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IMPORTANCE Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95%CI, 0.53-0.9], P = .006). CONCLUSIONS AND RELEVANCE Actionable drivers were detected in 64%of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01014286 [ABSTRACT FROM AUTHOR]

Abstract: Fibrosis is the important pathway for end-stage renal failure. Glucose has been demonstrated to be the most important fibrogenesis-inducing agent according to previous studies. Despite diosgenin has been demonstrated to be anti-inflammatory, the possible role in fibrosis regulation of diosgenin remain to be investigated. In this study, renal proximal tubular epithelial cells (designated as HK-2) were treated with high concentration of glucose (HG, 27.5mM) to determine whether diosgenin (0.1, 1 and 10μM) has the effects to regulate renal cellular fibrosis. We found that 10μM of diosgenin exert optimal inhibitory effects on high glucose-induced fibronectin expression in HK-2 cells. In addition, diosgenin markedly inhibited HG-induced increase in α-smooth muscle actin (α-SMA) and HG-induced decrease in E-cadherin. In addition, diosgenin antagonizes high glucose-induced epithelial-to-mesenchymal transition (EMT) signals partly by enhancing the catabolism of Snail in renal cells. Collectively, these data suggest that diosgenin has the potential to inhibit high glucose-induced renal tubular fibrosis possibly through EMT pathway. [Copyright &y& Elsevier]

It has been theorized for decades that mitochondria act as the biological clock of ageing, but the evidence is incomplete. Here we show a strong coupling between mitochondrial function and ageing by in vivo visualization of the mitochondrial flash (mitoflash), a frequency-coded optical readout reflecting free-radical production and energy metabolism at the single-mitochondrion level. Mitoflash activity in Caenorhabditis elegans pharyngeal muscles peaked on adult day 3 during active reproduction and on day 9 when animals started to die off. A plethora of genetic mutations and environmental factors inversely modified the lifespan and the day-3 mitoflash frequency. Even within an isogenic population, the day-3 mitoflash frequency was negatively correlated with the lifespan of individual animals. Furthermore, enhanced activity of the glyoxylate cycle contributed to the decreased day-3 mitoflash frequency and the longevity of daf-2 mutant animals. These results demonstrate that the day-3 mitoflash frequency is a powerful predictor of C. elegans lifespan across genetic, environmental and stochastic factors. They also support the notion that the rate of ageing, although adjustable in later life, has been set to a considerable degree before reproduction ceases. [ABSTRACT FROM AUTHOR]

Capsule is an important virulence factor in bacteria. A total of 78 capsular types have been identified in Klebsiella pneumoniae. However, there are limitations in current typing methods. We report here the development of a new genotyping method based on amplification of the variable regions of the wzc gene. Fragments corresponding to the variable region of wzc were amplified and sequenced from 76 documented capsular types of reference or clinical strains. The remaining two capsular types (reference strains K15 and K50) lacked amplifiable wzc genes and were proven to be acapsular. Strains with the same capsular type exhibited ≧94% DNA sequence identity across the variable region (CD1-VR2-CD2) of wzc. Strains with distinct K types exhibited <80% DNA sequence identity across this region, with the exception of three pairs of strains: K22/K37, K9/K45, and K52/K79. Strains K22 and K37 shared identical capsular polysaccharide synthesis (cps) genes except for one gene with a difference at a single base which resulted in frameshift mutation. The wzc sequences of K9 and K45 exhibited high DNA sequence similarity but possessed different genes in their cps clusters. K52 and K79 exhibited 89% wzc DNA sequence identity but were readily distinguished from each other at the DNA level; in contrast, strains with the same capsular type as K52 exhibited 100% wzc sequence identity. A total of 29 strains from patients with bacteremia were typed by the wzc system. wzc DNA sequences confirmed the documented capsular type for twenty-eight of these clinical isolates; the remaining strain likely represents a new capsular type. Thus, the wzc genotyping system is a simple and useful method for capsular typing of K. pneumoniae. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate whether semi-quantitative analysis of high temporal resolution dynamic contrast-enhanced MRI (DCE-MRI) acquired early in treatment can predict the response of locally advanced breast cancer (LABC) to neoadjuvant chemotherapy (NAC). Materials and Methods: As part of an IRB-approved prospective study, 21 patients with LABC provided informed consent and underwent high temporal resolution 3T DCE-MRI before and after 1cycle of NAC. Using measurements performed by two radiologists, the following parameters were extracted for lesions at both examinations: lesion size (short and long axes, in both early and late phases of enhancement), radiologist's subjective assessment of lesion enhancement, and percentages of voxels within the lesion demonstrating progressive, plateau, or washout kinetics. The latter data were calculated using two filters, one selecting for voxels enhancing ≥50% over baseline and one for voxels enhancing ≥100% over baseline. Pretreatment imaging parameters and parameter changes following cycle 1 of NAC were evaluated for their ability to discriminate patients with an eventual pathological complete response (pCR). Results: All 21 patients completed NAC followed by surgery, with 9 patients achieving a pCR. No pretreatment imaging parameters were predictive of pCR. However, change after cycle 1 of NAC in percentage of voxels demonstrating washout kinetics with a 100% enhancement filter discriminated patients with an eventual pCR with an area under the receiver operating characteristic curve (AUC) of 0.77. Changes in other parameters, including lesion size, did not predict pCR. Conclusion: Semi-quantitative analysis of high temporal resolution DCE-MRI in patients with LABC can discriminate patients with an eventual pCR after one cycle of NAC. [Copyright &y& Elsevier]

Cholesteryl ester transfer protein (CETP) inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT) were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD)  = 20.47, 95% CI [19.80 to 21.15]) and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = −10.47, 95% CI [−11.91 to −9.03]) and LDL-c (n = 3159, p<0.00001, MD = −17.12, 95% CI [−18.87 to −15.36]) irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60]) after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in triglyceride and LDL-c with satisfactory safety and tolerability in patients with dyslipidemia. However, the side-effect on blood pressure deserves more consideration in future studies. [ABSTRACT FROM AUTHOR]

