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This paper presents a novel anti-shock bulk silicon etching apparatus for solving a universal problem which occurs when releasing the diaphragm (e.g. SiNx), that the diaphragm tends to be probably cracked by the impact of heatinginduced bubbles, the swirling of heating-induced etchant, dithering of the hand and imbalanced etchant pressure during the wafer being taken out. Through finite element methods, the causes of the diaphragm cracking are analysed. The impact of heating-induced bubbles could be the main factor which results in the failure stress of the SiNx diaphragm and the rupture of it. In order to reduce the four potential effects on the cracking of the released diaphragm, an anti-shock bulk silicon etching apparatus is proposed for using during the last etching process of the diaphragm release. That is, the silicon wafer is first put into the regular constant temperature etching apparatus or ultrasonic plus, and when the residual bulk silicon to be etched reaches near the interface of the silicon and SiNx diaphragm, within a distance of 50-80 m (the exact value is determined by the thickness, surface area and intensity of the released diaphragm), the wafer is taken out carefully and put into the said anti-shock silicon etching apparatus. The wafer's position is at the geometrical centre, also the centre of gravity of the etching vessel. An etchant outlet is built at the bottom. The wafer is etched continuously, and at the same time the etchant flows out of the vessel. Optionally, two symmetrically placed low-power heating resistors are put in the anti-shock silicon etching apparatus to quicken the etching process. The heating resistors' power should be low enough to avoid the swirling of the heating-induced etchant and the impact of the heating-induced bubbles on the released diaphragm. According to the experimental results, the released SiNx diaphragm thus treated is unbroken, which proves the practicality of the said anti-shock bulk silicon etching apparatus. [ABSTRACT FROM AUTHOR]

We studied the effects of isoquinoline alkaloid neferine (Nef) extracted from the seed embryo of Nelumbo nucifera Gaertn on Human ether-à-go-go-related gene (HERG) channels stably expressed in human embryonic kidney (HEK293) cells using whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. Nef induced a concentration-dependent decrease in current amplitude according to the voltage steps and tail currents of HERG with an IC50 of 7.419 μM ( nH −0.5563). Nef shifted the activation curve in a significantly negative direction and accelerated recovery from inactivation and onset of inactivation, however, slowed deactivation. In addition, it had no significant influence on steady-state inactivation curve. Western blot and immunofluorescence results suggested Nef had no significant effect on the expression of HERG protein. In summary, Nef can block HERG K+ channels that functions by changing the channel activation and inactivation kinetics. Nef has no effect on the generation and trafficking of HERG protein. A blocked-off HERG channel was one mechanism of the anti-arrhythmic effects by Nef. [ABSTRACT FROM AUTHOR]

This paper describes a micro thermal shear stress sensor with a cavity underneath, based on vacuum anodic bonding and bulk micromachined technology. A Ti/Pt alloy strip, 2mm × 100mm, is deposited on the top of a thin silicon nitride diaphragm and functioned as the thermal sensor element. By using vacuum anodic bonding and bulk-si anisotropic wet etching process instead of the sacrificial-layer technique, a cavity, functioned as the adiabatic vacuum chamber, 200mm × 200mm × 400mm, is placed between the silicon nitride diaphragm and glass (Corning 7740). This method totally avoid adhesion problem which is a major issue of the sacrificial-layer technique. [ABSTRACT FROM AUTHOR]

Competing Interests: The authors declare that they have no conflict of interest.

