bim binary intensity: Topics by Science.gov

Sample records for bim binary intensity

Efficient processing of MPEG-21 metadata in the binary domain

NASA Astrophysics Data System (ADS)

Timmerer, Christian; Frank, Thomas; Hellwagner, Hermann; Heuer, Jörg; Hutter, Andreas

2005-10-01

XML-based metadata is widely adopted across the different communities and plenty of commercial and open source tools for processing and transforming are available on the market. However, all of these tools have one thing in common: they operate on plain text encoded metadata which may become a burden in constrained and streaming environments, i.e., when metadata needs to be processed together with multimedia content on the fly. In this paper we present an efficient approach for transforming such kind of metadata which are encoded using MPEG's Binary Format for Metadata (BiM) without additional en-/decoding overheads, i.e., within the binary domain. Therefore, we have developed an event-based push parser for BiM encoded metadata which transforms the metadata by a limited set of processing instructions - based on traditional XML transformation techniques - operating on bit patterns instead of cost-intensive string comparisons.
Pycnonuclear reaction rates for binary ionic mixtures

NASA Technical Reports Server (NTRS)

Ichimaru, S.; Ogata, S.; Van Horn, H. M.

1992-01-01

Through a combination of compositional scaling arguments and examinations of Monte Carlo simulation results for the interparticle separations in binary-ionic mixture (BIM) solids, we have derived parameterized expressions for the BIM pycnonuclear rates as generalizations of those in one-component solids obtained previously by Salpeter and Van Horn and by Ogata et al. We have thereby discovered a catalyzing effect of the heavier elements, which enhances the rates of reactions among the lighter elements when the charge ratio exceeds a critical value of approximately 2.3.
Probability of identification (POI): a statistical model for the validation of qualitative botanical identification methods

USDA-ARS?s Scientific Manuscript database

A qualitative botanical identification method (BIM) is an analytical procedure which returns a binary result (1 = Identified, 0 = Not Identified). A BIM may be used by a buyer, manufacturer, or regulator to determine whether a botanical material being tested is the same as the target (desired) mate...
Probability of identification: a statistical model for the validation of qualitative botanical identification methods.

PubMed

LaBudde, Robert A; Harnly, James M

2012-01-01

A qualitative botanical identification method (BIM) is an analytical procedure that returns a binary result (1 = Identified, 0 = Not Identified). A BIM may be used by a buyer, manufacturer, or regulator to determine whether a botanical material being tested is the same as the target (desired) material, or whether it contains excessive nontarget (undesirable) material. The report describes the development and validation of studies for a BIM based on the proportion of replicates identified, or probability of identification (POI), as the basic observed statistic. The statistical procedures proposed for data analysis follow closely those of the probability of detection, and harmonize the statistical concepts and parameters between quantitative and qualitative method validation. Use of POI statistics also harmonizes statistical concepts for botanical, microbiological, toxin, and other analyte identification methods that produce binary results. The POI statistical model provides a tool for graphical representation of response curves for qualitative methods, reporting of descriptive statistics, and application of performance requirements. Single collaborator and multicollaborative study examples are given.
Thermodynamic functions, freezing transition, and phase diagram of dense carbon-oxygen mixtures in white dwarfs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iyetomi, H.; Ogata, S.; Ichimaru, S.

1989-07-01

Equations of state for dense carbon-oxygen (C-O) binary-ionic mixtures (BIM's) appropriate to the interiors of white dwarfs are investigated through Monte Carlo simulations, by solution of relevant integral equations andvariational calculations in the density-functional formalism. It is thereby shown that the internal energies of the C-O BIM solids and fluids both obey precisely the linear mixing formulas. We then present an accurate calculation of the phase diagram associated with freezing transitions in such BIM materials, resulting in a novel prediction of an azeotropic diagram. Discontinuities of the mass density across the azeotropic phase boundaries areevaluated numerically for application to amore » study of white-dwarf evolution.« less
Targeting the Regulatory Machinery of BIM for Cancer Therapy

PubMed Central

Harada, Hisashi; Grant, Steven

2013-01-01

BIM represents a BH3-only proapoptotic member of the BCL-2 family of apoptotic regulatory proteins. Recent evidence suggests that in addition to its involvement in normal homeostasis, BIM plays a critical role in tumor cell biology, including the regulation of tumorigenesis through activities as a tumor suppressor, tumor metastasis, and tumor cell survival. Consequently, BIM has become the focus of intense interest as a potential target for cancer chemotherapy. The control of BIM expression is complex, and involves multiple factors, including epigenetic events (i.e., promoter acetylation or methylation, miRNA), transcription factors, posttranscriptional regulation, and posttranslational modifications, most notably phosphorylation. Significantly, the expression of BIM by tumor cells has been shown to play an important role in determining the response of transformed cells to not only conventional cytotoxic agents, but also to a broad array of targeted agents that interrupt cell signaling and survival pathways. Furthermore, modifications in BIM expression may be exploited to improve the therapeutic activity and potentially the selectivity of such agents. It is likely that evolving insights into the factors that regulate BIM expression will ultimately lead to novel BIM-based therapeutic strategies in the future. PMID:22856430
Preliminary Evaluation of BIM-based Approaches for Schedule Delay Analysis

NASA Astrophysics Data System (ADS)

Chou, Hui-Yu; Yang, Jyh-Bin

2017-10-01

The problem of schedule delay commonly occurs in construction projects. The quality of delay analysis depends on the availability of schedule-related information and delay evidence. More information used in delay analysis usually produces more accurate and fair analytical results. How to use innovative techniques to improve the quality of schedule delay analysis results have received much attention recently. As Building Information Modeling (BIM) technique has been quickly developed, using BIM and 4D simulation techniques have been proposed and implemented. Obvious benefits have been achieved especially in identifying and solving construction consequence problems in advance of construction. This study preforms an intensive literature review to discuss the problems encountered in schedule delay analysis and the possibility of using BIM as a tool in developing a BIM-based approach for schedule delay analysis. This study believes that most of the identified problems can be dealt with by BIM technique. Research results could be a fundamental of developing new approaches for resolving schedule delay disputes.
N-H···S Interaction Continues To Be an Enigma: Experimental and Computational Investigations of Hydrogen-Bonded Complexes of Benzimidazole with Thioethers.

PubMed

Wategaonkar, Sanjay; Bhattacherjee, Aditi

2018-05-03

The N-H···S hydrogen bond, even though classified as an unconventional hydrogen bond, is found to bear important structural implications on protein structure and folding. In this article, we report a gas-phase study of the N-H···S hydrogen bond between the model compounds of histidine (benzimidazole, denoted BIM) and methionine (dimethyl sulfide, diethyl sulfide, and tetrahydrothiophene, denoted Me 2 S, Et 2 S, and THT, respectively). A combination of laser spectroscopic methods such as laser-induced fluorescence (LIF), two-color resonant two-photon ionization (2cR2PI), and fluorescence depletion by infrared spectroscopy (FDIR) is used in conjunction with DFT and ab initio calculations to characterize the nature of this prevalent H-bonding interaction in simple bimolecular complexes. A single conformer was found to exist for the BIM-Me 2 S complex, whereas the BIM-Et 2 S and BIM-THT complexes showed the presence of three and two conformers, respectively. These conformers were characterized on the basis of IR spectroscopic results and electronic structure calculations. Quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO), and energy decomposition (NEDA) analyses were performed to investigate the nature of the N-H···S H-bond. Comparison of the results with the N-H···O type of interactions in BIM and indole revealed that the strength of the N-H···S H-bond is similar to N-H···O in these binary gas-phase complexes.
Alternating phase-shift mask and binary mask for 45-nm node and beyond: the impact on the mask error control

NASA Astrophysics Data System (ADS)

Kojima, Yosuke; Shirasaki, Masanori; Chiba, Kazuaki; Tanaka, Tsuyoshi; Inazuki, Yukio; Yoshikawa, Hiroki; Okazaki, Satoshi; Iwase, Kazuya; Ishikawa, Kiichi; Ozawa, Ken

2007-05-01

For 45 nm node and beyond, the alternating phase-shift mask (alt. PSM), one of the most expected resolution enhancement technologies (RET) because of its high image contrast and small mask error enhancement factor (MEEF), and the binary mask (BIM) attract attention. Reducing CD and registration errors and defect are their critical issues. As the solution, the new blank for alt. PSM and BIM is developed. The top film of new blank is thin Cr, and the antireflection film and shielding film composed of MoSi are deposited under the Cr film. The mask CD performance is evaluated for through pitch, CD linearity, CD uniformity, global loading, resolution and pattern fidelity, and the blank performance is evaluated for optical density, reflectivity, sheet resistance, flatness and defect level. It is found that the performance of new blank is equal to or better than that of conventional blank in all items. The mask CD performance shows significant improvement. The lithography performance of new blank is confirmed by wafer printing and AIMS measurement. The full dry type alt. PSM has been used as test plate, and the test results show that new blank can almost meet the specifications of pi-0 CD difference, CD uniformity and process margin for 45 nm node. Additionally, the new blank shows the better pattern fidelity than that of conventional blank on wafer. AIMS results are almost same as wafer results except for the narrowest pattern. Considering the result above, this new blank can reduce the mask error factors of alt. PSM and BIM for 45 nm node and beyond.
Transforming BIM to BEM: Generation of Building Geometry for the NASA Ames Sustainability Base BIM