Highlights: [•] A. oxyphylla extracts showed multiple bio-functions at various concentrations. [•] A. oxyphylla extracts presented anti-oxidative properties. [•] A. oxyphylla extracts inhibited LPS-induced inflammatory cytokine TNF-α released. [•] A. oxyphylla extracts possessed tyrosinase inhibition on both mushroom and B16F10. [•] A. oxyphylla extracts showed anti-growth and anti-migration effects in melanoma. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence supporting a role for microRNAs (miRNA) as targets in aberrant mechanisms of DNA hypermethylation. Epigenetic silencing of tumor suppressor miRNAs, including miR-663, which has recently been reported to be inactivated by hypermethylation in several cancers, may play important roles in pediatric acute myeloid leukemia (AML). However, expression of miR-663 and its promoter methylation remain status unclear in childhood leukemia. Methods: Promoter methylation status of miR-663 was investigated by methylation specific PCR (MSP) and bisulfate genomic sequencing (BGS). Transcriptional expression of miR-663 was evaluated by semi-quantitative and real-time PCR, and the relationship between expression of miR-663 and promoter methylation was confirmed using 5-aza-2'-deoxycytidine (5-Aza) demethylation reagent. Results: MiR-663 was aberrantly methylated in 45.5% (5/11) leukemia cell lines; BGS showed that the promoter was significantly methylated in three AML cell lines; methylation of miR-663 was significantly higher in Chinese pediatric AML patients [41.4% (29/70)] compared to normal bone marrow (NBM) control samples [10.0% (3/30)]. These results were confirmed by both BGS and 5-Aza demethylation analysis. In addition, miR-663 transcript expression was significantly lower in AML patients, both with and without miR-663 methylation, compared to controls; however, there were no significant differences in clinical features or French-American-British (FAB) classification between patients with and without miR-663 methylation. Conclusions: Expression of miR-663 was significantly lower in pediatric AML cells compared to NBM controls; furthermore, a high frequency of miR-663 promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Inactivation of miR-663 by promoter hypermethylation could be affected by 5-Aza demethylation. These findings suggest that hypermethylation of the miR-663 promoter may be an early event in the development of pediatric AML. [ABSTRACT FROM AUTHOR]

Background: Klebsiella pneumoniae is one of the major pathogens causing hospital-acquired multidrug-resistant infections. The capsular polysaccharide (CPS) is an important virulence factor of K. pneumoniae. With 78 capsular types discovered thus far, an association between capsular type and the pathogenicity of K. pneumoniae has been observed. Methodology/Principal Findings: To investigate an initially non-typeable K. pneumoniae UTI isolate NTUH-K1790N, the cps gene region was sequenced. By NTUH-K1790N cps-PCR genotyping, serotyping and determination using a newly isolated capsular type-specific bacteriophage, we found that NTUH-K1790N and three other isolates Ca0507, Ca0421 and C1975 possessed a new capsular type, which we named KN2. Analysis of a KN2 CPS− mutant confirmed the role of capsule as the target recognized by the antiserum and the phage. A newly described lytic phage specific for KN2 K. pneumoniae, named 0507-KN2-1, was isolated and characterized using transmission electron microscopy. Whole-genome sequencing of 0507-KN2-1 revealed a 159 991 bp double-stranded DNA genome with a G+C content of 46.7% and at least 154 open reading frames. Based on its morphological and genomic characteristics, 0507-KN2-1 was classified as a member of the Myoviridae phage family. Further analysis of this phage revealed a 3738-bp gene encoding a putative polysaccharide depolymerase. A recombinant form of this protein was produced and assayed to confirm its enzymatic activity and specificity to KN2 capsular polysaccharides. KN2 K. pneumoniae strains exhibited greater sensitivity to this depolymerase than these did to the cognate phage, as determined by spot analysis. Conclusions/Significance: Here we report that a group of clinical strains possess a novel Klebsiella capsular type. We identified a KN2-specific phage and its polysaccharide depolymerase, which could be used for efficient capsular typing. The lytic phage and depolymerase also have potential as alternative therapeutic agents to antibiotics for treating K. pneumoniae infections, especially against antibiotic-resistant strains. [ABSTRACT FROM AUTHOR]

Highlights: [•] We estimate potential PV location on buildings by a street block scale. [•] We analyze PV electrical energy when shaded and unshaded in summer and winter. [•] The efficiency of PV on vertical facades is compared with that on rooftops. [Copyright &y& Elsevier]

The article presents a study which aims to determine the effect of using a cane on movement time, joint moment, weight symmetry, and muscle activation patterns during sit-to-stand (STS) transfer in subjects with hemiparesis. It shows that subjects who uses a cane have shortened movement time, greater knee extensor moment, and better symmetrical performance. The authors conclude that cane use may promote more symmetrical STS transfers rather than compensation by the unaffected limb.

Abstract: Renal fibrosis progresses to end stage of diabetes kidney disease, which causes irreversible progressive proximal tubular injury. In a previous study, 20-hydroxyecdysterone (20-HE), a phytoecdysteroid, attenuated renal injury in diabetes models. However, the fibrosis regulatory role remains to be investigated. Methods: The proximal tubular epithelial cells (designated as HK-2) were treated for 48 h with TGF-β1 (5ng/ml) in different concentrations of 20-HE (0 to 500 nM/ml) in the last 24 h of culture. The extracellular fibronectin was measured by ELISA assay. Western blot and immunofluorescence were used to evaluate the expression of TGF-β1/Smads transducer (including Smad2/3, 4, and 7), epithelial and mesenchymal markers (e.g. E-cadherin and α-smooth muscle actin) and Snail (transcriptional regulators for EMT). Results: 20-HE reverses TGF-β1-induced increase in fibronectin (both intracellular and extracellular fibronectin). Simultaneously, 20-HE reverses TGF-β1-induced down-regulation of Smad7. In addition, 20-HE significantly attenuates TGF-β1-induced upregulation of Smad2/3 and pSmad2/3, and downregulation of E-Cadherin. Moreover, 20-HE dramatically suppresses TGF-β1-induced increases in the expression of Snail. Conclusion: We propose that 20-HE is a potential fibrosis antagonist for renal proximal tubule cells. 20-HE might act through suppressing post-receptor signaling of TGF-β1 and restoring tubule epithelial character by blocking the expression of Snail. [Copyright &y& Elsevier]