Flap endonuclease 1 (FEN1) is recognized as a pivotal factor in DNA replication, long-patch excision repair, and telomere maintenance. Excessive FEN1 expression has been reported to be closely associated with cancer progression, but the specific mechanism has not yet been explored. In the present study, we demonstrated that FEN1 promoted breast cancer cell proliferation via an epigenetic mechanism of FEN1-mediated up-regulation of DNA methyltransferase (DNMT)1 and DNMT3a. FEN1 was proved to interact with DNMT3a through proliferating cell nuclear antigen (PCNA) to suppress microRNA (miR)-200a-5p expression mediated by methylation. Furthermore, miR-200a-5p was identified to repress breast cancer cell proliferation by inhibiting the expression of its target genes, hepatocyte growth factor (MET), and epidermal growth factor receptor (EGFR). Overall, our data surprisingly demonstrate that FEN1 promotes breast cancer cell growth via the formation of FEN1/PCNA/DNMT3a complex to inhibit miR-200a expression by DNMT-mediated methylation and to recover the target genes expression of miR-200a, MET, and EGFR. The novel epigenetic mechanism of FEN1 on proliferation promotion provides a significant clue that FEN1 might serve as a predictive biomarker and therapeutic target for breast cancer.-Zeng, X., Qu, X., Zhao, C., Xu, L., Hou, K., Liu, Y., Zhang, N., Feng, J., Shi, S., Zhang, L., Xiao, J., Guo, Z., Teng, Y., Che, X. FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling.

Quantum-inspired genetic algorithms (QGAs) were recently introduced for the prediction of RNA secondary structures, and they showed some superiority over the existing popular strategies. In this paper, for RNA secondary structure prediction, we introduce a new QGA named multi-population assisted quantum genetic algorithm (MAQGA). In contrast to the existing QGAs, our strategy involves multi-populations which evolve together in a cooperative way in each iteration, and the genetic exchange between various populations is performed by an operator transfer operation. The numerical results show that the performances of existing genetic algorithms (evolutionary algorithms [EAs]), including traditional EAs and QGAs, can be significantly improved by using our approach. Moreover, for RNA sequences with middle-short length, the MAQGA improves even this state-of-the-art software in terms of both prediction accuracy and sensitivity., (© 2019 S. Karger AG, Basel.)

Background: Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance., Methods: MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth., Results: MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression., Conclusions: Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex.

Background: We conducted a phase II study by combining FOLFOX4 plus bevacizumab (BV) with erlotinib (ER) as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC)., Methods: Patients were divided into two groups in randomized double-blind manner. One group was given FOLFOX4 plus 5 mg/kg BV on day 1 of 2-week cycle. The other group was given 2-week-cycle of BV + FOLFOX4, and 100 mg ER every day. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), clinical response rates and adverse events (AEs)., Results: 66 patients received 2nd-line treatment of ER + BV+ FOLFOX4, and 65 received BV + FOLFOX4. Median PFS was 9.6 months of ER + BV + FOLFOX4 group, significantly better than 6.9 months of BV + FOLFOX4 group ( P = 0.021, HR = 1.15, 95% CI = 0.88-1.39). Medium OS for ER + BV + FOLFOX4 group was 12.5 months, not statistically different than 12.1 months for BV + FOLFOX4 group ( P = 00.146, HR = 0.63, 95% CI = 0.34-1.02). Combined partial response and stable disease rate was 48.5% for ER + BV + FOLFOX4 group, significantly higher than 32.2% for BV + FOLFOX4 group ( P = 0.015). Patients in ER + BV + FOLFOX4 group had higher incidence rates of AEs., Conclusion: In second-line chemotherapy for patients with mCRC, combining erlotinib with FOLFOX4 plus bevacizumab may improve PFS, clinical response rates, but not OS. AEs, though with high incidence rates, were generally tolerable among patients receiving multiple reagents., Competing Interests: None.

Studying the neural correlates of smoking behaviors in young adulthood is of great importance to improve treatment outcomes. In previous addiction studies, the important roles of the salience network (SN) in drug cue processing and cognitive control have been revealed. Unfortunately, few studies focused on the resting-state functional connectivity and structural integrity abnormalities of SN in young adult smokers, and less is known about its association with smoking behaviors and cognitive control deficits. Thirty-one young male adult smokers and 30 age-, education- and gender-matched nonsmokers participated in this study. The structural and functional connectivity differences of SN were investigated between young adult smokers and nonsmokers by using diffusion tensor imaging (DTI) and resting-state functional connectivity (RSFC), which were then correlated with the smoking behavioral assessments (pack-years and Fagerström Test for Nicotine Dependence (FTND)) as well as impaired cognitive control measured by the Stroop task. Within SN, reduced RSFC and increased fractional anisotropy (FA) were found between the anterior cingulate cortex (ACC) and the right insula in young adult smokers relative to nonsmokers. The RSFC between the ACC and right insula was negatively correlated with the number of errors during the incongruent condition of the Stroop task in young adult smokers. Additionally, the right insula-ACC RSFC was negatively correlated with pack-years in young adult smokers. Our results revealed abnormal RSFC and structural integrity within the SN in young adult smokers, which shed new insights into the neural mechanism of nicotine dependence.

