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Legends for Supplementary Tables S1-S5 and Supplementary Figures S1-S2.

Supplementary Figures 1-5, Tables 1-2 from Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells

Supplementary Table S4. Aggressive hybrid protein signature and gene ontology.

Supplementary Figure S1. Background information for lung adenocarcinoma cell lines.

Supplementary Methods and References. Description of additional methods and procedures used in the study. Also includes Supplementary References.

NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19INK4d) and CDKN1B (p27Kip1), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL. [Cancer Res 2009;69(7):3060–8]

(1) Objective: This paper conducts a comparative study on the perceptual value of fabrics dyed with tea leaves and tea stems and explores the changes and differences in the Kansei image of the dyed fabrics to provide practical guidance for the product design dyed of tea leaves and tea stems based on the experimental results. (2) Methods: firstly, an effective dyeing method was selected through literature research to dye the samples. Secondly, Kansei words were collected and screened out, and the SD scale was established for a perceptual experiment. Thirdly, a factor analysis was performed on the quantified perceptual evaluation data to compare the changes in the fabric perceptual value before and after dyeing. A T-test and cluster analysis were used to study the difference between them. Finally, according to the fabric perceptual experience results, the product design was put into practice. (3) Conclusion: the perceptual value of all the fabrics dyed with Oolong tea leaves and tea stems were improved. Except for silk chiffon and Tencel, there was no significant difference between tea stems dyeing and tea leaves dyeing in other fabrics, which shows that tea stems dyeing has great perceptual value and reuse value.

ObjectiveTo profile gut microbiome-associated metabolites in serum and investigate whether these metabolites could distinguish individuals with colorectal cancer (CRC) or adenoma from normal healthy individuals.DesignIntegrated analysis of untargeted serum metabolomics by liquid chromatography-mass spectrometry and metagenome sequencing of paired faecal samples was applied to identify gut microbiome-associated metabolites with significantly altered abundance in patients with CRC and adenoma. The ability of these metabolites to discriminate between CRC and colorectal adenoma was tested by targeted metabolomic analysis. A model based on gut microbiome-associated metabolites was established and evaluated in an independent validation cohort.ResultsIn total, 885 serum metabolites were significantly altered in both CRC and adenoma, including eight gut microbiome-associated serum metabolites (GMSM panel) that were reproducibly detected by both targeted and untargeted metabolomics analysis and accurately discriminated CRC and adenoma from normal samples. A GMSM panel-based model to predict CRC and colorectal adenoma yielded an area under the curve (AUC) of 0.98 (95% CI 0.94 to 1.00) in the modelling cohort and an AUC of 0.92 (83.5% sensitivity, 84.9% specificity) in the validation cohort. The GMSM model was significantly superior to the clinical marker carcinoembryonic antigen among samples within the validation cohort (AUC 0.92 vs 0.72) and also showed promising diagnostic accuracy for adenomas (AUC=0.84) and early-stage CRC (AUC=0.93).ConclusionGut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.

Our study mainly reports the specific mechanisms of microRNA (miR)-874-3p on drug resistance in gastric cancer (GC). Clinical specimen was collected. The upstream long non-coding RNA (lncRNA) and the downstream gene of miR-874-3p were predicted using bioinformatic analysis with the results being ascertained with dual-luciferase reporter assay. The viability, apoptosis, migration and invasion of transfected GC cells with or without cisplatin (DDP) treatment were evaluated by Cell Counting Kit-8 (CCK-8), flow cytometric, Scratch, and Transwell assays. An animal xenograft model was constructed. Expressions of long intergenic non-coding RNA 00922 (LINC00922), miR-874-3p and potential target genes were quantified by quantitative real-time polymerase-chain reaction (qRT-PCR) and Western blot. MiR-874-3p, which was lower-expressed in drug-resistant GC tissues and cells, was upregulated to repress the viability, migration and invasion but enhance the apoptosis and sensitivity in GC cells with or without DDP resistance. Downregulation of miR-874-3p eliminated the effects of silenced LINC00922, a upstream lncRNA of miR-874-3p, on cell viability, apoptosis, migration and invasion, as well as the expressions of Glycerophosphodiester Phosphodiesterase Domain Containing 5 (GDPD5) and the downstream gene of miR-874-3p in DDP-resistant GC cells. GDPD5 silencing diminished the effects of miR-874-3p downregulation on GDPD5 expression, viability, migration and invasion of DDP-resistant GC cells. Additionally, LINC00922 silencing enhanced the inhibitory effect of DDP on tumor growth, whereas reversing the effects of DDP on LINC00922, miR-874-3p and GDPD5 expressions in tumors. MiR-874-3p, an miRNA, which is sponged by LINC00922 and targets GDPD5, inhibits the GC progression yet enhances the DDP sensitivity in GC.

