer stages, no lymphatic metastasis status, and poor prognosis. Moreover, PDZD11 played a role in cell adhesion, cell proliferation, and immune responses. Also, PDZD11 was significantly related to the abundances of infiltrating immune cells in EOC, including neutrophils, macrophages, dendritic cells, CD8+ T cells, and CD4+ T cells, and its expression was positively co-expressed with well-known immune checkpoints, including TIGIT, TIM3, LAG3, CTLA4, and PD-1. Conclusion: These results suggest that PDZD11 could be a potential diagnostic and prognostic biomarker associated with immune infiltration in EOC, and our findings might help elucidate the function of PDZD11 in carcinogenesis.