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Donnell, James T.; Maile, Tobias; Rose, Cody

Typical processes of whole Building Energy simulation Model (BEM) generation are subjective, labor intensive, time intensive and error prone. Essentially, these typical processes reproduce already existing data, i.e. building models already created by the architect. Accordingly, Lawrence Berkeley National Laboratory (LBNL) developed a semi-automated process that enables reproducible conversions of Building Information Model (BIM) representations of building geometry into a format required by building energy modeling (BEM) tools. This is a generic process that may be applied to all building energy modeling tools but to date has only been used for EnergyPlus. This report describes and demonstrates each stage inmore » the semi-automated process for building geometry using the recently constructed NASA Ames Sustainability Base throughout. This example uses ArchiCAD (Graphisoft, 2012) as the originating CAD tool and EnergyPlus as the concluding whole building energy simulation tool. It is important to note that the process is also applicable for professionals that use other CAD tools such as Revit (“Revit Architecture,” 2012) and DProfiler (Beck Technology, 2012) and can be extended to provide geometry definitions for BEM tools other than EnergyPlus. Geometry Simplification Tool (GST) was used during the NASA Ames project and was the enabling software that facilitated semi-automated data transformations. GST has now been superseded by Space Boundary Tool (SBT-1) and will be referred to as SBT-1 throughout this report. The benefits of this semi-automated process are fourfold: 1) reduce the amount of time and cost required to develop a whole building energy simulation model, 2) enable rapid generation of design alternatives, 3) improve the accuracy of BEMs and 4) result in significantly better performing buildings with significantly lower energy consumption than those created using the traditional design process, especially if the simulation model was used as a predictive benchmark during operation. Developing BIM based criteria to support the semi-automated process should result in significant reliable improvements and time savings in the development of BEMs. In order to define successful BIMS, CAD export of IFC based BIMs for BEM must adhere to a standard Model View Definition (MVD) for simulation as provided by the concept design BIM MVD (buildingSMART, 2011). In order to ensure wide scale adoption, companies would also need to develop their own material libraries to support automated activities and undertake a pilot project to improve understanding of modeling conventions and design tool features and limitations.« less
BIM LAU-PE: Seedlings in Microgravity

NASA Astrophysics Data System (ADS)

Gass, S.; Pennese, R.; Chapuis, D.; Dainesi, P.; Nebuloni, S.; Garcia, M.; Oriol, A.

2015-09-01

The effect of gravity on plant roots is an intensive subject of research. Sounding rockets represent a costeffective platform to study this effect under microgravity conditions. As part of the upcoming MASER 13 sounding rocket campaign, two experiments on Arabidopsis thaliana seedlings have been devised: GRAMAT and SPARC. These experiments are aimed at studying (1) the genes that are specifically switched on or off during microgravity, and (2) the position of auxin-transporting proteins during microgravity. To perform these experiments, RUAG Space Switzerland site of Nyon, in collaboration with the Swedish Space Corporation (SSC) and the University of Freiburg, has developed the BIM LAU-PE (Biolology In Microgravity Late Access Unit Plant Experiment). In the following an overview of the BIM LAU-PE design is presented, highlighting specific module design features and verifications performed. A particular emphasis is placed on the parabolic flight experiments, including results of the micro-g injection system validation.
Automated Classification of Heritage Buildings for As-Built Bim Using Machine Learning Techniques

NASA Astrophysics Data System (ADS)

Bassier, M.; Vergauwen, M.; Van Genechten, B.

2017-08-01

Semantically rich three dimensional models such as Building Information Models (BIMs) are increasingly used in digital heritage. They provide the required information to varying stakeholders during the different stages of the historic buildings life cyle which is crucial in the conservation process. The creation of as-built BIM models is based on point cloud data. However, manually interpreting this data is labour intensive and often leads to misinterpretations. By automatically classifying the point cloud, the information can be proccesed more effeciently. A key aspect in this automated scan-to-BIM process is the classification of building objects. In this research we look to automatically recognise elements in existing buildings to create compact semantic information models. Our algorithm efficiently extracts the main structural components such as floors, ceilings, roofs, walls and beams despite the presence of significant clutter and occlusions. More specifically, Support Vector Machines (SVM) are proposed for the classification. The algorithm is evaluated using real data of a variety of existing buildings. The results prove that the used classifier recognizes the objects with both high precision and recall. As a result, entire data sets are reliably labelled at once. The approach enables experts to better document and process heritage assets.
Zinc-induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS.

PubMed

Hara, Hirokazu; Takeda, Tatsuya; Yamamoto, Nozomi; Furuya, Keisuke; Hirose, Kazuya; Kamiya, Tetsuro; Adachi, Tetsuo

2013-07-01

Bim is a member of the pro-apoptotic BH3-only Bcl-2 family of proteins. Bim gene undergoes alternative splicing to produce three predominant splicing variants (BimEL, BimL and BimS). The smallest variant BimS is the most potent inducer of apoptosis. Zinc (Zn(2+)) has been reported to stimulate apoptosis in various cell types. In this study, we examined whether Zn(2+) affects the expression of Bim in human neuroblastoma SH-SY5Y cells. Zn(2+) triggered alterations in Bim splicing and induced preferential generation of BimS, but not BimEL and BimL, in a dose- and time-dependent manner. Other metals (cadmium, cobalt and copper) and stresses (oxidative, endoplasmic reticulum and genotoxic stresses) had little or no effect on the expression of BimS. To address the mechanism of Zn(2+)-induced preferential generation of BimS, which lacks exon 4, we developed a Bim mini-gene construct. Deletion analysis using the Bim mini-gene revealed that predicted binding sites of the SR protein SRSF6, also known as SRp55, are located in the intronic region adjacent to exon 4. We also found that mutations in the predicted SRSF6-binding sites abolished generation of BimS mRNA from the mutated Bim mini-gene. In addition, a UV cross-linking assay followed by Western blotting showed that SRSF6 directly bound to the predicted binding site and Zn(2+) suppressed this binding. Moreover, Zn(2+) stimulated SRSF6 hyper-phosphorylation. TG003, a cdc2-like kinase inhibitor, partially prevented Zn(2+)-induced generation of BimS and SRSF6 hyper-phosphorylation. Taken together, our findings suggest that Zn(2+) inhibits the activity of SRSF6 and promotes elimination of exon 4, leading to preferential generation of BimS. © 2013 FEBS.
The Major Isoforms of Bim Contribute to Distinct Biological Activities that Govern the Processes of Autophagy and Apoptosis in Interleukin-7 Dependent Lymphocytes

PubMed Central

Ruppert, Shannon; Li, Wenqing; Zhang, Ge; Carlson, Adina L.; Limaye, Arati; Durum, Scott K.; Khaled, Annette R.

2012-01-01

Bim is a BH3-only member of the Bcl-2 family that enables the death of T-cells. Partial rescue of cytokine-deprived T-cells occurs when Bim and the receptor for the T-cell growth factor, interleukin-7 (IL-7), are deleted, implicating Bim as a possible target of IL-7-mediated signaling. Alternative splicing yields three major isoforms: BimEL, BimL and BimS. To study the effect of Bim deficiency and define the function of the major isoforms, Bim-containing and Bim-deficient T-cells, dependent on IL-7 for growth, were used. Loss of total Bim in IL-7-deprived T-cells resulted in delayed apoptosis. However, loss of Bim also impeded the later degradative phase of autophagy. p62, an autophagy-adaptor protein which is normally degraded, accumulated in Bim deficient cells. To explain this, BimL was found to support acidification of lysosomes that later may associate with autophagic vesicles. Key findings showed that inhibition of lysosomal acidification accelerated death upon IL-7 withdrawal only in Bim-containing T-cells. IL-7 dependent T-cells lacking Bim were less sensitive to inhibition of lysosomal acidification. BimL co-immunoprecipitated with dynein and Lamp1-containing vesicles, indicating BimL could be an adaptor for dynein to facilitate loading of lysosomes. In Bim deficient T-cells, lysosome-tracking probes revealed vesicles of less acidic pH. Over-expression of BimL restored acidic vesicles in Bim deficient T-cells, while other isoforms, BimEL and BimS, promoted intrinsic cell death. These results reveal a novel role for BimL in lysosomal positioning that may be required for the formation of degradative autolysosomes. PMID:22728771
Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation.