Resistance to chemotherapeutic drugs limits the control of gastric cancer (GC) development. The study intended to probe into the mechanism of aquaporin 3 (AQP3) on the chemoresistance of GC. Cisplatin (CDDP)-resistant cells were constructed. Parental AGS and HGC-27 cells and their respective CDDP-resistant cells were transfected with AQP3 overexpression plasmid, AQP3 short hairpin RNA (sh-AQP3) and sh-Kruppel-like factor 5 (shKLF5). The expressions of AQP3 and factors related to autophagy (LC3 I, LC3 II, Atg5, Beclin-1, p62)/epithelial-mesenchymal transition (EMT; E-cadherin and snail) were assessed by Western blot and qRT-PCR. Cell counting kit-8 assay was adopted to test cell viability and half maximal inhibitory concentration (IC 50) was determined. Transwell assay was used for the examination of cell migration and invasion. The regulatory relationship of AQP3 and KLF5 was tested by chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays. AQP3 was highly-expressed in GC cells and its level was even higher in CDDP-resistant GC cells. AQP3 silencing inhibited viability, autophagy and EMT in CDDP-resistant GC cells, while AQP3 overexpression had the opposite effect. KLF5 positively modulated AQP3 in GC cells resistant to CDDP. KLF5 knockdown reversed AQP3-induced autophagy, viability, migration, invasion and EMT in CDDP-resistant GC cells. KLF5-modulated AQP3 activated autophagy to facilitate the resistance of GC to CDDP.

Expressive neural text-to-speech (TTS) systems incorporate a style encoder to learn a latent embedding as the style information. However, this embedding process may encode redundant textual information. This phenomenon is called content leakage. Researchers have attempted to resolve this problem by adding an ASR or other auxiliary supervision loss functions. In this study, we propose an unsupervised method called the "information sieve" to reduce the effect of content leakage in prosody transfer. The rationale of this approach is that the style encoder can be forced to focus on style information rather than on textual information contained in the reference speech by a well-designed downsample-upsample filter, i.e., the extracted style embeddings can be downsampled at a certain interval and then upsampled by duplication. Furthermore, we used instance normalization in convolution layers to help the system learn a better latent style space. Objective metrics such as the significantly lower word error rate (WER) demonstrate the effectiveness of this model in mitigating content leakage. Listening tests indicate that the model retains its prosody transferability compared with the baseline models such as the original GST-Tacotron and ASR-guided Tacotron.

Relational triples extraction aims to detect entity pairs (subjects, objects) along with their relations. Previous work failed to deal with complex relationship triples, such as overlapping triples and nested entities, and lacked semantic representation in the process of extracting entity pairs and relationships. To mitigate these issues, we propose a joint extraction model called ReMERT, which first decomposes the joint extraction task into three interrelated subtasks, namely RSE (Relation-specific Subject Extraction), RM (Relational Memory) module construction and OE (Object Extraction). The first subtask is to distinguish all subjects that may be involved with target relations, the second is to retrieve target relational representation from RM module, and the last is to identify corresponding objects for each specific (s, r) pair. Additionally, RSE and OE subtasks are further deconstructed into sequence labeling problems based on the proposed hierarchical binary tagging scheme. Owing to the reasonable decomposition strategy, the proposed model can fully capture the semantic interdependency between different subtasks, as well as reduce noise from irrelevant entity pairs. Experimental results show that the proposed method outperforms previous work by 0.8% (F1 score), achieving a new state-of-the-art on Chinese DuIE datasets. We also adopt sufficient experiments and obtain promising results both in public English NYT and Chinese DuIE datasets.

The multi-format Information Extraction (IE) task in Language and Intelligence Challenge 2021 (LIC2021) consists of three subtasks: Relation Extraction (RE), Sentence-level Event Extraction (SentEE) and Document-level Event Extraction (DocEE). Deep learning methods have made great progress in each subtask these years. However, most of them cannot solve these subtasks by a unified platform. In this paper, we develop a unified neural model with two-stage process, which adopt the Enhanced NER module in stage one to obtained the ELEMENTs and corresponding LABELs. In stage two, we designed the customized manoeuvres to solve challenges in different subtasks. The submission shows that our model achieves competitive performance, which ranks 3rd on the final leaderboard.

