We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic ...role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.
An epidemic of severe acute respiratory syndrome (SARS) has been associated with an outbreak of atypical pneumonia originating in Guangdong Province, People's Republic of China. We aimed to identify ...the causative agent in the Guangdong outbreak and describe the emergence and spread of the disease within the province.
We analysed epidemiological information and collected serum and nasopharyngeal aspirates from patients with SARS in Guangdong in mid-February, 2003. We did virus isolation, serological tests, and molecular assays to identify the causative agent.
SARS had been circulating in other cities of Guangdong Province for about 2 months before causing a major outbreak in Guangzhou, the province's capital. A novel coronavirus, SARS coronavirus (CoV), was isolated from specimens from three patients with SARS. Viral antigens were also directly detected in nasopharyngeal aspirates from these patients. 48 of 55 (87%) patients had antibodies to SARS CoV in their convalescent sera. Genetic analysis showed that the SARS CoV isolates from Guangzhou shared the same origin with those in other countries, and had a phylogenetic pathway that matched the spread of SARS to the other parts of the world.
SARS CoV is the infectious agent responsible for the epidemic outbreak of SARS in Guangdong. The virus isolated from patients in Guangdong is the prototype of the SARS CoV in other regions and countries.
Fertilization of crops with livestock manure (LM) is a common waste disposal option, but repeated application of LM containing high concentrations of heavy metals such as Cu could lead to crop ...toxicity and environmental risk. To examine the Cu availability and uptake by wheat in a Mollisol affected by Cu-enriched LM, pot experiments were conducted. LM (376
mg
kg
−1 Cu originally) was spiked with different concentrations of Cu (0, 100, 200, 400, 600 and 800
mg
kg
−1 soil, added as CuSO
4) to simulate soil Cu contamination by LM application. The results indicated that Cu was predominately distributed in organic bound fraction, while the most drastic increase was found in reducible fraction. Acid-extractable fraction played a more important role than other fractions in controlling the mobility and bioavailability of Cu. DTPA-extractable Cu may overestimate the Cu bioavailability since DTPA solution could extract soluble and part of stable forms. The application of LM at 1% level significantly decline the Cu mobility, but that at 3% level exhibited the opposite effect.
Although the quantities of Cu in wheat was very low compared with the accumulation in soil, Cu concentrations in roots increased evidently from 12 to 533
mg
kg
−1 and that in aerial parts were in a narrow range from 12.1 to 32.7
mg
kg
−1, indicating the more sensitivity of roots to the Cu toxicity. The Cu concentrations in grains after 3% manure application did not approach the threshold for Cu toxicity (<20
mg
kg
−1) even at higher Cu addition rates.
We study the process e^{+}e^{-}→Λ_{c}^{+}Λover ¯_{c}^{-} at twelve center-of-mass energies from 4.6119 to 4.9509 GeV using data samples collected by the BESIII detector at the BEPCII collider. The ...Born cross sections and effective form factors (|G_{eff}|) are determined with unprecedented precision after combining the single and double-tag methods based on the decay process Λ_{c}^{+}→pK^{-}π^{+}. Flat cross sections around 4.63 GeV are obtained and no indication of the resonant structure Y(4630), as reported by Belle, is found. In addition, no oscillatory behavior is discerned in the |G_{eff}| energy dependence of Λ_{c}^{+}, in contrast to what is seen for the proton and neutron cases. Analyzing the cross section together with the polar-angle distribution of the Λ_{c}^{+} baryon at each energy point, the moduli of electric and magnetic form factors (|G_{E}| and |G_{M}|) are extracted and separated. For the first time, the energy dependence of the form factor ratio |G_{E}/G_{M}| is observed, which can be well described by an oscillatory function.