Renal interstitial fibrosis is characterized by increased extracellular matrix (ECM) synthesis. Epithelial-mesenchymal transition (EMT) in kidneys is driven by regulated expression of fibrogenic cytokines such as transforming growth factor-beta (TGF-β). Yam, or Dioscorea alata (DA) is an important herb in Chinese medicine widely used for the treatment of clinical diabetes mellitus. However, the fibrosis regulatory effect of DA is unclear. Thus, we examined TGF-β signaling mechanisms against EMT in rat fibroblast cells (NRK-49F). The characterization of DA water-extracts used various methods; after inducing cellular fibrosis in NRK-49F cells by treatment with β-hydroxybutyrate (β-HB) (10 mM), we used Western blotting to examine the protein expression in the TGF-β-related signal protein type I and type II TGF-β receptors, Smads2 and Smad3 (Smad2/3), pSmad2 and Smad3 (pSmad2/3), Smads4, Smads7, and EMT markers. These markers included E-cadherin, alpha-smooth muscle actin (α-SMA), and matrix metalloproteinase-2 (MMP-2). Bioactive TGF-β and fibronectin levels in the culture media were determined using ELISA. Expressions of fibronectin and Snail transcription factor, an EMT-regulatory transcription factor, were assessed by immunofluorescence staining. DA extract dose-dependently (50-200 µg/mL) suppressed β-HB- induced expression of fibronectin in NRK-49F cells concomitantly with the inhibition of Smad2/3, pSmad2/3, and Smad4. By contrast, Smad7 expression was significantly increased. DA extract caused a decrease in α-SMA (α-smooth muscle actin) and MMP-2 levels, and an increase in E-cadherin expression. We propose that DA extract might act as a novel fibrosis antagonist, which acts partly by down regulating the TGF-β/smad signaling pathway and modulating EMT expression. [ABSTRACT FROM AUTHOR]

The goal of this study was to examine the relationship between the validity of postural movement and bilateral motor integration in terms of sensory integration theory. Participants in this study were 61 Chinese children ages 48 to 70 months. Structural equation modeling was applied to assess the relation between measures tapping postural movement and bilateral motor integration: for postural movement, the measures involve the Monkey Task, Side-Sit Co-contraction, Prone on Elbows, Wheelbarrow Walk, Airplane, and Scooter Board Co-contraction from the DeGangi-Berk Test of Sensory Integration, and Standing Balance with Eyes Closed/Opened in Southern California Sensory Integration Tests. For bilateral motor integration, the measures chosen were the Rolling Pin Activity, Jump and Turn, Diadokokinesis, Drumming, and Upper Extremity Control from the DeGangi- Berk Test of Sensory Integration, and Cross the Midline in Southern California Sensory Integration Tests (SCSIT). Postural movement was highly correlated with the bilateral motor integration. The factor structure fit the theoretical conceptualization, classifying postural movement and bilateral motor integration together in the same category. Therapists could combine two separate objectives (postural movement and bilateral motor integration) of intervention in an activity to improve the adaptive skills based on the vestibular-proprioceptive integration. [ABSTRACT FROM AUTHOR]

A battery-powered in situ Underwater Miniature PIV (UWMPIV) has been developed and deployed for field studies. Instead of generating high-energy laser pulses as in a conventional PIV system, the UWMPIV employs a low-power Continuous Wave (CW) laser (class IIIb) and an oscillating mirror (galvanometer) to generate laser sheets. In a previous version of the UWMPIV, the time between exposures of a pair of particle images, $$\Updelta t$$, could not be reduced without loss of illumination strength. This limitation makes it unsuitable for high-speed flows. In this paper, we present a technique to solve this problem by adopting two CW lasers with different wavelength and two CCD cameras in a second-generation UWMPIV system. Several issues including optical alignment, non-uniform distribution of $$\Updelta t$$ due to the varying speed of the scanning beam and local flow velocities are discussed. The timing issue is solved through a simple calibration procedure that involves the reconstruction of maps of laser beam arrival time. Comparison of the performance between the new method and a conventional PIV system is presented. Measurements were performed in a laboratory open-channel flume. Excellent agreement was found between the new method and the standard PIV measurement in terms of the extracted vertical profiles of mean velocity, RMS fluctuation, Reynolds stress and dissipation rate of turbulent kinetic energy. [ABSTRACT FROM AUTHOR]

The article discusses a study aimed at determining the prevalence of metallo-B-lactamases (MBLs)-producing Entero-bacteriaceae isolates at a Taiwanese university hospital in 2006 and examining tigecycline activity against MBL producers. It cites the use of 527 Klebsiella pneumoniae, 1026 Escherichia coli and 274 Enterobacter isolates in investigating the prevalence of MBLs in Enterobacteriaceae. The results emphasized the importance of knowing the characteristics of endemic carbapenemase producers before choosing a screening strategy.

Abstract: Chemical-looping combustion (CLC) has been recognized as an energy-efficient method for CO2 capture. For calcium sulfate (CaSO4) oxygen carrier, the rapid fall in the mechanical strength and reactivity limits its application in CLC. In this study, Taguchi robust design method with L 9 orthogonal array was implemented to optimize extrusion condition for the preparation of binder-supported CaSO4 oxygen carriers. The orthogonal experiment results showed the addition of SB powder enhanced both mechanical strength and conversion of CaSO4, and the optimal extrusion condition was 30g CaSO4, 12g SB powder, 2.5mL acetic acid, and 15mL water. The favorable oxygen carriers were comprehensively studied in a fixed bed reactor. The results of reduction test showed the mass-based reaction rates of the binder-supported CaSO4 were significantly increased, because the fresh samples had the higher surface area which was evidenced by pore structure analysis. Moreover, the favorable performance of binder-supported CaSO4 was explained by formation of CaAl2O4 which had excellent thermal stability and provided a stable nanosized framework between the crystal grains observed by field emission scanning electron microscope (FESEM). [Copyright &y& Elsevier]