Background Aquaporin 3(AQP3) has been implicated in gastric intestinal metaplasia and gastric cancer, and considered as a biomarker to improve treatment strategy. Accumulating evidence suggests that AQP3 is involved in the gastric carcinogenesis and the disease progression. However, whether AQP3 is involved in the transformation from gastritis to gastric cancer remain elusive. In this study, we intended to realized the expression pattern and its significance of AQP3 in different gastric diseases. Methods A total of 101 patients diagnosed with gastric diseases were included in the study. A gastric tissue biopsy was taken from the gastric antrum during endoscopic examination. Expression of AQP3 protein is determined by immunohistochemistry using polyclonal rabbit anti-AQP3 antibody. Percentage of positive cells and staining intensity were counted and measured. Results The frequency of AQP3 positivity was similar between the disease types of chronic gastritis, gastric ulcer, gastric erosion, and atrophic gastritis, whereas the frequency of AQP3 positivity was significantly higher in patients with gastric intestinal metaplasia、gastric dysplasia 、gastric polyps and intestinal-type gastric adenocarcinoma than that in patients with gastritis, gastric ulcer, gastric erosion, or atrophic gastritis(p

The high color rendering index (CRI) and doping-free four-emitting-layer (EML) white orangic light-emitting diode (WOLED) with bipolar spacer layer was researched by different emitter sequence arrangements (positive emitter sequence: B-G-O-R, reverse emitter sequence: R-O-G-B). The resulting four-emitting-layer WOLEDs with different sequences show opposite CRI trends when voltage increases, which includes the decreased trend in B-G-O-R sequence and increased trend in R-O-G-B sequence. That leads to WOLEDs with different sequences exhibit the highest CRI at obviously distinguishing luminance, which are CRI of 86 @ 531 cd m−2 in B-G-O-R sequence and CRI of 87 @ 13,340 cd m−2 in R-O-G-B sequence, respectively. Meanwhile, the B-G-O-R and R-O-G-B sequences devices also exhibit a difference in the power efficiency. The different manifestations of CRI and effeciency characteristics are meticulously analyzed by a combined operation of energy transfer mechanism, carrier trap effect and the movement of carrier recombination zone in EML, resulting in a meaningful concept to design high CRI WOLEDs in different application scene.

Gastric cancer is one of the most common and deadly neoplasms with limited effective treatments. The emergence of the immunotherapy has brought great expectations for cancer patients. Sophoridine is extracted from the seeds of sophora alopecuroides and has various pharmacological actions including anti-tumor, anti-inflammatory, anti- arrhythmia and anti-virus. However, the effect of Sophoridine on gastric cancer microenvironment immunity and its underling mechanism remains poorly known. This study was aimed to investigate the effect of Sophoridine on the polarization status of gastric tumor-associated macrophages (TAMs) and its underlying mechanism. We isolated primary bone marrow-derived macrophages (BMDMs) and primary CD8

3539 Background: Gut microbiome and their metabolites have been revealed to be associated with the initiation and progression of colorectal cancer (CRC), and gut microbiome produced or associated metabolites could enter the circulation system. Methods: Integrated analysis of untargeted serum metabolomics by liquid chromatography–mass spectrometry (LS-MS) and metagenome sequencing of fecal samples derived from matched individuals were used to profile serum metabolites that are both significantly affected by CRC and co-related with the gut microbiome. Targeted LC-MS was further used to test the ability of these metabolites for discriminating CRC and adenoma from healthy individuals. Results: More than 300 gut microbiome–associated serum metabolites with significantly altered abundance in both colorectal carcinoma (CRC) and adenoma patients have been identified. A panel of eight gut microbiome–associated serum metabolites (GMSM panel) was established and accurately discriminated CRC and adenoma from normal population. The GMSM panel–based CRC and colorectal adenoma prediction model yielded an area under the curve (AUC) of 0.94 (95% confidence interval: 0.90–0.99) and AUC of 0.91 (sensitivity 82%, specificity 91%) in the training and validation set respectively. This GMSM model shows significantly superior performance to the clinical marker carcinoembryonic antigen (CEA) (AUC 0.72), and more importantly, it suggests promising diagnostic potential in detecting adenoma (AUC = 0.81) and early-stage CRC (AUC = 0.91). Conclusions: Our results indicate that gut microbiome reprogramming in CRC patients is associated with the alterations of the serum metabolome, and these gut microbiome–associated serum metabolites has potential application for the detection of earlier CRC and adenoma.

// Yixuan Gong 1, * , Li Wang 2, 3, * , Uma Chippada-Venkata 1 , Xudong Dai 2, 3 , William K. Oh 1 , Jun Zhu 1, 2, 3 1 The Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Jun Zhu, email: jun.zhu@mssm.edu William K. Oh, email: William.oh@mssm.edu Keywords: Bayesian networks, NLGN4Y, prostate cancer, negative regulator, gene expression Received: April 15, 2016 Accepted: August 24, 2016 Published: September 10, 2016 ABSTRACT To understand the heterogeneity of prostate cancer (PCa) and identify novel underlying drivers, we constructed integrative molecular Bayesian networks (IMBNs) for PCa by integrating gene expression and copy number alteration data from published datasets. After demonstrating such IMBNs with superior network accuracy, we identified multiple sub-networks within IMBNs related to biochemical recurrence (BCR) of PCa and inferred the corresponding key drivers. The key drivers regulated a set of common effectors including genes preferentially expressed in neuronal cells. NLGN4Y—a protein involved in synaptic adhesion in neurons—was ranked as the top gene closely linked to key drivers of myogenesis subnetworks. Lower expression of NLGN4Y was associated with higher grade PCa and an increased risk of BCR. We show that restoration of the protein expression of NLGN4Y in PC-3 cells leads to decreased cell proliferation, migration and inflammatory cytokine expression. Our results suggest that NLGN4Y is an important negative regulator in prostate cancer progression. More importantly, it highlights the value of IMBNs in generating biologically and clinically relevant hypotheses about prostate cancer that can be validated by independent studies.