Studying the neural correlates of craving to smoke in young adulthood is of great importance to improve treatment outcomes in nicotine dependence. Previous nicotine dependence studies mainly focused on the neural substrates of craving elicited by smoking-related cues. More explicit attention to abstinence-induced craving during resting state in nicotine dependence has the potential to yield valuable information about craving, and characterizing this kind of craving is critical for developing effective interventions. Twenty-five young male smokers were enrolled in the present study. A within-subject experiment design was carried out to compare regional homogeneity (ReHo) between 12-h smoking abstinence and smoking satiety conditions during resting state in young adult smokers. Then, the ReHo changes associated with smoking abstinence (compared with satiety) were further examined for correlations with abstinence-induced changes in subjective craving. We found young adult smokers in abstinence state (compared with satiety) had higher ReHo in brain regions in fronto-striatal circuits including bilateral caudate, anterior cingulate cortex (ACC) and bilateral dorsal lateral prefrontal cortex (DLPFC), as well as brain regions in default mode network (DMN) including posterior cingulate cortex (PCC)/precuneus and angular gyrus. Additionally, we found the ReHo changes of the ACC and the bilateral caudate were positively correlated with the changes in craving induced by abstinence (i.e., abstinence minus satiety) in young adult smokers. The present findings improve the understanding of the effects of acute smoking abstinence on spontaneous brain activity and may contribute new insights into the neural mechanism of abstinence-induced craving in nicotine dependence.

In this study, a novel sandwiched electrochemiluminescence (ECL) immunosensor for the detection of carcinoembryonic antigen (CEA) was developed. The nanocomposite of polydopamine and Ag nanoparticles (PDA-AgNPs) was prepared by the redox reaction between Ag + and dopamine. This nanocomposite not only provided an effective matrix for the immobilization of primary antibody (Ab 1 ) but also enhanced the conductivity of the electrode. Carbon quantum dots (CQDs) were immobilized on the poly(ethylenimine) functionalized graphene oxide (PEI-GO) through amido-bond. Then Au nanoparticles were decorated on the CQDs modified PEI-GO matrix, and the resulted complex AuNPs/CQDs-PEI-GO was introduced to link secondary antibody (Ab 2 ). The CQDs can be connected to the electrode surface through the combination of CEA with Ab 1 and Ab 2 , and then the amplified electrochemiluminescence signal of CQDs was obtained with the synergistic effect of AgNPs, polydopamine, AuNPs and PEI-GO. Under the optimal conditions, the ECL intensity was proportional to the logarithm value of CEA concentration in the linear range from 5pgmL -1 to 500ngmL -1 with a detection limit of 1.67pgmL -1 for CEA detection. The immunosensor was applied for the CEA detection in real samples with satisfactory results. The proposed ECL immunosensor showed good performance with high sensitivity, specificity, reproducibility, stability and will be potential in clinical detection., (Copyright © 2016. Published by Elsevier B.V.)