The active components of a primary pyrogenic liver abscess (PLA) Klebsiella pneumoniae in stimulating cytokine expression in macrophages are still unclear. The capsular polysaccharide (CPS) of PLA K. pneumoniae is important in determining clinical manifestations, and we have shown that it consists of repeating units of the trisaccharide (→3)-β-d-Glc-(1→4)-[2,3-(S)-pyruvate]-β-d-GlcA-(1→4)-α-l-Fuc-(1→) and has the unusual feature of extensive pyruvation of glucuronic acid and acetylation of C2-OH or C3-OH of fucose. We demonstrated that PLA K. pneumoniae CPS induces secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by macrophages through Toll-like receptor 4 (TLR4) and that this effect was lost when pyruvation and O-acetylation were chemically destroyed. Furthermore, expression of TNF-α and IL-6 in PLA K. pneumoniae CPS-stimulated macrophages was shown to be regulated by the TLR4/ROS/PKC-δ/NF-κB, TLR4/PI3-kinase/AKT/NF-κB, and TLR4/MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: The effects of patterned sensory enhancement (PSE) music on muscle power and movement control in children with spastic diplegia (SD) during loaded sit-to-stand (LSTS) were investigated. Twenty-three children with SD aged 5 to 12 years were recruited. Individualized PSE was composed by a music therapist based on each subject''s sit-to-stand (STS) movement with 50% 1-repetition maximum load. Each subject performed LSTS continuously for eight repetitions under randomly assigned music or no-music (Control) conditions while the kinematic and kinetic data were measured simultaneously. For the music condition, PSE music was played only during the first five repetitions (PSE condition), and the following three repetitions were referred to as the Continuation condition. Paired t- or Wilcoxon signed rank tests were used to compare the variables between the PSE and Control conditions, and between the Continuation and Control conditions. Compared to the Control condition, greater peak knee extensor power (P =0.009), greater total extensor power (P =0.015), and better center-of-mass smoothness (P =0.01), but less movement time (P =0.003) were found in the PSE condition. Significant effects of the PSE music on the above variables were also found for Continuation condition. The current results showed that individualized PSE music helped improve the performance of LSTS in children with SD. The associated biomechanical features also continued to exist in subsequent movement cycles after the music had ceased. These findings suggest that therapy using LSTS combined with PSE music may be beneficial for rehabilitating children with SD. [Copyright &y& Elsevier]

Background: Several studies have shown that the predominant genotype of Chinese Japanese encephalitis virus (JEV) is evolving from genotype 3 to genotype 1. However, in recent years, almost all genotype 1 isolates were from mosquitoes, and genotype 1 has been less associated with human disease than genotype 3. This study reports the isolation of human genotype 1 JEV and its genetic characteristics to provide additional insights into human JE pathogens that are currently circulating in China. Methods and Results: In 2009, 31 cerebrospinal fluid samples were collected from patients living in Yunnan and Shanxi provinces and were used to inoculate Aedes albopictus C6/36 cells for virus isolation. The JEV strains were identified using immunofluorescent assays and the reverse transcription-polymerase chain reaction. Phylogenetic analyses based on the partial capsid/pre-membrane and full envelope (E) sequences were performed using Clustalx 1.8 software. Three JEV isolates were obtained from a 4-year-old girl and a 2-year-old boy living in Yunnan and an 82-year-old woman in Shanxi. The boy had been immunized with one dose of JE live attenuated vaccine. New isolates were grouped into genotype 1. Amino acid sequence for the viral E protein indicated 95% to 100% identity with each other and with other JEV strains. When compared with a consensus sequence of E protein, two amino acid substitutions were found: SerE-123-Asn in the two Yunnan isolates and LysE-166-Arg in the Shanxi isolate. Conclusions: Our findings indicate that the genotype 1 of JEV is causing human infections in China. Our observation of a previously vaccinated boy developing JE from genotype 1 virus infection also calls for more detailed studies, both in vitro and in vivo neutralization tests as well as active surveillance, to examine the possibility of a lack of complete protection conferred by the live attenuated JE vaccine against genotype 1 virus. [ABSTRACT FROM AUTHOR]

Abstract: The investigation explores the factors that influence the long-term performance of high-power 1W white light emitting diodes (LEDs). LEDs underwent an aging test in which they were exposed to various temperatures and electrical currents, to identify both their degradation mechanisms and the limitations of the LED chip and package materials. The degradation rates of luminous flux increased with electrical and thermal stresses. High electric stress induced surface and bulk defects in the LED chip during short-term aging, which rapidly increased the leakage current. Yellowing and cracking of the encapsulating lens were also important in package degradation at 0.7A/85°C and 0.7A/55°C. This degradation reduced the light extraction efficiency to an extent that is strongly related to junction temperature and the period of aging. Junction temperatures were measured at various stresses to determine the thermal contribution and the degradation mechanisms. The results provided a complete understanding of the degradation mechanisms of both chip and package, which is useful in designing highly reliable and long-lifetime LEDs. [Copyright &y& Elsevier]

We describe here a simple and efficient system of soybean ( Glycine max L. Merrill) regeneration through direct somatic embryogenesis by using immature embryonic shoot tips (IEST) as explants. The cultivar Kaohsiung 10 (cv. K10) used in this study did not show embryogenic response either from mature seed-derived explants (cotyledon, embryonic tip, leaf, shoot and root) or immature cotyledons. However, it showed a high percentage (55.8%) of somatic embryo (SEm) formation from the IEST excised 2–3 wk after flowering, thus indicating the crucial roles of type and age of explants. The IEST put forth primary SEm after 2 mo of culturing on Murashige and Skoog (MS) medium supplemented with 6% sucrose, 164.8 µM 2,4-dichlorophenoxyacetic acid (2,4-D), 5 mM asparagine and 684 µM glutamine. Subsequently, secondary SEm were developed 1 mo after culturing on MS medium containing 123.6 µM 2,4-D and 3% sucrose. Cotyledonary embryos were induced on MS medium supplemented with 0.5% activated charcoal after 1 mo. The embryos were desiccated for 72–96 h on sterile Petri dishes and regenerated on hormone-free MS medium. Plantlets with well-developed shoots and roots were obtained within 5–6 mo of culturing of IEST. The SEm-derived plants were morphologically normal and fertile. Various parameters thought to be responsible for efficient regeneration of soybean through somatic embryogenesis are discussed. To our knowledge, this is the first report to employ IEST as explants for successful direct somatic embryogenesis in soybean. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Experimental and clinical observations suggest that CXCL16, a recently discovered transmembrane chemokine combining functions of a chemokine and a scavenger receptor, could be an important player in atherosclerosis, but the relationship of its common variants with coronary artery disease (CAD) has not been extensively studied. Methods: We designed an angiography-based case-controlled study consisting of 1176 CAD patients and 850 control subjects to investigate the association between five common single nucleotide polymorphisms (SNPs) of CXCL16 gene and CAD risk in Chinese Han population. The plasma concentration of CXCL16 was measured by enzyme-linked immunosorbent assay. Results: No significant differences were observed for the distributions of rs2250333, rs2304973, rs2277680, and rs1051009 between CAD patients and control subjects. However, both the genotype and allele frequencies of rs3744700 showed significant differences between cases and controls (P =0.001 and P <0.001, respectively). The GG homozygotes had significantly higher CAD risk compared with the T allele carriers (GT+TT) (OR, 1.77; 95% CI, 1.28–2.43; adjusted P <0.001) in a logistic regression model after adjustment for the conventional risk factors for CAD. The GG genotypes also had increased plasma CXCL16 levels compared with T allele carriers in both cases and control subjects. Conclusions: SNP rs3744700 of CXCL16 gene is independently associated with the development of CAD in Chinese Han population, and GG homozygote which is associated with increased expression of CXCL16 may have a promoting effect on CAD. [Copyright &y& Elsevier]