We have demonstrated color stable white organic light-emitting diodes (WOLEDs) with bipolar mixed spacer based on ultrathin non-doped phosphorescent emitting layers (EMLs). The introduced bipolar mixing spacer which contributes to the uniform distribution of recombined excitons plays an important role in stabilizing the spectrum. Through different emitters orders: blue/green/orange (named B-G-O) and orange/green/blue (named O-G-B), the thickness ratio of the EML at the anode and cathode side is proved to be the core factor on spectral stability. The spectral stability is attributed to two key mechanisms: sequential energy transfer offsets the change of emission intensity caused by exciton recombination zone (RZ) drift under different voltages, and direct carrier trapping effect compensates the emission intensity at low voltage. The resulting three-color WOLED shows an insignificant chromatic coordinate change of (0.001, 0.001) when the luminance increases from 1000 cd/m2 to 10000 cd/m2. This discovery provides a significant method for achieving high-performance WOLED with superior color stability.

Tetra-chromatic (Blue–Green–Red–Orange) white organic light-emitting diodes (WOLEDs) with superior color stability was demonstrated. Strong carrier trapping effects of red dyes cause significant color shift in multi-color WOLEDs. The high color stability here is attributed to the decrease of red dye trapping sites and enhancement of effective energy transfer to red dye while maintaining appropriate exciton concentration near red dye. As luminance increased from 1000 to 10 000 cd m−2, variations in Commission Internationale de L'Eclairage are merely (0.007, 0.007). Furthermore, this color-stable WOLED achieved a color rendering index close to 90 simultaneously. Our work shows the manipulation of red dye is crucial for achieving superior color stability in multi-color WOLEDs.

Gastric cancer is one of the most common and deadly neoplasms with limited effective treatments. The emergence of the immunotherapy has brought great expectations for cancer patients. Sophoridine is extracted from the seeds of sophora alopecuroides and has various pharmacological actions including anti-tumor, anti-inflammatory, anti- arrhythmia and anti-virus. However, the effect of Sophoridine on gastric cancer microenvironment immunity and its underling mechanism remains poorly known. This study was aimed to investigate the effect of Sophoridine on the polarization status of gastric tumor-associated macrophages (TAMs) and its underlying mechanism. We isolated primary bone marrow-derived macrophages (BMDMs) and primary CD8+ T cells to perform coculture assay. Sophoridine educated TAMs polarize to M1-TAMs and suppressed M2-TAMs polarization through TLR4/IRF3 axis. Sophoridine-treated TAMs exhibited stronger pro-inflammatory function through upregulation the expression of INOS, IFN-β and IL-12α, and downregulation the expression of Arg-1, CD206 and IL-10. Sophoridine -primed TAMs increased the proliferation and cytotoxic function of CD8+ T by upregulating the expression of Granzyme-B, TNF-α and Perforin, and downregulated the expression of CD8+ T cells function exhaustion markers PD-1, Tim-3 and Lag-3. Furthermore, Sophoridine inhibited the migration ability of macrophage by decrease the CCR2 expression. Thus, Sophoridine acted on macrophages and CD8+ T cells to reshape gastric cancer immune microenvironment. Our studies provided preclinical basis for clinical application of Sophoridine.

In this paper, efficient phosphorescent white organic light-emitting diodes (WOLEDs) were fabricated based on ultrathin doping-free emissive layers and mixed bipolar interlayers. The energy transfer processes were proved via the research of WOLEDs with different interlayer thicknesses and transient photoluminescence lifetime. WOLEDs with optimized thickness of doping-free emissive layers show maximum current efficiency of 47.8 cd/A and 44.9 cd/A for three-colors and four-colors WOLEDs, respectively. The Commission Internationale de L’Eclairage coordinates shows a very slight variation of ( ± 0.02, ± 0.02) from 5793 cd/m2 to 11370 cd/m2 for three-colors WOLEDs and from 3038 cd/m2 to 13720 cd/m2 for four-colors WOLEDs, respectively. The stability of the spectra is attributed to the stable and sequential energy transfer among the various dyes. The color temperature of four-colors WOLEDs can be obtained from 2659 to 6636 by adjusting the thickness of ultrathin emissive layer.