PubMed

Isobe, Kazutoshi; Kakimoto, Atsushi; Mikami, Tetsuo; Kaburaki, Kyohei; Kobayashi, Hiroshi; Yoshizawa, Takahiro; Makino, Takashi; Otsuka, Hajime; Sano, G O; Sugino, Keishi; Sakamoto, Susumu; Takai, Yujiro; Tochigi, Naobumi; Iyoda, Akira; Homma, Sakae

This pilot study assessed the association of BIM deletion polymorphism and BIM RNA isoform in patients with EGFR-positive non-small cell lung cancer (NSCLC). The study included 33 patients with EGFR-positive NSCLC treated with gefitinib. BIM deletion polymorphism and BIM RNA isoform (EL/L/S/γ) were determined by polymerase chain reaction (PCR). BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism inside tumors (p=0.038) and around tumors (p=0.0024). Relative BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism (p=0.0017). Patients with BIM-γ had significantly shorter progression-free survival than those without BIM-γ (median: 304 vs. 732 days; p=0.023). Expression of BIM-γ mRNA and BIM deletion polymorphism were strongly associated. BIM-γ overexpression may have a role in apoptosis related to EGFR-tyrosine kinase inhibitor. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.
A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis.

PubMed

Chen, Shuang; Zhang, Yu; Zhou, Liang; Leng, Yun; Lin, Hui; Kmieciak, Maciej; Pei, Xin-Yan; Jones, Richard; Orlowski, Robert Z; Dai, Yun; Grant, Steven

2014-10-23

Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy. © 2014 by The American Society of Hematology.
Apoptosis in activated T cells: what are the triggers, and what the signal transducers?

PubMed

Häcker, Georg; Bauer, Anette; Villunger, Andreas

2006-11-01

At the end of an immune response, apoptosis drastically reduces the numbers of activated T cells. It has been a matter of intense research how this form of apoptosis is regulated and initiated, and a number of proteins have been identified that contribute to this process. The present, widely accepted model assumes that the interplay of pro- and anti -apoptotic Bcl-2 family members determines the onset of activated T cell death, with the BH3-only protein Bim activating pro-apoptotic Bax/Bak. In the search for up-stream signals, factors from other immune cells have been shown to play a role, and the NFkappaB family member Bcl-3 has been implicated as a signalling-intermediate in T cells. Recent work has tested the interrelation of these factors and has suggested that Bcl-3 acts as a regulator of Bim activation, that the induction of apoptosis through Bim can be complemented by its relative Puma, and that the presence of certain cytokines during T cell activation delays the activation of Bim and Puma. Here we discuss these recent insights and provide a view on how the regulation of activated T cell death is achieved and how extrinsic signals may translate into the activation of the apoptotic pathway.
Research on the application of BIM technology in the whole life cycle of construction projects

NASA Astrophysics Data System (ADS)

Chang-liu, CHEN; Wei-wei, KOU; Shuai-hua, YE

2018-05-01

BIM technology can realize information sharing, and good BIM application will reduce the whole life cycle cost of construction projects. The popularization of BIM technology challenges the application of BIM technology at all stages of the whole life cycle of the construction project. It will give full play to the value of BIM, if developing a reasonable BIM project execution plan, defining BIM requirements, specifying Level of Development, determining the BIM quality control plan and clearing BIM application content of each stage, and will provide a unified method for project stakeholders, realize the whole life cycle of construction projects, and achieve the desired information sharing in construction project.
A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

PubMed Central

Chen, Shuang; Zhang, Yu; Zhou, Liang; Leng, Yun; Lin, Hui; Kmieciak, Maciej; Pei, Xin-Yan; Jones, Richard; Orlowski, Robert Z.; Dai, Yun

2014-01-01

Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bimhi) in most MM cell lines and primary CD138+ MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bimhi cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bimhi cells. In Bimlow cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737–induced apoptosis in bim−/− mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy. PMID:25208888
Bim Inhibits Autophagy by Recruiting Beclin 1 to Microtubules

PubMed Central

Luo, Shouqing; Garcia-Arencibia, Moises; Zhao, Rui; Puri, Claudia; Toh, Pearl P.C.; Sadiq, Oana; Rubinsztein, David C.

2012-01-01

Summary Bim is a proapoptotic BH3-only Bcl-2 family member. In response to death stimuli, Bim dissociates from the dynein light chain 1 (DYNLL1/LC8), where it is inactive, and can then initiate Bax/Bak-mediated mitochondria-dependent apoptosis. We found that Bim depletion increases autophagosome synthesis in cells and in vivo, and this effect is inhibited by overexpression of cell death-deficient Bim. Bim inhibits autophagy by interacting with Beclin 1, an autophagy regulator, and this interaction is facilitated by LC8. Bim bridges the Beclin 1-LC8 interaction and thereby inhibits autophagy by mislocalizing Beclin 1 to the dynein motor complex. Starvation, an autophagic stimulus, induces Bim phosphorylation, which abrogates LC8 binding to Bim, leading to dissociation of Bim and Beclin 1. Our data suggest that Bim switches locations between apoptosis-inactive/autophagy-inhibitory and apoptosis-active/autophagy-permissive sites. PMID:22742832

Bim, a Proapoptotic Protein, Up-regulated via Transcription Factor E2F1-dependent Mechanism, Functions as a Prosurvival Molecule in Cancer*

PubMed Central

Gogada, Raghu; Yadav, Neelu; Liu, Junwei; Tang, Shaohua; Zhang, Dianmu; Schneider, Andrea; Seshadri, Athul; Sun, Leimin; Aldaz, C. Marcelo; Tang, Dean G.; Chandra, Dhyan

2013-01-01

Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax/Bak-mediated cytochrome c release and apoptosis. Here, we provide evidence for a novel prosurvival function of Bim in cancer cells. Bim was constitutively overexpressed in multiple prostate and breast cancer cells as well as in primary tumor cells. Quantitative real time PCR analysis showed that Bim was transcriptionally up-regulated. We have identified eight endogenous E2F1-binding sites on the Bim promoter using in silico analysis. Luciferase assay demonstrated that Bim expression was E2F1-dependent as mutation of the E2F1-binding sites on the Bim promoter inhibited luciferase activities. In support, E2F1 silencing led to the loss of Bim expression in cancer cells. Bim primarily localized to mitochondrial and cytoskeleton-associated fractions. Bim silencing or microinjection of anti-Bim antibodies into the cell cytoplasm resulted in cell rounding, detachment, and subsequent apoptosis. We observed up-regulation of prosurvival proteins Bcl-xL and Mcl-1, which sequester Bim in cancer cells. In addition, a phosphorylated form of Bim was also elevated in cancer cells. These findings suggest that the constitutively overexpressed Bim may function as a prosurvival molecule in epithelial cancer cells, and phosphorylation and association with Bcl-xL/Mcl-1 block its proapoptotic functions. PMID:23152504
Understanding BIM Adoption in the AEC Industry: The Case of Jordan

NASA Astrophysics Data System (ADS)

Btoush, M.; Haron, AT

2017-11-01

Building information modelling (BIM) is a new and powerful technology implemented by many countries. The construction industry in Jordan plays a vital role and contributes immensely to the economic growth and development. In order to boost the industry and the economy, many industry players including engineers and contractors have recommended the implementation of BIM in Jordan. However, research demonstrates that successful BIM implementation is possible through the awareness of the different levels of BIM, which is a basic precondition for BIM implementation. Without a clear understanding of BIM, many companies would be unable to fully achieve BIM potentials or implement BIM in their building lifecycle. The objective of this study is to assess the current awareness of BIM technology in the Jordanian construction industry. A field interviews were conducted and 15 responses were collected and. The findings indicate that a significant proportion of respondents have little or no understanding of the concept of BIM. Also, the usage was found to be very low. Based on the results, a holistic roadmap was developed to spread the BIM adoption through the Jordanian construction industry. It is expected that this roadmap would lead to a better understanding and enable the industry towards more extensive implementation of BIM.
Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function.

PubMed

Qi, Xiao-Jun; Wildey, Gary M; Howe, Philip H

2006-01-13

Bim, the Bcl-2 interacting mediator of cell death, is a member of the BH3-only family of pro-apoptotic proteins. Recent studies have demonstrated that the apoptotic activity of Bim can be regulated through a post-translational mechanism whereby ERK phosphorylation serves as a signal for Bim ubiquitination and proteasomal degradation. In this report, we investigated the signaling pathways leading to Bim phosphorylation in Ba/F3 cells, an interleukin-3 (IL-3)-dependent B-cell line. IL-3 stimulation induced phosphorylation of Bim(EL), one of the predominant isoforms of Bim expressed in cells, at multiple sites, as evidenced by the formation of at least three to four bands by Western blotting that were sensitive to phosphatase digestion. The appearance of multiple, phosphorylated species of Bim(EL) correlated with Akt, and not ERK, activation. The PI3K inhibitor, LY294002, blocked IL-3-stimulated Akt activity and partially blocked Bim(EL) phosphorylation. In vitro kinase assays showed that recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). We propose that Ser(87) of Bim(EL) is an important regulatory site that is targeted by Akt to attenuate the pro-apoptotic function of Bim(EL), thereby promoting cell survival.
Synergy of the Developed 6D BIM Framework and Conception of the nD BIM Framework and nD BIM Process Ontology

ERIC Educational Resources Information Center

O'Keeffe, Shawn Edward

2013-01-01

The author developed a unified nD framework and process ontology for Building Information Modeling (BIM). The research includes a framework developed for 6D BIM, nD BIM, and nD ontology that defines the domain and sub-domain constructs for future nD BIM dimensions. The nD ontology defines the relationships of kinds within any new proposed…
Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

PubMed Central

Xia, Jinjing; Bai, Hao; Yan, Bo; Li, Rong; Shao, Minhua; Xiong, Liwen; Han, Baohui

2017-01-01

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo, erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity. PMID:29312548
Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer.