During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine-adenosine A2A receptor (A2AR) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A2AR agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5- (ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinaseA(PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A2AR signaling from the PKA to the PKC pathway, resulting in a switch in A2AR effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-α, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A2AR antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl]amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor (S)-4C3HPG [(S)-4-carboxy-3- hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A2AR activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine-A2AR system. [ABSTRACT FROM AUTHOR]

Abstract: Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P =0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P =0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P =0.012, McNemar''s test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC. [Copyright &y& Elsevier]

The article presents kinematic and kinetic analysis of subjects who experienced standing and ambulation after stroke with or without the help of a 5-degree lateral-wedged insole. It states that the study was conducted by asking 10 hemiparetic individuals who experienced unilateral stroke to perform a quiet stance and ambulation with no insole wedge, and nonparetic side wedged in a random order. It reveals that the insole improves stance symmetry and reduces abductor load in paretic knee.

Insulin and (—)-epigallocatechin gallate (EGCG) have been reported to regulate fat cell mitogenesis and adipogenesis, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated mitogenesis in 3T3-L1 preadipocytes. EGCG inhibited insulin stimulation of preadipocyte proliferation in a dose- and time-dependent manner. EGCG also suppressed insulin-stimulated phosphorylation of the insulin receptor-β, insulin receptor (IR) substrates 1 and 2 (IRS1 and IRS2), and mitogen-activated protein kinase pathway proteins, RAF1, MEK1/2, and ERK1/2, but not JNK. Furthermore, EGCG inhibited the association of IR with the IRS1 and IRS2 proteins, but not with the IRS4 protein. These data suggest that EGCG selectively affects particular types of IRS and MAPK family members. Generally, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in modulating insulin-stimulated mitogenic signaling. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and found that its expression was sensitive to growth phase, tissue type, and differentiation state. Pre-treatment of preadipocytes with 67LR antiserum prevented the effects of EGCG on insulin-stimulated phosphorylation of IRS2, RAF1, and ERK1/2 and insulin-stimulated preadipocyte proliferation (cell number and bromodeoxyuridine incorporation). Moreover, EGCG tended to increase insulin-stimulated associations between the 67LR and IR, IRS1, IRS2, and IR54 proteins. These data suggest that EGCG mediates anti-insulin signaling in preadipocyte mitogenesis via the 67LR pathway. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To investigate in a Chinese population the occurrence of polymorphisms Bcl I, N363S and ER22/23EK in the glucocorticoid receptor and their association with outcome of trauma. Methods: In all, 266 healthy volunteers and 95 victims of major trauma were recruited. The presence of glucocorticoid receptor polymorphisms (ER22/23EK, N363S and Bcl I) was sought by restriction fragment length polymorphism analysis. The injured group were monitored as to respiratory, renal, hepatic, cardiovascular, haematological and central nervous functions. The association was determined between polymorphisms and the development of multiple organ dysfunction syndrome and sepsis after trauma. Results: Only the Bcl I polymorphism was identified. The frequency of its G allele was 23.5% among volunteers and 26.3% among casualties. There were no significant differences in MOD score or sepsis rate between participants classified according to genotype. Conclusions: Only the Bcl I polymorphism of the glucocorticoid receptor gene is common in the Chinese Han population; it may not influence the development of complications following major trauma. [Copyright &y& Elsevier]

Simple Summary: Endometrial cancer is the most common gynecological cancer in developed countries. At initial diagnosis, extra-uterine spread is observed in about 25% of patients. Chemotherapy is the suggested mode of treatment for patients with extra-uterine metastasis; however, the 5-year overall survival rate of these patients remains poor. The development of new therapeutic strategies to improve the poor clinical outcome of patients with advanced endometrial cancer is still in great demand. In this study, we aim to understand the genomic landscape of advanced endometrial cancer and identify new therapeutic targets. Integrated genomic, pathological, and clinical data are analyzed to identify the survival-associated genomic alterations. In addition, the impacts of the genomic alterations are examined in silico, in vitro, and in vivo. The results of this study may aid in developing biomarker-guided treatments for patients with advanced endometrial cancer. An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. To identify genomic aberrations associated with clinical outcomes, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. The mutation status of MET, U2AF1, BCL9, PPP2R1A, IDH2, CBL, BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p-value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in hepatocyte growth factor (HGF)-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant that causes chemoresistance to cisplatin, with a high incidence in Eastern Asia. This study highlights the ethnic differences in the biology of the disease, which can influence treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer. [ABSTRACT FROM AUTHOR]

Abstract: ZnS hollow microspheres were prepared via a facile template-free chemical vapor deposition (CVD) route using metallic zinc powders and sulphur sublimed as reactants. The products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectrometer (EDX). The results showed that the as-prepared ZnS hollow spheres had uniform size about 4–8μm in diameter. The growth mechanism of such interesting was discussed. The optical property of the products was also recorded by means of photoluminescence (PL) spectroscopy. [Copyright &y& Elsevier]

To investigate the bioavailability and bio-enrichment of metals from soils to vegetables, the concentrations of ni, Pb, Zn, and Cu in vegetables and their grown soils sampled from eight suburban areas of Nanjing, China, were determined, and the fractions of these metals in soils was characterized by using the BCR sequential extraction procedure. The results showed that the residual fraction was the dominant proportion for Pb (46%-64% in total), Cu (49%-73% in total) and Ni (40%-61% in total) in soils, whereas Zn was found mainly in the oxidizable fraction (31%-69% in total). The translocation coefficients of metals in leaf/root systems revealed that Cu, Zn and Ni were mainly accumulated in roots, whereas Pb mainly in the leaves of these vegetables. The enrichment coefficients of metals in leaf/root systems indicated that Zn had the strongest capacity of accumulation from soils to vegetables among all four elements. No significant correlations were found among metal concentrations in the vegetables, the metal fractions in corresponding soils, and the enrichment coefficients from soils to plants. [ABSTRACT FROM AUTHOR]