Endoplasmic reticulum resident protein 44 (ERp44) is a member of the protein disulfide isomerase family and functions in oxidative protein folding in the endoplasmic reticulum. A structurally flexible C-terminal tail (C-tail) of ERp44 plays critical roles in dynamically regulating ERp44's function in protein folding quality control. The structure-function dynamics of ERp44's C-tail may be studied further using fluorescence and other techniques, if methods are found to label the C-tail site-specifically with a fluorescent group or segmentally with other desired labels. Here we have developed such methods, employing split inteins capable of protein trans-splicing, and identifying atypical S1 split inteins able to function efficiently at a suitable split site in the ERp44 sequence. One method demonstrated segmental expression of ERp44 for segmental labeling of the C-tail, another method efficiently added a commercially available fluorescent group to the C-terminus of ERp44, and both methods may also be generally useful for studying other proteins.

Site-specific protein labeling are powerful means of protein research and engineering; however, new and improved labeling methods are greatly needed. Split inteins catalyze a protein trans-splicing reaction that can be used for enzymatic and nearly seamless protein labeling. Non-canonical S11 split intein has been used in an earlier method of protein C-terminal labeling; however, its relatively large (~150 aa) N-intein fused to the target protein often hindered protein expression, folding, and solubility. To solve this problem, here, we have designed and demonstrated a new method of protein C-terminal labeling, by first engineering a functional non-canonical S1 split intein that has an extremely small (12 aa) N-intein and a cysteine-free C-intein. An engineered Rma DnaB S1 split intein was modified to have a cysteine-free C-intein, while still retaining its robust trans-splicing function, which permitted the C-extein in a C-precursor to have a single cysteine for easy and specific linkage with desired labeling groups. The resulting new and generally useful method has two unique advantages: (1) The extremely small (12 aa) N-intein, which must be fused to the C terminus of the target protein, is less likely to hinder the protein expression, folding, and solubility; and (2) the single cysteine in the C-extein may be readily linked to a variety of labeling or modification groups using commercially available reagents.

As an index of maintaining low fuel consumption, the digging force of an excavator is affected fully by the performance of the hydraulic actuators including boom cylinder, stick cylinder, and bucket cylinder. The seals are used widely in a fluid power system to prevent fluid leakage. However, wear induces changes in the diameter of the seal's cross-section area, having an effect on the sealing capability of seals. This article proposes a model for performance degradation induced by wear of a hydraulic actuator of an excavator. The model in this article describes the physical process of performance degradation of a hydraulic actuator by analyzing piston response when wear occurs. The model includes a dynamic model of a hydraulic actuator, a model of squeezing stress and deformation of a compressed elastomeric O-ring seal, a wear model of a seal, and a leak rate model. These models can be used for deducing the laws of performance degradation of a hydraulic actuator of an excavator and for predicting the useful life of a key component such as the seal. Finally, based on the established model, simulation results of a hydraulic actuator’s response are provided.

Color-stable white organic light-emitting diode (WOLED) with bipolar mixed spacer based on ultrathin non-doped phosphorescent emitting layers was investigated. We find that the location and thickness of Bis(3,5-difluoro-2-(2-pyridyl) phenyl-(2-carboxypyridyl)iridium(III) (FIrPic) play a critical role on the spectral stability. Transient PL lifetime results show that the spectral variations with the driving voltage can be effectively controlled by enhanced energy transfer or weakened energy transfer respectively depending on different location of FIrPic. Meanwhile, green layer, located between blue layer and orange layer, acts an indispensable role in keeping the color stability by alleviating triplet–triplet annihilation and maintaining sequential energy transfer. The most stable spectrum of WOLED can be obtained with the change in Commission Internationale de L'Eclairage coordinates less than (0.001, 0.002) as the luminance increase from 697 cd m−2 to about 16 550 cd m−2 when FIrPic is on anode side. This discovery provides a significant method for achieving high-quality WOLEDs with superior color stability.

Under severe operating conditions, the thermal effects and various deformations play an important role in determining the performance of misaligned plain journal bearings. However, the thermal effects and various deformations are rarely considered simultaneously in most studies on the misaligned plain journal bearings. In this article, a comprehensive thermoelastohydrodynamic model of the misaligned plain journal bearings is developed that involves the synthetic solution of the generalized Reynolds equation, three-dimensional energy equation, and heat conduction equations of the solids. Based on this model, series of simulation results are provided to examine the influence of the thermal effects and deformations on the behavior of the misaligned plain journal bearings. In addition, the comparisons between the thermohydrodynamic and complete thermoelastohydrodynamic model are also presented for different misalignment angle and magnitude. Results show that the thermal effects and various deformations should not be ignored because of their significant influence on the film thickness, film pressure as well as other bearings characteristics.