Spatiotemporal variations of dissolved organic carbon (DOC) and inorganic carbon (DIC) in 26 waters across the semi-humid/semi-arid Songnen Plain, China, were examined with data collected during ...2008–2011. Fresh (n = 14) and brackish (n = 12) waters were grouped according to electrical conductivity (threshold = 1000 μS cm−1) Significant differences in the average DOC and DIC concentrations were observed between the fresh (5.63 mg L−1, 37.39 mg L−1) and the brackish waters (15.33 mg L−1, 142.93 mg L−1). Colored dissolved organic matter (CDOM) and DOC concentrations were mainly controlled by climatic–hydrologic conditions. The investigation indicated that the outflow conditions in the semi-arid region had condensed effects on the dissolved carbon, resulting in close relationships between salinity vs. DOC (R2 = 0.66), and salinity vs. DIC (R2 = 0.94). An independent data set collected in May 2012 also confirmed this finding (DOC: R2 = 0.79, DIC: R2 = 0.91), highlighting the potential of quantifying DOC and DIC via salinity measurements for waters dispersed in the plain. Indices based on the CDOM absorption spectra (e.g., the DOC-specific CDOM absorption (SUVA254), absorption ratio a250 : a365 (E250 : E365) and the spectral slope ratio (Sr, S275−295/S350−400) were applied to characterize CDOM composition and quality. Our results indicate that high molecular weight CDOM fractions are more abundant in the fresh waters than the brackish waters.
DRAM1 (DNA damage-regulated autophagy modulator 1) is a TP53 target gene that modulates autophagy and apoptosis. We previously found that DRAM1 increased autophagy flux by promoting lysosomal ...acidification and protease activation. However, the molecular mechanisms by which DRAM1 regulates apoptosis are not clearly defined. Here we report a novel pathway by which DRAM1 regulates apoptosis involving BAX and lysosomes. A549 or HeLa cells were treated with the mitochondrial complex II inhibitor, 3-nitropropionic acid (3NP), or an anticancer drug, doxorubicin. Changes in the protein and mRNA levels of BAX and DRAM1 and the role of DRAM1 in BAX induction were determined. The interaction between DRAM1 and BAX and its effect on BAX degradation, BAX lysosomal localization, the release of cathepsin B and cytochrome c by BAX and the role of BAX in 3NP- or doxorubicin-induced cell death were studied. The results showed that BAX, a proapoptotic protein, was induced by DRAM1 in a transcription-independent manner. BAX was degraded by autophagy under basal conditions; however, its degradation was inhibited when DRAM1 expression was induced. There was a protein interaction between DRAM1 and BAX and this interaction prolonged the half-life of BAX. Furthermore, upregulated DRAM1 recruited BAX to lysosomes, leading to the release of lysosomal cathepsin B and cleavage of BID (BH3-interacting domain death agonist). BAX mediated the release of mitochondrial cytochrome c, activation of caspase-3 and cell death partially through the lysosome-cathepsin B-tBid pathway. These results indicate that DRAM1 regulates apoptosis by inhibiting BAX degradation. In addition to mitochondria, lysosomes may also be involved in BAX-initiated apoptosis.
Deafness or hearing loss is a major issue in human health. Inner ear hair cells are the main sensory receptors responsible for hearing. Defects in hair cells are one of the major causes of deafness. ...A combination of induced pluripotent stem cell (iPSC) technology with genome-editing technology may provide an attractive cell-based strategy to regenerate hair cells and treat hereditary deafness in humans. Here, we report the generation of iPSCs from members of a Chinese family carrying MYO15A c.4642G>A and c.8374G>A mutations and the induction of hair cell-like cells from those iPSCs. The compound heterozygous MYO15A mutations resulted in abnormal morphology and dysfunction of the derived hair cell-like cells. We used a CRISPR/Cas9 approach to genetically correct the MYO15A mutation in the iPSCs and rescued the morphology and function of the derived hair cell-like cells. Our data demonstrate the feasibility of generating inner ear hair cells from human iPSCs and the functional rescue of gene mutation-based deafness by using genetic correction.
To evaluate the efficacy and safety of HSK3486 for the induction and maintenance of general anesthesia in elective surgical patients, but excluding emergency, cardiothoracic, cerebral and endoscopic ...sinus cases.
A total of 40 eligible patients were randomly assigned to HSK3486 (n = 30) or propofol (n = 10) dosage groups in a ratio of 3:1. Drugs were administered as a bolus injection of 0.4 mg/kg (HSK3486) or 2.0 mg/kg (propofol) for induction, followed by maintenance infusion with the same anesthetic. An additional 6 non-randomized patients received propofol (2.0 mg/kg) for induction and were given HSK3486 for maintenance.