Abstract: Tri(8-hydroquinoline)aluminum (AlQ3) nanowires, nanowalls, complex nanostructure composed of microspheres and nanowires, micro-spherical chains were successfully synthesized by simple physical vapor condensation. The effect of the deposition temperature on the morphologies of AlQ3 has been investigated. Fourier transform infrared spectroscopy (FT-IR) was used to examine the chemical bonding of products as-prepared. Environmental scanning electronic microscopy (ESEM) was performed to analyze the morphologies of the samples. FT-IR results indicated that the AlQ3 molecules had a strong thermal stability. The photoluminescence (PL) spectra showed that there was no apparent blue shift because the AlQ3 molecules are bonded by relatively weak Van der Waals forces. These different structures depended on the deposition temperatures would be believed to attractive building field-emission devices and other optical devices. [Copyright &y& Elsevier]

Genomic heterogeneity has been shown to be associated with Klebsiella pneumoniae strains causing pyogenic liver abscesses (PLA) and metastatic infections. In order to explore the mechanism responsible for genomic heterogeneity in K. pneumoniae, we compared the complete genomic sequences of strains NTUH-K2044 and MGH78578. An ∼76-kbp DNA fragment located adjacent to an asparagine (asn) tRNA gene was present in NTUH-K2044 but not in MGH78578. This fragment could be divided into three regions with different functions, and structurally it resembled a functional integrative and conjugative element (ICE), ICEEc1, in Escherichia coli. The 5' region of this fragment contained genes similar to a high-pathogenicity island (HPI) of Yersinia pestis and Yersinia pseudotuberculosis. The middle region was similar to part of a large plasmid in K. pneumoniae, and the 3' region contained genes responsible for DNA conjugative transfer. Therefore, this DNA fragment was designated ICEKp1. Precise excision and extrachromosomal circularization of ICEKp1 were detected in K. pneumoniae wild-type strain NTUH-K2044. ICEKp1 could integrate into the asn tRNA loci of the chromosome of another K. pneumoniae isolate. The prevalence of ICEKp1 was higher in PLA strains (38 of 42 strains) than in non-tissue-invasive strains (5 of 32 strains). Therefore, ICEKp1 may contribute to the transmission of the HPI and result in K. pneumoniae PLA infection-associated genomic heterogeneity. [ABSTRACT FROM AUTHOR]

Primary objective : This study sought to identify navigation patterns and illuminate the barriers to and possible solutions for independent community travel in people with chronic cognitive impairments as a result of acquired brain injury. Research design : Two investigative methods were used to explore navigation in the population of interest: Study 1 was a field study and study 2 convened a series of focus groups with relevant stakeholders. Methods and procedures : For study 1, each week during a 4 month period, researchers administered a navigational survey and structured interview to a typical case sample of six participants in order to catalogue all trips taken outside the assistive living facility. Study 2 convened six focus groups to access perspectives on navigational issues for individuals with cognitive impairments (CI) from a number of stakeholder groups including individuals with CI, care providers for this population and public transportation workers. Conclusions : The results of both studies were consistent and indicated that community access is severely restricted for individuals with CI. The majority of trips that were taken tended to be routine and assisted. The variety of travel was limited; participants ventured to the same set places with the same people. Participants described barriers accounting for these problems and suggested a number of strategies to minimize problems. [ABSTRACT FROM AUTHOR]

Abstract: Toll-like receptor 4 (TLR4) has become a new target for combating Gram-negative bacterium-induced sepsis. In this study, we screened peptides that can interact with TLR4 from a random 16-peptide library using yeast two-hybrid system and performed functional identification for the obtained peptides. We got two positive clones out of 1.28×107 transformants. The peptides were sequenced and synthesized. Protein sequence comparison confirmed that the two peptides had no homologous proteins. The two peptides were found to significantly inhibit LPS-induced NF-κB activation in HEK-293 cells that were transfected with TLR4 cDNA, LPS-induced IκBα (IκB alpha) phosphorylation and NF-κB activation in monocytes, and release of IL-1, IL-6, and TNF-α by monocytes. We further confirmed that the No. 9 peptide could bind to TLR4 extracellular domain, but the No. 24 peptide could not, suggesting that two novel peptides were identified as the antagonists of TLR4, which significantly inhibited the effects of endotoxin in vitro. The No. 9 peptide may function through binding to TLR4 extracellular domain. Our findings suggest a promising countermeasure against Gram-negative bacterium-induced sepsis. [Copyright &y& Elsevier]

The potential for bioterrorism involving smallpox has led to a debate about the durability of protective immunity against smallpox from vaccination. By assessing the T cell reactivity to vaccinia virus in a healthy population, we show that subjects who were vaccinated within the past 3 decades and who have a visible vaccination scar had remarkable T cell reactivity. However, person who were vaccinated within the past 3 decades but who do not have a scar and those who were vaccinated 14 decades ago had responses as low as those in unvaccinated subjects. Thus, we estimate that the significant T cell memory response to vaccinia virus from successful vaccination may persist for only 20-30 years. Furthermore, we found the vaccinia-specific cellular immunity could be easily assessed by determination of the frequencies of vaccinia-specific CD69 expression on T cell subsets. These data may help in the development of public health strategies to counter bioterrorism threats associated with smallpox. [ABSTRACT FROM AUTHOR]