For the definition of knowledge flow, knowledge-flow control and knowledge-acquisition in integrated product design within distributed knowledge resources environment, this paper studies the structural modeling of design activity for integrated product design. The common features of integrated design in distributed resources environment are summarized as follows: centering on specific design requirements, organizing related design resources to perform design activities, outputting design results, carrying on value analysis of design results, and then making design decisions on the basis of value analysis. Based on the common features, a structural model of integrated design activities in distributed resources environment is built, which presents the structural expression of knowledge flow by defining the design requirements, the design resource input, the result output, the design activities, the relationship between the design activities, and the values of the design activities. Design activities at different levels are defined according to the design process models at different levels. A design activity that has been defined can be packaged into design components. The essence of integrated design lies in knowledge integration, which is to be realized by defining the input and output relationship between the design components and the knowledge components.

Design for life-time performance and proper maintenance measures are usually needed to prolong the mean-time-between-failures of complex equipments such as internal combustion engines. To reach this, it is important to obtain the information of time-varying system performance in design stage and to identify the structural change at each moment. So a multidisciplinary model based method is studied in this paper to unify the time-varying performance(TVP) prediction and system identification(SI) of equipments. The related multidisciplinary model in this paper should be not only precise to give simulation results but also sensitive to the variation of system parameters. So the varying history of system performance along with the structural change can be obtained from the model. Then the value of system parameters can be identified by seeking roots with given detected responding data and relationship between system responding data and system parameters. A case study on a low power gasoline engine shows that the method presented in this paper can provide useful information for the development and maintenance of complex equipments.

The hypoxia-inducible factor (HIF) pathway is essential for cell survival under low oxygen and plays an important role in tumor cell homeostasis. We investigated the function of miR-210, the most prominent microRNA upregulated by hypoxia and a direct transcriptional target of HIFs. miR-210 expression was elevated in multiple cancer types and correlated with metastasis of breast and melanoma tumors. miR-210 overexpression in cancer cell lines bypassed hypoxia-induced cell cycle arrest and partially reversed the hypoxic gene expression signature. We identified MNT, a known MYC antagonist, as a miR-210 target. MNT mRNA contains multiple miR-210 binding sites in the 3' UTR and its knockdown phenocopied miR-210 overexpression. Furthermore, loss of MYC abolished miR-210-mediated override of hypoxia-induced cell cycle arrest. Comparison of miR-210 and MYC overexpression with MNT knockdown signatures also indicated that miR-210 triggered a "MYC-like" transcriptional response. Thus, miR-210 influences the hypoxia response in tumor cells through targeting a key transcriptional repressor of the MYC-MAX network.

In this paper, we will present a design of a DDS based frequency synthesizer whose output is 67∲83MHz, and which will be used in an X band sweep frequency source as the phase detect frequency of PLL. According to the analysis of DDS structure and operating principle, we can get the output with excellent frequency switching time, low phase noise and extremely tiny resolution. And we can use some methods to make the spurs as small as possible.

Epithelial-to-mesenchymal transition (EMT) is a key process associated with tumor progression and metastasis. To define molecular features associated with EMT states, we undertook an integrative approach combining mRNA, miRNA, DNA methylation, and proteomic profiles of 38 cell populations representative of the genomic heterogeneity in lung adenocarcinoma. The resulting data were integrated with functional profiles consisting of cell invasiveness, adhesion, and motility. A subset of cell lines that were readily defined as epithelial or mesenchymal based on their morphology and E-cadherin and vimentin expression elicited distinctive molecular signatures. Other cell populations displayed intermediate/hybrid states of EMT, with mixed epithelial and mesenchymal characteristics. A dominant proteomic feature of aggressive hybrid cell lines was upregulation of cytoskeletal and actin-binding proteins, a signature shared with mesenchymal cell lines. Cytoskeletal reorganization preceded loss of E-cadherin in epithelial cells in which EMT was induced by TGFβ. A set of transcripts corresponding to the mesenchymal protein signature enriched in cytoskeletal proteins was found to be predictive of survival in independent datasets of lung adenocarcinomas. Our findings point to an association between cytoskeletal and actin-binding proteins, a mesenchymal or hybrid EMT phenotype and invasive properties of lung adenocarcinomas. Cancer Res; 75(9); 1789–800. ©2015 AACR.

RNA interference (RNAi) has great potential as a tool for studying gene function in mammals. However, the specificity and magnitude of the in vivo response to RNAi remains to be fully characterized. A molecular and phenotypic comparison of a genetic knockout mouse and the corresponding knockdown version would help clarify the utility of the RNAi approach. Here, we used hydrodynamic delivery of small interfering RNA (siRNA) to knockdown peroxisome proliferator activated receptor alpha (Ppara), a gene that is central to the regulation of fatty acid metabolism. We found that Ppara knockdown in the liver results in a transcript profile and metabolic phenotype that is comparable to those of Ppara-/- mice. Combining the profiles from mice treated with the PPARalpha agonist fenofibrate, we confirmed the specificity of the RNAi response and identified candidate genes proximal to PPARalpha regulation. Ppara knockdown animals developed hypoglycemia and hypertriglyceridemia, phenotypes observed in Ppara-/- mice. In contrast to Ppara-/- mice, fasting was not required to uncover these phenotypes. Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies.