The primary efficacy endpoint - the success rate of anesthesia maintenance - was 100% in the 3 arms. The secondary efficacy endpoints included times from discontinuation of HSK3486 or propofol maintenance to full alertness, respiratory recovery, extubation and reaching the goal of the Aldrete score. Also, the proportion of patients who constantly maintained BIS40-60 or those with a period of BIS40-60 during maintenance anesthesia showed no significant difference in the HSK3486 and propofol groups (all p > 0.05). Patients who received HSK3486 exhibited a higher satisfaction score from anesthesiologists during the induction period (p = 0.024). The occurrence and types of treatment-emergent adverse events were similar among the 3 arms, both with a severity of grade 1 or 2. Drug-related hypotension occurred in 14 (46.7%) and 7 (70.0%) patients treated with HSK3486 and propofol, respectively.
HSK3486 exhibited good efficacy for the induction and maintenance of general anesthesia and was well tolerated by patients who underwent elective surgery.
Fusarium graminearum is the primary causal agent of Fusarium head blight (FHB) of wheat. The phenylpyrrole fungicide fludioxonil is not currently registered for the management of FHB in China. The ...current study assessed the fludioxonil sensitivity of a total of 53 F. graminearum isolates collected from the six most important wheat-growing provinces of China during 2018 and 2019. The baseline fludioxonil sensitivity distribution indicated that all of the isolates were sensitive, exhibiting a unimodal cure with a mean effective concentration for 50% inhibition value of 0.13 ± 0.12 μg/ml (standard deviation). Five fludioxonil-resistant mutants were subsequently induced by exposure to fludioxonil under laboratory conditions. Ten successive rounds of subculture in the absence of the selection pressure indicated that the mutation was stably inherited. However, the fludioxonil-resistant mutants were found to have reduced pathogenicity, higher glycerol accumulation, and higher osmotic sensitivity than the parental wild-type isolates, indicating that there was a fitness cost associated with fludioxonil resistance. In addition, the study also found a positive cross resistance between fludioxonil, procymidone, and iprodione, but not with other fungicides such as boscalid, carbendazim, tebuconazole, and fluazinam. Sequence analysis of four candidate target genes (FgOs1, FgOs2, FgOs4, and FgOs5) revealed that the HBXT2R mutant contained two point mutations that resulted in amino acid changes at K223T and K415R in its FgOs1 protein, and one point mutation at residue 520 of its FgOs5 protein that resulted in a premature stop codon. Similarly, the three other mutants contained point mutations that resulted in changes at the K192R, K293R, and K411R residues of the FgOs5 protein but none in the FgOs2 and FgOs4 genes. However, it is important to point out that the FgOs2 and FgOs4 expression of all the fludioxonil-resistant mutants was significantly (P < 0.05) downregulated compared with the sensitive isolates (except for the SQ1-2 isolate). It was also found that one of the resistant mutants did not have changes in any of the sequenced target genes, indicating that an alternative mechanism could also lead to fludioxonil resistance.
Abstract
A 4
th
generation ECR (Electron Cyclotron Resonance) ion source FECR (First 4
th
generation ECR ion source) is under development at IMP. Aiming to be operated with the microwave power of 20 ...kW at 45 GHz, FECR is equipped with a fully superconducting Nb3Sn magnet and conventional parts durable for high power ECR plasma heating and optimum for intense beam production and extraction. Breakthroughs on the Nb3Sn superconducting magnet, high power density plasma chamber, high temperature oven, and so on have been successfully demonstrated recently. The prototype Nb3Sn cold mass has been successfully tested. The plasma chamber with an innovative structure of micro-channel cooling structure has been tested which enables SECRAL-II ion source operated continuously for more than 1,100 hours with ∼300 eμA Kr
26
+ for routine operation at the microwave power level of ∼5 kW. A high temperature inductive heating oven has also been developed and used for intense uranium beam production. This talk will present the recent progress on the development of key technologies for the 4th generation ECR ion source.
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