Populus euphratica is an important native tree found in arid regions from North Africa and South Europe to China, and is known to tolerate many forms of environmental stress, including drought. We describe cuticle waxes, cutin and cuticle permeability for the heteromorphic leaves of P. euphratica growing in two riparian habitats that differ in available soil moisture. Scanning electron microscopy revealed variation in epicuticular wax crystallization associated with leaf type and site. P. euphratica leaves are dominated by cuticular wax alkanes, primary-alcohols and fatty acids. The major cutin monomers were 10,16-diOH C 16 :0 acids. Broad-ovate leaves (associated with adult phase growth) produced 1.3- and 1.6-fold more waxes, and 2.1- and 0.9-fold more cutin monomers, than lanceolate leaves (associated with juvenile phase growth) at the wetter site and drier site, respectively. The alkane-synthesis-associated ECERIFERUM1 (CER1), as well as ABC transporter- and elongase-associated genes, were expressed at much higher levels at the drier than wetter sites, indicating their potential function in elevating leaf cuticle lipids in the dry site conditions. Higher cuticle lipid amounts were closely associated with lower cuticle permeability (both chlorophyll efflux and water loss). Our results implicate cuticle lipids as among the xeromorphic traits associated with P. euphratica adult-phase broad-ovate leaves. Results here provide useful information for protecting natural populations of P. euphratica and their associated ecosystems, and shed new light on the functional interaction of cuticle and leaf heterophylly in adaptation to more arid, limited-moisture environments., (© 2016 Scandinavian Plant Physiology Society.)

Cigarette smoking during young adult may result in serious health issues in later life. Hence, it is extremely necessary to study the smoking neurophysiological mechanisms in this critical transitional period. However, few studies revealed the electrophysiological mechanisms of cognitive processing biases in young adult smokers. In present study, nineteen young smokers with 12h abstinent and 19 matched nonsmokers were recruited. By employing event-related potentials (ERP) measurements during a smoking cue induced craving task, electrophysiological brain responses were compared between the young adult smokers and nonsmokers. The Slow Positive Wave (SPW) amplitude of smoking-related cues was enhanced in young adult smokers compared with nonsmokers. In addition, increased P300/SPW component of smoking-related cues relative to neutral cues were found in young adult smokers. Meanwhile, a positive correlation between Cigarette Per Day (CPD) and the amplitude of ERPs wave (P300/SPW) at anterior (Fz), central (Cz) were observed in young adult smokers. Our findings provided direct electrophysiological evidence for the cognitive processing bias of smoking cue and may shed new insights into the smoking behavior in young adult smokers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Tobacco use during later adolescence and young adulthood may cause serious neurophysiological changes; rationally, it is extremely important to study the relationship between brain dysfunction and behavioral performances in young adult smokers. Previous resting state studies investigated the neural mechanisms in smokers. Unfortunately, few studies focused on spontaneous activity differences between young adult smokers and nonsmokers from both intra-regional and inter-regional levels, less is known about the association between resting state abnormalities and behavioral deficits. Therefore, we used fractional amplitude of low frequency fluctuation (fALFF) and resting state functional connectivity (RSFC) to investigate the resting state spontaneous activity differences between young adult smokers and nonsmokers. A correlation analysis was carried out to assess the relationship between neuroimaging findings and clinical information (pack-years, cigarette dependence, age of onset and craving score) as well as cognitive control deficits measured by the Stroop task. Consistent with previous addiction findings, our results revealed the resting state abnormalities within frontostriatal circuits, i.e., enhanced spontaneous activity of the caudate and reduced functional strength between the caudate and anterior cingulate cortex (ACC) in young adult smokers. Moreover, the fALFF values of the caudate were correlated with craving and RSFC strength between the caudate and ACC was associated with the cognitive control impairments in young adult smokers. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in young smokers by providing regional and brain circuit spontaneous neuronal activity properties as well as their association with cognitive control impairments.