Aluminum alloy shells are increasingly used in public buildings as a supporting structure for roofing enclosure construction in large spaces. In performance-based fire protection design, an empirical design criterion of 150 °C and relevant empirical formulas are used; however, the safety margin and prediction effect are not verified through full-scale experiments, and therefore, the effect of the roof system on the near-roof temperature field in practical engineering is yet to be investigated. In this study, a simulated fire experiment was conducted using a cylindrical aluminum alloy reticulated roof system model. The heat release rate of this restricted fuel fire source during the stable burning stage reached 8.1 MW. Fire Dynamics Simulator (FDS) was used to reproduce experimental results, and the numerical model of the shell member was simplified; further, existing empirical formulas of scholars such as Li were compared. The results indicated that although 150 °C is a large safety margin, it may limit architectural function. The simplified shell model provides an effect-equivalent approach for building thin-walled members in FDS. The shell is the main factor that delays the time required for the near-roof space to reach thermal equilibrium. The existing empirical formulas cannot be used for the studied roof system directly, and they may be improved through coefficient adjustment and other such methods. • First fire test of full-scale aluminum alloy arched roof system. • 150 °C critical criterion in performance-based design has a large safety margin. • Thermal equilibrium moment prolonged by aluminum alloy shell members. • Existing empirical formulas cannot be used to predict studied roof system. [ABSTRACT FROM AUTHOR]

Toll-like receptor 4 (TLR4) is an important mediator of hypertension and AngII induced cardiac inflammation and remodelling. In this study, the potential of nerolidol to ameliorate hypertension induced cardiac injuries and the underlying mechanism of action was explored by using in vitro and in vivo models. The in vitro analysis was performed on AngII challenged H9c2 cells and their ability to overcome cardiac inflammation and cardiac remodelling effects was determined by evaluating TLR4/NF-κB signalling cascade using Western blot analysis and immunofluorescence. The results were further ascertained using in vivo experiments. Eighteen week old male rats were randomly allocated into different groups i.e. Wistar Kyoto (WKY) rats, hypertensive SHRs, SHRs treated with a low-dose (75 mg/kg b.w) and high-dose of nerolidol (150 mg/kg b.w) and SHRs treated with captopril (50 mg/kg b.w) through oral gauge and finally analysed through echocardiography, histopathological techniques and molecular analysis. The results show that nerilodol target TLR4/NF-κB signalling and thereby attenuate hypertension associated inflammation and oxidative stress thereby provides effective cardioprotection. Echocardiography analysis showed that nerolidol improved cardiac functional characteristics including Ejection Fraction and Fractional Shortening in the SHRs. Collectively, the data of the study demonstrates nerolidol as a cardio-protective agent against hypertension induced cardiac remodelling. Image 1 [ABSTRACT FROM AUTHOR]

• Pure and Au decorated β -Ga 2 O 3 single nanowire were prepared using VLS technique. • The room temperature CO gas sensing properties were studied for both Bulk and single nanowire fabricated devices. • Moreover, we have demonstrated the resistive switching characteristics of the pure and Au decorated β -Ga 2 O 3. High-density single crystalline β -Ga 2 O 3 nanowires on silicon (1 0 0) substrates were grown by vapour-liquid-solid growth method. We have characterized the pure β -Ga 2 O 3 nanowires along with the Au-decorated β -Ga 2 O 3 nanowires. The CO gas sensors at room temperature (RT) have been studied for pure and Au decorated nanowires with multiple-networked array and single nanowire devices. The diameter of the 1D nanostructure ranged from 127 ± 5 nm. The synthesized nanowires were studied using Field Emission Scanning Electron Microscope (FESEM), Transmission Electron Microscope (TEM), Energy Dispersive X-ray Spectroscopy (EDS), Gracing Incidence X-ray Diffraction (GI-XRD), Photoluminescence (PL), Raman spectroscopy and X-ray Photoelectron Spectroscopy (XPS). Using the Focussed Ion Beam (FIB) technique, single nanowire gas sensor devices were fabricated. Single nanowire RT CO gas sensors using the proposed Au decorated β -Ga 2 O 3 nanowire achieved remarkable sensitivity for 100 ppm CO gas at room temperature. Besides, we have compared the RT CO gas sensing properties of multiple-networked Au decorated β -Ga 2 O 3 nanowires with single Au-decorated β -Ga 2 O 3 nanowire and single pure β -Ga 2 O 3 nanowire. In addition, bipolar resistive switching property is inspected for the Au/pure β -Ga 2 O 3 nanowires/p-Si and Au/Au decorated β -Ga 2 O 3 nanowires/p-Si structures. [ABSTRACT FROM AUTHOR]

• Inhibitory effects of sixty-six natural alkaloids against hCES2A were assayed. • Primary structure–activity relationships (SAR) analysis of isoquinoline alkaloids. • Reserpine exhibits strong hCES2A inhibition activity and selectivity over other human serine hydrolases. • Inhibition kinetic analyses demonstrated that reserpine was a non-competitive inhibitor. • Molecular docking simulations explore the key interactions between reserpine and hCES2A. Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure–activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC 50 = 0.94 μM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications. [ABSTRACT FROM AUTHOR]

In this work, we have inspected the theoretical resistive switching properties of two ReRAM models based on heterojunction structures of Cu/SiOx nanoparticles (NPs)/Si and Si/SiOx NPs/Si, in which dielectric layers of the silica nanoparticles present dislocations at bicrystal interfaces. To validate the theoretical model, a charge storage device with the structure Cu/SiOx/Si was fabricated and its ReRAM properties were studied. Our examinations on the electrical, thermal and structural aspects of resistive switching uncovered the switching behavior relies upon the material properties and electrical characteristics of the switching layers, as well as the metal electrodes and the interfacial structure of grains within the dielectric materials. We also determined that the application of an external electric field at Grain Boundaries (GB) is crucial to resistive switching behavior. Moreover, we have demonstrated that the switching behavior is influenced by variations in the atomic structure and electronic properties, at the atomic length scale and picosecond timescale. Our findings furnish a useful reference for the future development and optimization of materials used in this technology. [ABSTRACT FROM AUTHOR]

Compounds 3j inhibited human placenta steroid sulfatse with IC 50 of 0.13 μM and displayed ireversible kinetic of K I 0.08 μM and K in cat 158 min−1. • Nineteen 3-aminocoumarin-7- O -sulfamates were designed and synthesized. • SAR revealed that modification at 3-position of coumarin resulted in enhancing STS inhibition. • Substitution at benzyl of 3-benzyl-aminocoumarin-7- O -sulfamates was crucial for STS inhibition. • Compound 3j inhibited STS from human placenta (IC 50 130 nM) and MCF-7 (IC 50 1.35 µM). Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7- O -sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC 50 0.13 μM) and MCF-7 cell lines (IC 50 1.35 µM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with K I and k inact value of 86.9 nM and 158.7 min−1, respectively. [ABSTRACT FROM AUTHOR]