PubMed

Xia, Jinjing; Bai, Hao; Yan, Bo; Li, Rong; Shao, Minhua; Xiong, Liwen; Han, Baohui

2017-12-12

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo , erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity.
Assessing students' sentiments towards the use of a Building Information Modelling (BIM) learning platform in a construction project management course

NASA Astrophysics Data System (ADS)

Suwal, Sunil; Singh, Vishal

2018-07-01

Building Information Modelling (BIM) tools and processes are increasingly adopted and implemented in the construction industry. Consequently, BIM education is considered increasingly important in Architecture, Engineering and Construction (AEC) education. While most of the research and literature on BIM education in engineering studies has focused on BIM implementation strategies, processes, benefits, and challenges, there is limited study on students' perception towards the implementation of BIM courses, or about online BIM learning platforms, or about the BIM tools themselves. Therefore, this paper takes the first steps towards addressing this gap. This study analyses students' (57 students) perception and sentiments towards the use of an online BIM learning platform and explores the potential implications of the findings for BIM education. The findings suggest that online BIM learning platforms are highly rated by students as a positive learning experience, indicating the need for greater integration of such tools and approaches in AEC courses.
Impaired removal of Vβ8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim).

PubMed

Leucht, K; Caj, M; Fried, M; Rogler, G; Hausmann, M

2013-09-01

We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim(-/-) animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type mice. The number of autoreactive T cell receptor (TCR) Vβ8(+) lymphocytes was significantly higher in Bim(-/-) mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim(-/-) mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation. © 2013 British Society for Immunology.
Building information modelling (BIM) after ten years: Malaysian construction players’ perception of BIM

NASA Astrophysics Data System (ADS)

Latiffi, A. Ahmad; Brahim, J.; Fathi, M. S.

2017-08-01

Building Information Modelling (BIM) concept has expanded widely in many countries for more than a decade with its role of improving current practices in construction projects. However, the understanding of BIM differs among construction players, depending on how construction players utilize the concept in their projects. Therefore, this paper aims to explore the understanding of BIM concept among construction players in the Malaysian construction industry. A literature review on BIM concept and semi-structured interviews with construction players in BIM such as client, civil and structural (C&S) engineer and mechanical and electrical (M&E) engineer, quantity surveyor (QS), contractor, facilities manager and BIM consultant have been conducted in order to achieve this study’s the aim. The results show that the understanding of BIM concept among the construction players is limited to BIM as a process and technology. It is important for the construction players to improve their understanding of BIM as it can be used to enhance performance and productivity of construction projects.
Building Information Modeling (BIM) Roadmap: Supplement 2 - BIM Implementation Plan for Military Construction Projects, Bentley Platform

DTIC Science & Technology

2011-01-01

ER D C TR -0 6- 10 , S up pl em en t 2 Building Information Modeling ( BIM ) Roadmap Supplement 2 – BIM Implementation Plan for Military...release; distribution is unlimited. ERDC TR-06-10, Supplement 2 January 2011 Building Information Modeling ( BIM ) Roadmap Supplement 2 – BIM ...ERDC TR-06-10, Supplement 2 (January 2011) 2 Abstract: Building Information Modeling ( BIM ) technology provides the communities of practice in
Bim regulates alloimmune-mediated vascular injury through effects on T-cell activation and death.

PubMed

von Rossum, Anna; Enns, Winnie; Shi, Yu P; MacEwan, Grace E; Malekesmaeli, Mehrnoush; Brinkman, Ryan; Choy, Jonathan C

2014-06-01

Bim is a proapoptotic Bcl-2 protein known to downregulate immune responses and to also be required for antigen-induced T-cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T-cell responses in a model of vascular rejection. Bim was required for proliferation of CD4 and CD8 T cells, and for interleukin-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T-cell activation, whereas a complete elimination of Bim was required to prevent CD4 T-cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim(+/-), but not Bim(-/-), graft recipients. T-cell proliferation in response to allograft arteries was significantly reduced in both Bim(+/-) and Bim(-/-) mice, but cell death was attenuated only in Bim(-/-) animals. Bim controls both T-cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries. © 2014 American Heart Association, Inc.
Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature.

PubMed

Wang, Shoujian; Zaitoun, Ismail S; Johnson, Ryan P; Jamali, Nasim; Gurel, Zafer; Wintheiser, Catherine M; Strasser, Andreas; Lindner, Volkhard; Sheibani, Nader; Sorenson, Christine M

2017-01-01

Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb-cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision.
Stimulating a Sustainable Construction through Holistic BIM Adoption: The Root Causes of Recurring Low BIM Adoption in Malaysia

NASA Astrophysics Data System (ADS)

Mamter, S.; Abdul-Aziz, AR; Mamat, ME

2017-06-01

Fostering the Building Information Modelling (BIM) implementation is one of Malaysia sustainable strategies towards greener construction. Hence, the Eleventh Malaysia plan focuses on transforming construction industry through the increase of technology adoption in order to enhance construction productivity. Therefore, there is a growing and urgent demand to provide BIM competent. However, a significant number of parties are reluctant to develop and invest in BIM due to unsolved root causes. Scholars have identified barriers relating to the infancy stage of BIM adoption in Malaysia. Unfortunately, there is a lack of study to explore deeper the root causes of recurring for the barriers anticipate the low BIM adoption. This paper attempts to delve into the initiatives of BIM stake players in fostering BIM adoption and to determine the root causes of recurring barriers due to low BIM adoption. The study adopted the semi-structured interviews which involved BIM stake players as a sample population. From the findings, authors revealed four root causes of recurring barriers; absence of BIM policy and BIM compulsion, poor holistic readiness, software integration competition strategy, and reluctant in sharing knowledge. The findings espoused here are preliminary and more results are expected to emerge as the research progresses.
Implementation of Building Information Modeling (BIM) in Construction: A Comparative Case Study

NASA Astrophysics Data System (ADS)

Rowlinson, Steve; Collins, Ronan; Tuuli, Martin M.; Jia, Yunyan

2010-05-01

Building Information Modeling (BIM) approach is increasingly adopted in coordination of construction projects, with a number of parties providing BIM services and software solutions. However, the empirical impact of BIM on construction industry has yet to be investigated. This paper explores the interaction between BIM and the construction industry during its implementation, with a specific focus on the empirical impacts of BIM on the design and construction processes and professional roles during the process. Two cases were selected from recent construction projects coordinated with BIM systems: the Venetian Casino project in Macau and the Cathy Pacific Cargo Terminal project in Hong Kong. The former case illustrates how the conflicts emerged during the design process and procurement were addressed by adopting a BIM approach. The latter demonstrates how the adoption of BIM altered the roles of architect, contractor, and sub-contractors involved in the project. The impacts of BIM were critically reviewed and discussed.
The perceived value of using BIM for energy simulation

NASA Astrophysics Data System (ADS)

Lewis, Anderson M.