Background and Aims: The intestinal epithelial barrier plays an important role in the pathogenesis of non-steroidal anti-inflammatory drug-induced enteropathy, and its disruption is often associated with increased cell shedding. The purpose of this report is to observe the gap density in indomethacin-induced small intestinal damage by confocal laser endomicroscopy (CLE) and to investigate the mechanisms involved in this process and how mucosal protectants improve intestinal epithelial barrier dysfunction. CLE is expected to provide a new way for evaluating non-steroidal anti-inflammatory drugs-induced enteropathy in humans and assessing drug efficacy., Methods: Using the new technique of CLE, we established a method to evaluate, in real time, intestinal damage after the administration of indomethacin in Wistar rats by investigating the gap density in the small intestine. The mucosal protectant teprenone and acid-suppressant rabeprazole were then given by gavage before and after the administration of indomethacin, and the mechanisms affecting the intestinal epithelial barrier were investigated., Results: Using CLE, gaps could be clearly observed and easily distinguished from goblet cells. Gap density was increased after the administration of indomethacin. During this process, the expression of tumor necrosis factor-α, nuclear factor-κB, and caspase-3 was up-regulated and the expression of tight junctions was down-regulated, which led to the damage of the epithelial barrier. Teprenone and rabeprazole could intervene in this pathway and protect the integrity of the epithelial barrier., Conclusions: CLE can be objective, accurate, and real time in investigating gap density. Teprenone and rabeprazole can prevent indomethacin-induced intestinal lesions and protect the epithelial barrier by intervening in the tumor necrosis factor-α pathway. Gap density was expected to be an indicator of evaluating intestinal inflammation and drug efficacy.

The title eremophilenolide, C(15)H(22)O(3), is a natural compound isolated from Senecio laetus Edgew. The two cis-fused six-membered rings have chair confomations and the five-membered ring has a planar envelope conformation [maximum deviation = 0.010 (1) Å]. The β-hy-droxy group participates in inter-molecular O-H⋯O hydrogen bonding, forming mol-ecular chains along the a axis.

Multiple lines of evidence have implicated that nicotinic acetylcholine receptor (nAChR) may be an important therapeutic target for the treatment of Alzheimer's disease (AD). Although there are reports suggesting a link between alpha7 nAChR subtype and AD, there has been little report on the mechanism. The present study investigates whether and how α7 nAChR activation affects APP695 processing in SH-EP1 cell model. Cell line co-expressing α7 nAChR gene and human amyloid precursor protein 695 (hAPP695) gene were constructed by stable transfection. Expression of β-amyloid, α-form of secreted APP (αAPPs) and APP1695 was measured by ELISA, western blotting and real-time PCR respectively. Additionally, α, β, and γ-secretase activities were also analyzed in constructed SH-EP1-α7 nAChR-hAPP695 cell line. The results showed that SH-EP1-α7 nAChR-hAPP695 cell line, expressing both hAPP695 gene and α7 nAChR subtype gene, was constructed successfully. The secreted Aβ was decreased and αAPPs was significantly increased by non-selective nAChR agonist nicotine (10 μM) and specific α7 nAChR agonist GTS-21 (1 μM), and APP expression was not affected. Furthermore, specific α7 nAChR antagonist methyllycaconitine (MLA) reversed the alterations induced by activation of α7 nAChR. CTF-α was increased and CTF-γ was decreased when treated with nicotine (10 μM). In addition, the results of enymatic activity analysis showed that nicotine (1μM) and GTS-21 (0.1, 1 μM) decreased γ-secretase activity, but has no effects on α-secretase activity and β-secretase activity. Our findings demonstrate that, through regulating γ-secretase activity, α7 nAChR activation reduces APP processing in amyloidogenic pathway, and at the same time enhances APP processing in non-amyloidogenic pathway. The constructed SH-EP1-α7 nAChR-hAPP695 cell line might be useful for screening specific nAChR agonists against AD., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We studied the effects of isoquinoline alkaloid neferine (Nef) extracted from the seed embryo of Nelumbo nucifera Gaertn on Human ether-à-go-go-related gene (HERG) channels stably expressed in human embryonic kidney (HEK293) cells using whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. Nef induced a concentration-dependent decrease in current amplitude according to the voltage steps and tail currents of HERG with an IC(50) of 7.419 microM (n(H) -0.5563). Nef shifted the activation curve in a significantly negative direction and accelerated recovery from inactivation and onset of inactivation, however, slowed deactivation. In addition, it had no significant influence on steady-state inactivation curve. Western blot and immunofluorescence results suggested Nef had no significant effect on the expression of HERG protein. In summary, Nef can block HERG K(+) channels that functions by changing the channel activation and inactivation kinetics. Nef has no effect on the generation and trafficking of HERG protein. A blocked-off HERG channel was one mechanism of the anti-arrhythmic effects by Nef.