In rodents, treatment with peroxisome proliferator-activated receptor alpha (PPARalpha) agonists results in peroxisome proliferation, hepatocellular hypertrophy, and hepatomegaly. Drugs in the fibrate class of PPARalpha agonists have also been reported to produce rare skeletal muscle toxicity. Although target-driven hepatic effects of PPARalpha treatment have been extensively studied, a characterization of the transcriptional effects of this nuclear receptor/transcription factor on skeletal muscle responses has not been reported. In this study we investigated the effects of PPARalpha agonists on skeletal muscle gene transcription in rats. Further, since statins have been reported to preferentially effect type II muscle fibers, we compared PPARalpha signaling effects between type I and type II muscles. By comparing the transcriptional responses of agonists that signal through different nuclear receptors and using a selection/deselection analytical strategy based on ANOVA, we identified a PPARalpha activation signature that is evident in type I (soleus), but not type II (quadriceps femoris), skeletal muscle fibers. The fiber-type-selective nature of this response is consistent with increased fatty acid uptake and beta-oxidation, which represent the major clinical benefits of the hypolipidemic compounds used in this study, but does not reveal any obvious off-target pathways that may drive adverse effects.

To examine species-specific aspects of the induction of absorption, distribution, metabolism and excretion (ADME)-related genes, we used 25 000 gene oligonucleotide microarrays to construct a rodent gene-response compendium that compared hepatic gene expression profiles and developed consensus aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) ligand signatures relevant to drug clearance. Twenty-six inducer compounds were chosen from the literature. Rats and mice received one of six dose levels (log2 dose escalation, 32-fold dose range) of each compound daily for 3 days. Animals were necropsied 6-9 h after the last dose, and tissues were collected for RNA analysis. Hepatic gene expression profiles were obtained using Rosetta Resolver expression analysis system, and ADME-related genes were extracted. Cross-talk among nuclear receptors or hepatoxicity at high dose levels resulted in large signatures (usually1000 genes at p0.01) for most compounds. After ADME gene transcript enrichment, agglomerative clustering separated AhR ligands from CAR/PXR ligands, but it was difficult to distinguish CAR from PXR ligands. Consensus signatures were derived from groups of AhR, CAR and PXR ligands; and cross-talk among responding genes was determined. Many compounds had distinct log dose-response profiles, and relative potencies for ligands were established. Robust responses by CYP1A1, CYP2B10 (CAR responsive in mice) and CYP2B15 (CAR responsive in rats) and CYP3A1 (PXR responsive in rats) were used to benchmark the relative potency of different ligands and to determine the relative selectivity for AhR, CAR or PXR. By using a compendium of gene expression profiles, we defined species-specific induction patterns across the ADME transcriptome.

Oligonucleotide microarrays were used to study the variability of pharmacokinetics and drug metabolism (PKDM)-related gene expression in 75 normal human livers. The objective was to define and use absorption, distribution, metabolism and excretion (ADME) gene expression variability to discern co-regulated genes and potential surrogate biomarkers of inducible gene expression. RNA was prepared from donor tissue and hybridized on Agilent microarrays against an RNA mass balanced pool from all donors. Clustering of PKDM gene sets revealed donors with distinct patterns of gene expression that grouped genes known to be regulated by the nuclear receptor, pregnane X-receptor (PXR). Fold range metrics and frequency distributions from the heterogeneous human population were used to define the variability of individual PKDM genes in the 75 human livers and were placed in context by comparing expression data with basal ADME gene expression variability in an inbred and diet/environment controlled population of 27 Rhesus livers. The most variable genes in the hepatic transcriptome were mainly related to drug metabolism, intermediary metabolism, inflammation and cell cycle control. Unique patterns of expression across 75 individuals of inducible ADME gene expression allowed their expression to be correlated with the expression of many other genes. Correlated genes for AhR, CAR and PXR responsive genes (CYP1A2, CYP2B6 and CYP3A4) were identified that may be co-regulated and, therefore, provide clues to the identity of surrogate gene or protein markers for CYP induction. In conclusion, microarrays were used to define the variable expression of hepatic ADME genes in a diverse human population, the expression variability of ADME genes was compared with the expression variability in an inbred population of Rhesus monkeys, and genes were defined that may be co-regulated with important inducible CYP genes.