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3−/−) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein–stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders. Ching-Feng Cheng et al. find that expression of the transcription factor ATF3 in mice provides protection from obesity and insulin resistance under a high-fat diet. They show that expression of ATF3 can be induced by ST32da, a compound derived from the Chinese sage plant, Salvia miltiorrhiza. [ABSTRACT FROM AUTHOR]

Summary In mammals, gene silencing by the RNA-induced silencing complex (RISC) is a well-understood cytoplasmic posttranscriptional gene regulatory mechanism. Here, we show that embryonic stem cells (ESCs) contain high levels of nuclear AGO proteins and that in ESCs nuclear AGO protein activity allows for the onset of differentiation. In the nucleus, AGO proteins interact with core RISC components, including the TNRC6 proteins and the CCR4-NOT deadenylase complex. In contrast to cytoplasmic miRNA-mediated gene silencing that mainly operates on cis -acting elements in mRNA 3′ untranslated (UTR) sequences, in the nucleus AGO binding in the coding sequence and potentially introns also contributed to post-transcriptional gene silencing. Thus, nuclear localization of AGO proteins in specific cell types leads to a previously unappreciated expansion of the miRNA-regulated transcriptome. Graphical Abstract Highlights • Nuclear AGO proteins in ESCs allow for the onset of differentiation • Nuclear RISC silences target RNAs in a miRNA-dependent manner • Nuclear miRNA target repertoire includes intronic, CDS, and 3′ UTR sequences • Nuclear RISC requires CCR4-NOT for RNA destabilization In stem cells, half of the AGO proteins are found in the nucleus and allow for the onset of ESC differentiation. Nuclear AGO assembles functional RISC complexes to silence target RNAs in a miRNA- and CCR4-NOT-dependent manner at target sites that include intronic and coding sequences. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is a worldwide health problem. Allergen avoidance is strongly recommended for AR patients. Air purification can reduce concentrations of particles in indoor air, including those of allergens. Air purifiers have been recommended by clinicians for AR patients, but few studies have focused on the removal of airborne allergens from home environments. Such studies have been limited by a lack of blinding, small samples, or a failure to measure allergen levels, disease activity, or a combination of these factors. This study investigates the efficacy of a high-efficiency air purifier in reducing disease activity in the homes of AR patients sensitive to the allergens produced by Artemisia (mugwort) pollen.Methods: This is a randomized, double-blind, clinical controlled trial that will test active and inactive versions of an air purifier (Atmosphere®; Amway China). Sixty AR patients sensitive to the allergens produced by Artemisia pollen will be assigned randomly to two groups of equal numbers. All patients will undergo a 4-week treatment period and a 4-week observation period. Evaluation will be conducted at baseline (day 0) and on days 7, 14, 21, 28, and 56. The primary outcome measure will be the difference in visual analog scale scores from baseline. Secondary outcomes will be changes from baseline in nasal symptoms, allergy symptom scores, responses to the Rhinoconjunctivitis Quality of Life Questionnaire, Epworth Sleepiness Scale scores, and tolerability scores for the air purifier. Side effects of treatment will be recorded.Discussion: Reducing exposure to allergens can reduce the risk of conditions such as AR. We hypothesise that AR patients sensitive to the allergens produced by Artemisia pollen will not suffer symptoms in a pollen-free environment. AR patients can remove pollen from their homes using air purifiers, decreasing the risk of symptoms. We expect that our study results will provide reliable evidence for determining the effects of air-purification therapy.Trial Registration: ChiCTR-INR-17012481 . (Retrospectively registered 26 August 2017). [ABSTRACT FROM AUTHOR]

Summary Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation, and mRNA processing. Here, we report that depleting Spt6 in embryonic stem cells (ESCs) reduced expression of pluripotency factors, increased expression of cell-lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective downregulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers, where Spt6 controls histone H3K27 acetylation and methylation and super-enhancer RNA transcription. In ESCs, Spt6 interacted with the PRC2 core subunit Suz12 and prevented H3K27me3 accumulation at ESC super-enhancers and associated promoters. Biochemical as well as functional experiments revealed that Spt6 could compete for binding of the PRC2 methyltransferase Ezh2 to Suz12 and reduce PRC2 chromatin engagement. Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions. [ABSTRACT FROM AUTHOR]

The initial growth and microstructure feature of Ag films formation were investigated, which were prepared by using the very-high-frequency (VHF) (60 MHz) magnetron sputtering. Because of the moderate energy and very low flux density of ions impinging on the substrate, the evolutions of initial growth for Ag films formation were well controlled by varying the sputtering power. It was found that the initial growth of Ag films followed the island (Volmer—Weber, VW) growth mode, but before the island nucleation, the adsorption of Ag nanoparticles and the formation of Ag clusters dominated the growth. Therefore, the whole initial stages of Ag films formation included the adsorption of nanoparticles, the formation of clusters, the nucleation by the nanoparticles and clusters simultaneously, the islands formation, and the coalescence of islands. [ABSTRACT FROM AUTHOR]

The effect of driving frequency on the structure of silicon grown on Ag (111) film is investigated, which was prepared by using the very-high-frequency (VHF) (40.68 MHz and 60 MHz) magnetron sputtering. The energy and flux density of the ions impinging on the substrate are also analyzed. It is found that for the 60-MHz VHF magnetron sputtering, the surface of silicon on Ag (111) film exhibits a small cone structure, similar to that of Ag (111) film substrate, indicating a better microstructure continuity. However, for the 40.68-MHz VHF magnetron sputtering, the surface of silicon on Ag (111) film shows a hybrid structure of hollowed-cones and hollowed-particles, which is completely different from that of Ag (111) film. The change of silicon structure is closely related to the differences in the ion energy and flux density controlled by the driving frequency of sputtering. [ABSTRACT FROM AUTHOR]

Growth and structural properties of thin a-C films prepared by the 60 MHz very-high-frequency (VHF) magnetron sputtering were investigated. The energy and flux of ions impinging the substrate were also analyzed. It is found that the thin a-C films prepared by the 60 MHz sputtering have a lower growth rate, a smooth surface, and more sp3 contents. These features are related to the higher ion energy and the lower ions flux onto the substrate. Therefore, the 60 MHz VHF sputtering is more suitable for the preparation of thin a-C film with more sp3 contents. [ABSTRACT FROM AUTHOR]