Building Information Modeling (BIM) is becoming an increasingly important tool in the Architectural, Engineering & Construction (AEC) industries. Some of the benefits associated with BIM include but are not limited to cost and time savings through greater trade and design coordination, and more accurate estimating take-offs. BIM is a virtual 3D, parametric design software that allows users to store information of a model within and can be used as a communication platform between project stakeholders. Likewise, energy simulation is an integral tool for predicting and optimizing a building's performance during design. Creating energy models and running energy simulations can be a time consuming activity due to the large number of parameters and assumptions that must be addressed to achieve reasonably accurate results. However, leveraging information imbedded within Building Information Models (BIMs) has the potential to increase accuracy and reduce the amount of time required to run energy simulations and can facilitate continuous energy simulations throughout the design process, thus optimizing building performance. Although some literature exists on how design stakeholders perceive the benefits associated with leveraging BIM for energy simulation, little is known about how perceptions associated with leveraging BIM for energy simulation differ between various green design stakeholder user groups. Through an e-survey instrument, this study seeks to determine how perceptions of using BIMs to inform energy simulation differ among distinct design stakeholder groups, which include BIM-only users, energy simulation-only users and BIM and energy simulation users. Additionally, this study seeks to determine what design stakeholders perceive as the main barriers and benefits of implementing BIM-based energy simulation. Results from this study suggest that little to no correlation exists between green design stakeholders' perceptions of the value associated with using information from BIMs to inform energy simulation and their engagement level with BIM and/or energy simulation. However, green design stakeholder perceptions of the value associated with using information from BIMs to inform energy simulation and their engagement with BIM and/or energy simulation may differ between different user groups (i.e. BIM users only, energy simulation users only, and BIM and energy simulation users). For example, the BIM-only user groups appeared to have a strong positive correlation between the perceptions of the value associated with using information from BIMs to inform energy simulation and their engagement with BIM. Additionally, this study suggests that the top perceived benefits of using BIMs to inform energy simulations among green design stakeholders are: facilitation of communication, reducing of process related costs, and giving users the ability examine more design options. The main perceived barrier of using BIMs to inform energy simulations among green design stakeholders was a lack of BIM standards for model integration with multidisciplinary teams. Results from this study will help readers understand how to better implement BIM-based energy simulation while mitigating barriers and optimizing benefits. Additionally, examining discrepancies between user groups can lead the identification and improvement of shortfalls in current BIM-based energy simulation processes. Understanding how perceptions and engagement levels differ among different software user groups will help in developing a strategies for implementing BIM-based energy simulation that are tailored to each specific user group.
Application of 6D Building Information Model (6D BIM) for Business-storage Building in Slovenia

NASA Astrophysics Data System (ADS)

Pučko, Zoran; Vincek, Dražen; Štrukelj, Andrej; Šuman, Nataša

2017-10-01

The aim of this paper is to present an application of 6D building information modelling (6D BIM) on a real business-storage building in Slovenia. First, features of building maintenance in general are described according to the current Slovenian legislation, and also a general principle of BIM is given. After that, step-by-step activities for modelling 6D BIM are exposed, namely from Element list for maintenance, determination of their lifetime and service measures, cost analysing and time analysing to 6D BIM modelling. The presented 6D BIM model is designed in a unique way in which cost analysis is performed as 5D BIM model with linked data to use BIM Construction Project Management Software (Vico Office), integrated with 3D BIM model, whereas time analysis as 4D BIM model is carried out as non-linked data with the help of Excel (without connection to 3D BIM model). The paper is intended to serve as a guide to the building owners to prepare 6D BIM and to provide an insight into the relevant dynamic information about intervals and costs for execution of maintenance works in the whole building lifecycle.
Content validity of governing in Building Information Modelling (BIM) implementation assessment instrument

NASA Astrophysics Data System (ADS)

Hadzaman, N. A. H.; Takim, R.; Nawawi, A. H.; Mohamad Yusuwan, N.

2018-04-01

BIM governance assessment instrument is a process of analysing the importance in developing BIM governance solution to tackle the existing problems during team collaboration in BIM-based projects. Despite the deployment of integrative technologies in construction industry particularly BIM, it is still insufficient compare to other sectors. Several studies have been established the requirements of BIM implementation concerning all technical and non-technical BIM adoption issues. However, the data are regarded as inadequate to develop a BIM governance framework. Hence, the objective of the paper is to evaluate the content validity of the BIM governance instrument prior to the main data collection. Two methods were employed in the form of literature review and questionnaire survey. Based on the literature review, 273 items with six main constructs are suggested to be incorporated in the BIM governance instrument. The Content Validity Ratio (CVR) scores revealed that 202 out of 273 items are considered as the utmost critical by the content experts. The findings for Item Level Content Validity Index (I-CVI) and Modified Kappa Coefficient however revealed that 257 items in BIM governance instrument are appropriate and excellent. The instrument is highly reliable for future strategies and the development of BIM projects in Malaysia.
BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations

PubMed Central

Carranza, Hernán; Vargas, Carlos; Otero, Jorge; Corrales-Rodriguez, Luis; Martín, Claudio; Reguart, Noemí; Archila, Pilar; Rodríguez, July; Cuello, Mauricio; Ortíz, Carlos; Franco, Sandra; Rolfo, Christian; Rosell, Rafael

2016-01-01

Background Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. Results BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). Methods We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. Conclusions The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation. PMID:27926478
BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations.

PubMed

Cardona, Andrés F; Rojas, Leonardo; Wills, Beatriz; Arrieta, Oscar; Carranza, Hernán; Vargas, Carlos; Otero, Jorge; Corrales-Rodriguez, Luis; Martín, Claudio; Reguart, Noemí; Archila, Pilar; Rodríguez, July; Cuello, Mauricio; Ortíz, Carlos; Franco, Sandra; Rolfo, Christian; Rosell, Rafael; on behalf of the CLICaP

2016-09-19

Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.
Enhancing Knowledge Sharing Management Using BIM Technology in Construction

PubMed Central

Ho, Shih-Ping; Tserng, Hui-Ping

2013-01-01

Construction knowledge can be communicated and reused among project managers and jobsite engineers to alleviate problems on a construction jobsite and reduce the time and cost of solving problems related to constructability. This paper proposes a new methodology for the sharing of construction knowledge by using Building Information Modeling (BIM) technology. The main characteristics of BIM include illustrating 3D CAD-based presentations and keeping information in a digital format and facilitation of easy updating and transfer of information in the BIM environment. Using the BIM technology, project managers and engineers can gain knowledge related to BIM and obtain feedback provided by jobsite engineers for future reference. This study addresses the application of knowledge sharing management using BIM technology and proposes a BIM-based Knowledge Sharing Management (BIMKSM) system for project managers and engineers. The BIMKSM system is then applied in a selected case study of a construction project in Taiwan to demonstrate the effectiveness of sharing knowledge in the BIM environment. The results demonstrate that the BIMKSM system can be used as a visual BIM-based knowledge sharing management platform by utilizing the BIM technology. PMID:24723790

Enhancing knowledge sharing management using BIM technology in construction.

PubMed

Ho, Shih-Ping; Tserng, Hui-Ping; Jan, Shu-Hui

2013-01-01

Construction knowledge can be communicated and reused among project managers and jobsite engineers to alleviate problems on a construction jobsite and reduce the time and cost of solving problems related to constructability. This paper proposes a new methodology for the sharing of construction knowledge by using Building Information Modeling (BIM) technology. The main characteristics of BIM include illustrating 3D CAD-based presentations and keeping information in a digital format and facilitation of easy updating and transfer of information in the BIM environment. Using the BIM technology, project managers and engineers can gain knowledge related to BIM and obtain feedback provided by jobsite engineers for future reference. This study addresses the application of knowledge sharing management using BIM technology and proposes a BIM-based Knowledge Sharing Management (BIMKSM) system for project managers and engineers. The BIMKSM system is then applied in a selected case study of a construction project in Taiwan to demonstrate the effectiveness of sharing knowledge in the BIM environment. The results demonstrate that the BIMKSM system can be used as a visual BIM-based knowledge sharing management platform by utilizing the BIM technology.
The Bcl-2 family member BIM has multiple glaucoma-relevant functions in DBA/2J mice

PubMed Central

Harder, Jeffrey M.; Fernandes, Kimberly A.; Libby, Richard T.

2012-01-01

Axonal insult induces retinal ganglion cell (RGC) death through a BAX-dependent process. The pro-apoptotic Bcl-2 family member BIM is known to induce BAX activation. BIM expression increased in RGCs after axonal injury and its induction was dependent on JUN. Partial and complete Bim deficiency delayed RGC death after mechanical optic nerve injury. However, in a mouse model of glaucoma, DBA/2J mice, Bim deficiency did not prevent RGC death in eyes with severe optic nerve degeneration. In a subset of DBA/2J mice, Bim deficiency altered disease progression resulting in less severe nerve damage. Bim deficient mice exhibited altered optic nerve head morphology and significantly lessened intraocular pressure elevation. Thus, a decrease in axonal degeneration in Bim deficient DBA/2J mice may not be caused by a direct role of Bim in RGCs. These data suggest that BIM has multiple roles in glaucoma pathophysiology, potentially affecting susceptibility to glaucoma through several mechanisms. PMID:22833783
The US Army Corps of Engineers Roadmap for Life-Cycle Building Information Modeling (BIM). Supplement 2 - BIM Implementation Guide for Military Construction (MILCON) Projects Using the Bentley Platform

DTIC Science & Technology

2012-11-01

Building Information Modeling ( BIM ...12-2, Supplement 2 November 2012 The US Army Corps of Engineers Roadmap for Life-Cycle Building Information Modeling ( BIM ) Supplement 2 – BIM ...39180 ERDC SR-12-2, Supplement 2 (November 2012) ii Abstract Building Information Modeling ( BIM ) technology has rapidly gained ac-
The US Army Corps of Engineers Roadmap for Life-Cycle Building Information Modeling (BIM). Supplement 1- BIM Implementation Guide for Military Construction (MILCON) Projects Using the Autodesk Platform