Ligand-mediated activation of the pregnane X receptor (PXR, NR1I2) is postulated to affect both hepatic and intestinal gene expression, because of the presence of this nuclear receptor in these important drug metabolizing organs; as such, activation of this receptor may elicit the coordinated regulation of PXR target genes in both tissues. Induction of hepatic and intestinal drug metabolism can contribute to the increased metabolism of drugs, and can result in adverse or undesirable drug-drug interactions. 2(S)-((3,5-bis(Trifluoromethyl)benzyl)-oxy)-3(S)phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742694) is a potent activator of the rat PXR and was characterized for its effects on hepatic and intestinal gene expression in female Sprague-Dawley rats by DNA microarray analysis. Transcriptional profiling in liver and small intestine revealed that L-742694 and dexamethasone (DEX) induced the prototypical battery of PXR target genes in liver, including CYP3A, Oatp2, and UGT1A1. In addition, both DEX and L-742694 induced common gene expression profiles that were specific to liver or small intestine, but there was a distinct lack of coordinated gene expression of genes common to both tissues. This pattern of gene regulation occurred in liver and small intestine independent of PXR, constitutive androstane receptor, or hepatic nuclear factor-4alpha expression, suggesting that other factors are involved in controlling the extent of coordinated gene expression in response to a PXR agonist. Overall, these results suggest that ligand-mediated activation of PXR and induction of hepatic, rather than small intestinal, drug metabolism genes would contribute to the increased metabolism of orally administered pharmaceuticals.

Product design is a process of knowledge flowing and integrating. From the perspective, product design in distributed resource environment could be defined as the constructing process of a product knowledge model to satisfy specific needs of customers. This paper studies and builds structured models of product design knowledge, i.e. a customer need knowledge model, a DE knowledge model and a RU knowledge model. A product design knowledge model is the structured specification of a desired artifact including customer Need, Function with Environment (constraints), Physical principle with its Structure and Implement method and Technology detail (FEPSAT). A customer need knowledge model is constructed by customer Group feature, need Content and product Meaning (GCM). The DE knowledge model is constructed by Value, Profession, Culture and Experience background (VPCE). The RU knowledge model is built by knowledge service Content, service Input and service Output (CIO). The evolution of the product design knowledge models and the interaction with each other were analyzed.Copyright © 2014 by ASME

Previous studies suggest that oligodendrocytes express trophic molecules, including neurotrophins. These molecules have been shown to influence nearby neurons. To determine whether neuronal signals may, in turn, affect oligodendrocyte-derived trophins, we examined regulation of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) mRNA expression in cultured oligodendrocytes of the basal forebrain. Neuronal signals had distinct effects on individual neurotrophins. KCl elicited increases in BDNF mRNA, but did not affect expression of NGF or NT-3. The cholinergic agonist, carbachol, increased expression of NGF, but did not affect expression of BDNF or NT-3. Glutamate elicited a decrease in BDNF, but did not affect expression of NGF or NT-3. This glutamate effect is not due to toxicity, since the number of total cells was unchanged, while the number of mature myelin basic protein positive (MBP+) cells increased. Our observations suggest that individual neuronal signals distinctly influence the trophic function of oligodendrocytes.

Potential roles of trophins in the normal and injured spinal cord are largely undefined. However, a number of recent studies suggest that adult spinal cord expresses neurotrophin receptors and responds to the neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3), particularly after injury. The data indicate that trophins may enhance regrowth after damage and may represent a new therapeutic approach to injury. Neurotrophins are reportedly present in the spinal cord, but the cellular localization is unknown. This information is critical to begin delineating mechanisms of actions. To approach this problem, we examined whether spinal cord glia express BDNF and NT3 in vivo and have begun to define cellular distribution. Specific antibodies directed against the neurotrophins were utilized to visualize neurotrophin protein. Initial studies indicated that small cells in the white matter of adult rat spinal cord express BDNF and NT3. Large neurotrophin-positive neurons were also identified in the ventral cord. To identify the neurotrophin-positive cells, co-localization studies were performed utilizing neurotrophin polyclonal antisera together with monoclonal antibodies directed against the astrocyte marker, glial fibrillary acidic protein (GFAP). In the white matter of adult spinal cord, GFAP-positive and GFAP-negative cells expressed BDNF and NT3. Our study suggests that astrocyte and non-astrocyte cells provide trophic support to the adult spinal cord. J. Neurosci. Res. 56:1–7, 1999. © 1999 Wiley-Liss, Inc.

To evaluate the relationship among indoor air pollution, depression and oncogenesis of lung cancer.An 1:3 matched case-control study was carried out. Conditional logistic regression was applied to process the data.After some confounding factors were adjusted, the ORs increased 122% and 113% for the amount of coal using ≥46kg/m² and heating by coal stove respectively. The ORs elevated more than five-folds for disharmony and rupture of marriage, difference of accommodation and acclimation by oneself and human relationship respectively. The risk of lung caner obviously increased for frequent exposure to indoor cooking smoke combinated with depressed mood or mental scar respectively.The indoor air pollution, depression and mental scar are important factors of oncogenesis of lung cancer.

NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19INK4d) and CDKN1B (p27Kip1), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL. [Cancer Res 2009;69(7):3060–8]