DTIC Science & Technology

2012-11-01

Building Information Modeling ( BIM ...12-2, Supplement 1 November 2012 The US Army Corps of Engineers Roadmap for Life-Cycle Building Information Modeling ( BIM ) Supplement 1 – BIM ...ERDC SR-12-2, Supplement 1 (November 2012) ii Abstract Building Information Modeling ( BIM ) technology has rapidly gained ac- ceptance throughout
Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax

PubMed Central

Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

2014-01-01

Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo. PMID:25175936
Regulation of Bim in Health and Disease

PubMed Central

Sionov, Ronit Vogt; Vlahopoulos, Spiros A.; Granot, Zvi

2015-01-01

The BH3-only Bim protein is a major determinant for initiating the intrinsic apoptotic pathway under both physiological and pathophysiological conditions. Tight regulation of its expression and activity at the transcriptional, translational and post-translational levels together with the induction of alternatively spliced isoforms with different pro-apoptotic potential, ensure timely activation of Bim. Under physiological conditions, Bim is essential for shaping immune responses where its absence promotes autoimmunity, while too early Bim induction eliminates cytotoxic T cells prematurely, resulting in chronic inflammation and tumor progression. Enhanced Bim induction in neurons causes neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Moreover, type I diabetes is promoted by genetically predisposed elevation of Bim in β-cells. On the contrary, cancer cells have developed mechanisms that suppress Bim expression necessary for tumor progression and metastasis. This review focuses on the intricate network regulating Bim activity and its involvement in physiological and pathophysiological processes. PMID:26405162
Regulation of Bim in Health and Disease.

PubMed

Sionov, Ronit Vogt; Vlahopoulos, Spiros A; Granot, Zvi

2015-09-15

The BH3-only Bim protein is a major determinant for initiating the intrinsic apoptotic pathway under both physiological and pathophysiological conditions. Tight regulation of its expression and activity at the transcriptional, translational and post-translational levels together with the induction of alternatively spliced isoforms with different pro-apoptotic potential, ensure timely activation of Bim. Under physiological conditions, Bim is essential for shaping immune responses where its absence promotes autoimmunity, while too early Bim induction eliminates cytotoxic T cells prematurely, resulting in chronic inflammation and tumor progression. Enhanced Bim induction in neurons causes neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Moreover, type I diabetes is promoted by genetically predisposed elevation of Bim in β-cells. On the contrary, cancer cells have developed mechanisms that suppress Bim expression necessary for tumor progression and metastasis. This review focuses on the intricate network regulating Bim activity and its involvement in physiological and pathophysiological processes.
Bim is an Independent Prognostic Marker in Intrahepatic Cholangiocarcinoma.

PubMed

Zhang, Henan; Jenkins, Sarah M; Lee, Chuang-Ta; Harrington, Susan M; Liu, Zhuogang; Dong, Haidong; Zhang, Lizhi

2018-04-23

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignant tumor and has a poor prognosis. The prognostic factors associated with outcome remain poorly defined. In this study, we investigated the role of an important cell apoptosis initiator, Bcl-2 interacting mediator of cell death (Bim), by evaluating its expression and association with other clinicopathologic features in ICCs. We analyzed 56 cases of ICC with clinical follow-up. The expression of Bim in ICC cells and other cellular components was evaluated by immunohistochemistry. Bim expression was considered upregulated if Bim was detected in 10% or more of tumor cells. Of the 56 ICC samples, 19 (34%) had high Bim expression level, 15 (27%) were completely negative, and 22 (39%) were classified as low Bim expression (<10% positivity). Patients who had tumors with high Bim level had significantly longer overall survival than those with low or no staining (median survival, 7.6 vs 2.6 years; hazard ratio, 0.40; P=.006). High Bim expression was also correlated with low Ki-67 index, and more importantly, none of the tumors with high Bim expression had lymph node metastases at the time of surgery. Our study demonstrates that Bim is an important and independent prognostic factor in ICC. Tumors with high Bim expression are associated with better prognosis through inhibiting tumor cell proliferation and metastatic ability. The development of new agents directly or indirectly targeting Bim may provide promising anticancer treatments. Copyright © 2018. Published by Elsevier Inc.
Bcl-2-like Protein 11 (BIM) Expression Is Associated with Favorable Prognosis for Patients with Cervical Cancer.

PubMed

Kim, Bo Wook; Cho, Hanbyoul; Ylaya, Kris; Kitano, Haruhisa; Chung, Joon-Yong; Hewitt, Stephen M; Kim, Jae-Hoon

2017-09-01

Bcl-2-like protein 11 (BIM) is a pro-apoptotic member of the Bcl-2 protein family. BIM elicits cell death by binding to pro-survival Bcl-2 proteins. Even though the association of BIM expression with cell death has been investigated, its clinical survival significance in cervical cancer has not. In the current study, the prognostic significance of BIM in cervical cancer was investigated. The study included normal cervical tissues (n=254), cervical intraepithelial neoplasia (CIN) tissues (n=275), and invasive cervical cancer (n=164). In order to identify BIM expression, immunohistochemistry (IHC) was performed, and IHC scoring by quantitative digital image analysis was determined. Then, the association of BIM with prognostic factors was investigated. BIM expression was higher in cervical cancer than normal cervical tissues (p<0.001). Well and moderate differentiation indicated higher BIM expression than did poor differentiation (p=0.001). Also, BIM expression was high in radiation-sensitive cervical cancer relative to radiation-resistant cancer (p=0.049). High BIM expression showed better 5-year disease-free survival (DFS) and overall survival (OS) rates (p=0.049 and π=0.030, respectively) than did low expression. In a multivariate analysis, BIM was shown to be an independent risk factor for DFS and OS in cervical cancer, with hazard ratios of 0.22 (p=0.006) and 0.46 (p=0.046), respectively. BIM is associated with favorable prognostic markers for prediction of DFS and OS in cervical cancer. High BIM expression is a potential prognostic marker as well as a chemotherapeutic target for cervical cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Awareness of BIM adoption in Brunei

NASA Astrophysics Data System (ADS)

Rahman, Md Motiar

2017-09-01

Building Information Modelling (BIM) is getting increased attention day-by-day due to its many benefits, including clash detection, collaboration between contract parties, visualization future structure, optimized schedule and project control, waste control, design documentation, and harmonized facilities management. As such, many countries have already adopted BIM, and many other countries are exploring the potential of adopting it. However, it is still relatively new and unknown to some other countries like Brunei. This study was therefore undertaken to generate and/or gauge the awareness of Brunei construction industry participants, targeting adoption of BIM, through a structured questionnaire survey. Responses from 90 industry participants reveal that Brunei Construction industry is not well aware of BIM, lack the required technical knowledge and application in construction, and cost involvement. They are unsure about the potential benefits and barriers to implementing BIM. However, respondents are hopeful that BIM can bring the required changes in construction, willing to adopt BIM, expects cliental support with initial investment for its adoption, and believe that BIM is the future of construction project information management. On the whole, private sector was seen to be more aware on BIM than public sector. The study outcomes are expected to provide the policy makers a first-hand information on the industry awareness on BIM, which in turn help them for further exploration / examination and to design any action plan and guidelines for BIM adoption.
Endogenous association of Bim BH3-only protein with Mcl-1, Bcl-xL and Bcl-2 on mitochondria in human B cells.

PubMed

Gomez-Bougie, Patricia; Bataille, Régis; Amiot, Martine

2005-03-01

Bim is an essential regulator of lymphoid system homeostasis and appears essential for B cell apoptosis induction. The mechanism by which Bim isoforms are held in an inactive form remains poorly documented in normal B cells. In the current study, we demonstrated that in normal tonsil B cells the three major Bim isoforms are strongly associated with the anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2 and Bcl-x(L). On the other hand, only a weak association of BimEL and L with the dynein LC8 chain has been found. In addition, there is no free Bim in normal B cells. Moreover, subcellular fractionation demonstrated that Bim and the anti-apoptotic counterparts are localized preferentially in the mitochondria-rich fraction. The fact that most Bim was found in this fraction supports the hypothesis that it is sequestered by anti-apoptotic molecules in mitochondria where its pro-apoptotic activity is controlled. Of interest, BimS is essentially complexed to Mcl-1 and the Mcl-1/Bim complex is the most abundant among the three types of complexes. This supports the idea that this complex is critical for the control of B cell death. In conclusion, these results favor a model in which Bim release from anti-apoptotic proteins is a critical event for initiation of apoptosis.
Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex12

PubMed Central

Piazza, Rocco; Magistroni, Vera; Mogavero, Angela; Andreoni, Federica; Ambrogio, Chiara; Chiarle, Roberto; Mologni, Luca; Bachmann, Petra S; Lock, Richard B; Collini, Paola; Pelosi, Giuseppe; Gambacorti-Passerini, Carlo

2013-01-01

BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation. PMID:23633923
Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations.

PubMed

Ebi, Hiromichi; Oze, Isao; Nakagawa, Takayuki; Ito, Hidemi; Hosono, Satoyo; Matsuda, Fumihiko; Takahashi, Meiko; Takeuchi, Shinji; Sakao, Yukinori; Hida, Toyoaki; Faber, Anthony C; Tanaka, Hideo; Yatabe, Yasushi; Mitsudomi, Tetsuya; Yano, Seiji; Matsuo, Keitaro

2015-01-01

The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown. The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals. Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78). The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.
Pim-2 protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via downregulation of Bim expression.

PubMed

Xu, Yan; Xing, Yawei; Xu, Yanjie; Huang, Chahua; Bao, Huihui; Hong, Kui; Cheng, Xiaoshu

2016-12-01

We know that silencing Bim, a pro-apoptosis protein, significantly attenuates glucose and oxygen-deprived induced apoptosis in cardiomyocytes. However, the mechanisms underlying the regulation of the Bim activation in the heart have remained unknown. Pim-2 is one of three Pim serine/threonine kinase family members thought to be involved in cell survival and proliferation. H9c2 cardiomyocytes were subjected to a hypoxia/reoxygenation (H/R) condition in vitro, mimicking ischemic/reperfusion injury in vivo. H/R augmented the expression of Bim, Cyt C, and Pim-2 and induced H9c2 cell apoptosis. Overexpression of Pim-2 attenuated apoptosis which induced by H/R in H9c2 cells, via downregulation of Bim and Cyt C expression. Silencing of Pim-2 promoted H/R-induced apoptosis via upregulation of Bim and Cyt C expression. Co-IP revealed the interaction between Pim-2 and Bim protein, with Bim Ser 65 phosphorylated by Pim-2. Furthermore, blocking proteasome activity by MG132 prevented Bim degradation, and Bim S65A mutation could reverse the anti-apoptotic role of Pim-2 which induced by H/R. These data demonstrated that Pim-2 is a novel Bim-interacting protein, which negatively regulates Bim degradation and protects H9c2 cardiomyocytes from H/R-induced apoptosis. Copyright Â© 2016 Elsevier B.V. All rights reserved.
Utilization of design data on conventional system to building information modeling (BIM)

NASA Astrophysics Data System (ADS)

Akbar, Boyke M.; Z. R., Dewi Larasati

2017-11-01

Nowadays infrastructure development becomes one of the main priorities in the developed country such as Indonesia. The use of conventional design system is considered no longer effectively support the infrastructure projects, especially for the high complexity building design, due to its fragmented system issues. BIM comes as one of the solutions in managing projects in an integrated manner. Despite of the all known BIM benefits, there are some obstacles on the migration process to BIM. The two main of the obstacles are; the BIM implementation unpreparedness of some project parties and a concerns to leave behind the existing database and create a new one on the BIM system. This paper discusses the utilization probabilities of the existing CAD data from the conventional design system for BIM system. The existing conventional CAD data's and BIM design system output was studied to examine compatibility issues between two subject and followed by an utilization scheme-strategy probabilities. The goal of this study is to add project parties' eagerness in migrating to BIM by maximizing the existing data utilization and hopefully could also increase BIM based project workflow quality.
Histone deacetylation, as opposed to promoter methylation, results in epigenetic BIM silencing and resistance to EGFR TKI in NSCLC.

PubMed

Zhao, Mingchuan; Zhang, Yishi; Li, Jiayu; Li, Xuefei; Cheng, Ningning; Wang, Qi; Cai, Weijing; Zhao, Chao; He, Yayi; Chang, Jianhua; Zhou, Caicun

2018-01-01

Drug resistance remains a major challenge in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Bcl-2-like protein 11 (BIM), a B-cell lymphoma 2 family pro-apoptotic protein, is a prime target for specific anti-cancer therapeutics. However, the epigenetic regulation of BIM in non-small cell lung cancer (NSCLC) cell lines and patients with NSCLC in association with EGFR-TKI resistance requires investigation. Methylation-specific PCR (MSP), pyrosequencing, and nested quantitative (q)-MSP were conducted to explore the methylation status of BIM in NSCLC cell lines. In addition, the methylation profile of BIM in patients with NSCLC was assessed by nested q-MSP using circulating free DNA. Cell lines, treated with methylation inhibitor 5-Aza-2'-deoxycytidine (AZA) or histone deacetylation inhibitor trichostatin A (TSA) prior to gefitinib treatment, were examined for BIM gene expression and resistance to gefitinib. All cell lines used in the present study presented with hypo-methylated BIM . Treatment with AZA had no effect on BIM RNA expression in PC9 cells or the gefitinib-resistant cell lines PC9/R and PC9/G2, nor did it reverse their resistance to gefitinib. In contrast, TSA treatment produced the opposite result. In the present study, 25 (78.1%) patients with hypo-methylated BIM and 7 patients (21.9%) with partial or hyper-methylated BIM were identified. The clinicopathological data revealed a random hypo-methylated BIM distribution amongst patients with NSCLC. In the overall study group and EGFR mutant group, hypo-methylated BIM carriers presented with no significant differences in progression free survival compared with patients with partial or hyper-methylated BIM . All cell lines in the present study and the majority of patients with NSCLC carried hypo-methylated BIM . Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing of BIM and lead to EGFR TKI resistance in NSCLC.
Esophagogastric metaplasia relates to nodal metastases in adenocarcinoma of esophagus and cardia.

PubMed

Ruffato, Alberto; Mattioli, Sandro; Perrone, Ottorino; Lugaresi, Marialuisa; Di Simone, Massimo Pierluigi; D'Errico, Antonietta; Malvi, Deborah; Aprile, Maria Rosaria; Raulli, Giandomenico; Frassineti, Luca

2013-04-01

Immunohistochemical profiles of esophageal and cardia adenocarcinoma differ according to the presence or absence of Barrett's epithelium (BIM) and gastric intestinal metaplasia (GIM) in the fundus and antrum. Different lymphatic spreading has been demonstrated in esophageal adenocarcinoma. We investigated the correlation among the presence or absence of intestinal metaplasia in the esophagus and stomach and lymphatic metastases in patients who underwent radical surgery for esophageal and cardia adenocarcinoma. The mucosa surrounding the adenocarcinoma and the gastric mucosa were analyzed. The BIM+ patients underwent subtotal esophagectomy and gastric pull up, and the BIM- patients underwent esophagectomy at the azygos vein, total gastrectomy, and esophagojejunostomy. The radical thoracic (station numbers 2, 3, 4R, 7, 8, and 9) and abdominal (station numbers 15 through 20) lymphadenectomy was identical in both procedures except for the greater curvature. One hundred ninety-four consecutive patients were collected in three major groups: BIM+/GIM-, 52 patients (26.8%); BIM-/GIM-, 90 patients (46.4%); BIM-/GIM+, 50 patients (25.8%). Two patients (1%) were BIM+/GIM+. A total of 6,010 lymph nodes were resected: 1,515 were recovered in BIM+, 1,587 in BIM-/GIM+, and 2,908 in BIM-/GIM- patients. The percentage of patients with pN+ stations 8 and 9 was higher in BIM+ (p=0.001), and the percentage of patients with pN+ perigastric stations was higher in BIM- (p=0.001). The BIM-/GIM- patients had a number of abdominal metastatic lymph nodes higher than did the BIM-/GIM+ patients (p=0.0001). According to the presence or absence of BIM and GIM in the esophagus and cardia, adenocarcinoma correspond to three different patterns of lymphatic metastasization, which may reflect different biologic and carcinogenetic pathways. Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Bim is Responsible for the Inherent Sensitivity of the Developing Retinal Vasculature to Hyperoxia

PubMed Central

Wang, Shoujian; Park, SunYoung; Fei, Ping; Sorenson, Christine M.

2010-01-01

Apoptosis plays an important role in development and remodeling of vasculature during organogenesis. Coordinated branching and remodeling of the retinal vascular tree is essential for normal retinal function. Bcl-2 family members, such as bim can not only influence apoptosis, but also cell adhesive and migratory properties essential during vascular development. Here we examined the impact of bim deficiency on postnatal retinal vascularization, as well as retinal neovascularization during oxygen-induced ischemic retinopathy (OIR) and laser-induced choroidal neovascularization. Loss of bim expression was associated with increased retinal vascular density in mature animals. This was mainly attributed to increased numbers of pericytes and endothelial cells. However, the initial spread of the superficial layer of retinal vasculature and, the appearance and density of the tip cells were similar in bim +/+ and bim -/- mice. In addition, hyaloid vessel regression was attenuated in the absence of bim. Furthermore, in the absence of bim retinal vessel obliteration and neovascularization did not occur during OIR. Instead, normal inner retinal vascularization proceeded independent of changes in oxygen levels. In contrast, choroidal neovascularization occurred equally well in bim +/+ and bim -/- mice. Together our data suggest bim expression may be responsible for the inherent sensitivity of the developing retinal vasculature to changes in oxygen levels, and promotes vessel obliteration in response to hyperoxia. PMID:21047504
Lack of association between deletion polymorphism of BIM gene and in vitro drug sensitivity in B-cell precursor acute lymphoblastic leukemia.

PubMed

Huang, Meixian; Miyake, Kunio; Kagami, Keiko; Abe, Masako; Shinohara, Tamao; Watanabe, Atsushi; Somazu, Shinpei; Oshiro, Hiroko; Goi, Kumiko; Goto, Hiroaki; Minegishi, Masayoshi; Iwamoto, Shotaro; Kiyokawa, Nobutaka; Sugita, Kanji; Inukai, Takeshi

2017-09-01

A deletion polymorphism in the BIM gene was identified as an intrinsic mechanism for resistance to tyrosine kinase inhibitor in chronic myeloid leukemia patients in East Asia. BIM is also involved in the responses to glucocorticoid and chemotherapy in acute lymphoblastic leukemia (ALL), suggesting a possible association between deletion polymorphism of BIM and the chemosensitivity of ALL. Thus, we analyzed 72 B-cell precursor (BCP)-ALL cell lines established from Japanese patients. Indeed, higher BIM gene expression was associated with good in vitro sensitivities to glucocorticoid and chemotherapeutic agents used in induction therapy. We also analyzed the methylation status of the BIM gene promoter by next generation sequencing of genome bisulfite PCR products, since genetic polymorphism could be insignificant when epigenetically inactivated. Hypermethylation of the BIM gene promoter was associated with lower BIM gene expression and poorer sensitivity to vincristine. Of note, however, the prevalence of a deletion polymorphism was not associated with the BIM gene expression level or drug sensitivities in BCP-ALL cell lines, in which the BIM gene was unmethylated. These observations suggest that an association of a deletion polymorphism of BIM and the response to induction therapy in BCP-ALL may be clinically minimal. Copyright © 2017. Published by Elsevier Ltd.
Bim may be a poor prognostic biomarker in breast cancer patients especially in those with luminal A tumors.

PubMed

Maimaiti, Yusufu; Dong, Lingling; Aili, Aikebaier; Maimaitiaili, Maimaitiaili; Huang, Tao; Abudureyimu, Kelimu

2017-07-04

Bcl-2 interacting mediator of cell death (Bim) appears to have contradictory roles in cancer. It is uncertain whether Bim show prognostic significance in patients with breast cancer. To investigate the correlation between Bim expression and clinicopathological characteristics of breast cancer and to evaluate Bim's effect on overall survival (OS). We used immunohistochemistry (IHC) technique to detect the expression of Bim via tissue microarray in 275 breast cancer samples, Kaplan-Meier analysis to perform survival analysis, and Cox proportional hazards regression model to explore the risk factors of breast cancer. The results revealed that Bim expression was significantly correlated with age, estrogen receptor (ER) and/or progesterone receptor (PR), human epidermal growth factor receptor (HER2) and Ki67 expression (P< 0.05). Bim expression was significantly different in the four molecular subtypes (P= 0.000). Survival analysis showed that Bim positive expression contributed to a shorter OS (P= 0.034), especially in patients with luminal A tumors (P= 0.039). Univariate and multivariate regression analysis showed that Bim was an independent prognostic factor for breast cancer (P< 0.05). Bim may serve as an effective predictive factor for lower OS in breast cancer patients, especially in those with luminal A tumors.

Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.

PubMed

Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

2014-12-01

Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Based on the development status of British BIM, exploring China’s BIM road

NASA Astrophysics Data System (ADS)

Tiangang, Chu; hui, Li; shanjun, Zhang; Ningshan, Jiang; Dan, Zhang; Yu, Zhang; Guibo, Bao

2018-05-01

This article mainly analyses the development and application status and development trend of BIM technology after the implementation of the British government, to explore the policies and methods that our government should carry out in the development of BIM. The article also summarizes and analyses the relevant policies and standards implemented by various provincial and municipal governments in promoting BIM technology in China and summarizes the strengths and weaknesses of each other by comparing the development status of the implementation of BIM policies in various provinces and cities. The article also analysed the obstacles encountered in the implementation of some specific projects at the current stage of BIM technology, and summarized the feasible solutions. The article mainly analyses the application prospects of BIM from the technical aspects of design, the application of technology in the construction process, and the strategic implementation and operation of the company, and provides a reference for promoting the application of BIM in the construction industry in China, especially in the western region.
Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming.

PubMed

Conage-Pough, Jason E; Boise, Lawrence H

2018-05-18

Mcl-1 is a highly labile protein, subject to extensive post-translational regulation. This distinguishes Mcl-1 from other antiapoptotic proteins and necessitates further study to better understand how interactions with proapoptotic Bcl-2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl-1, and Bim phosphorylation has been associated with increased Mcl-1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl-1 stability. We found that Bim stabilizes and primes Mcl-1 in RPCI-WM1 cells and is constitutively phosphorylated. Additionally, introduction of several phospho-mimetic and unphosphosphorylateable Bim mutations resulted in altered Mcl-1 stability and distinct Bim binding to antiapoptotic proteins. These findings suggest Bim phosphorylation not only regulates Mcl-1 stability but also is a potential mechanism for enforcing Mcl-1 dependence. © 2018 Federation of European Biochemical Societies.
BH3-only protein Bim is associated with the degree of Helicobacter pylori-induced gastritis and is localized to the mitochondria of inflammatory cells in the gastric mucosa

PubMed Central

Akazawa, Yuko; Matsuda, Katsuya; Isomoto, Hajime; Matsushima, Kayoko; Kido, Yoko; Urabe, Shigetoshi; Yamaghchi, Naoyuki; Ohnita, Ken; Takeshima, Fuminao; Kondo, Hisayoshi; Tsugawa, Hitoshi; Suzuki, Hidekazu; Moss, Joel; Nakao, Kazuhiko; Nakashima, Masahiro

2015-01-01

BH3-only protein, Bim, is a pro-apoptotic protein that mediates mitochondria-dependent cell death. However, the role of Bim in Helicobacter pylori-associated gastritis remains unclear. This study aimed to assess the cellular localization of Bim and its possible role in H. pylori-induced gastritis. The study was conducted on biopsy specimens obtained from 80 patients who underwent upper gastrointestinal endoscopy (H. pylori-negative: n = 30, positive: n = 50). Association between Bim mRNA expression and severity of gastritis was evaluated and the localization of Bim was examined by immunofluorescence. Bim mRNA expression was positively correlated with the degree of gastritis, as defined by the Sydney system. Immunohistochemical analysis confirmed increased Bim expression in H. pylori-infected gastric mucosa compared with uninfected mucosa in both humans and mice. Bim localized in myeloperoxidase- and CD138-positive cells of H. pylori-infected lamina propria and submucosa of the gastric tract, indicating that this protein is predominantly expressed in neutrophils and plasma cells. In contrast, Bim did not localize in CD20-, CD3-, or CD68-positive cells. Bim was expressed in the mitochondria, where it partially co-localized with activated Bax and cleaved-PARP. In conclusion, Bim is expressed in neutrophils and plasma cells in H. pylori-associated gastritis, where it may participate in the termination of inflammatory response by causing mitochondria-mediated apoptosis in specific leucocytes. PMID:26197709
HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis.

PubMed

Deng, Lin; Chen, Ming; Tanaka, Motofumi; Ku, Yonson; Itoh, Tomoo; Shoji, Ikuo; Hotta, Hak

2015-09-01

We previously reported that hepatitis C virus (HCV) infection induces Bax-triggered, mitochondrion-mediated apoptosis by using the HCV J6/JFH1 strain and Huh-7.5 cells. However, it was still unclear how HCV-induced Bax activation. In this study, we showed that the HCV-induced activation and mitochondrial accumulation of Bax were significantly attenuated by treatment with a general antioxidant, N-acetyl cysteine (NAC), or a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, with the result suggesting that the reactive oxygen species (ROS)/JNK signalling pathway is upstream of Bax activation in HCV-induced apoptosis. We also demonstrated that HCV infection transcriptionally activated the gene for the pro-apoptotic protein Bim and the protein expression of three major splice variants of Bim (BimEL, BimL and BimS). The HCV-induced increase in the Bim mRNA and protein levels was significantly counteracted by treatment with NAC or SP600125, suggesting that the ROS/JNK signalling pathway is involved in Bim upregulation. Moreover, HCV infection led to a marked accumulation of Bim on the mitochondria to facilitate its interaction with Bax. On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV-mediated activation of Bax and caspase 3. Taken together, these observations suggest that HCV-induced ROS/JNK signalling transcriptionally activates Bim expression, which leads to Bax activation and apoptosis induction.
Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.

PubMed

Reynolds, C; Roderick, J E; LaBelle, J L; Bird, G; Mathieu, R; Bodaar, K; Colon, D; Pyati, U; Stevenson, K E; Qi, J; Harris, M; Silverman, L B; Sallan, S E; Bradner, J E; Neuberg, D S; Look, A T; Walensky, L D; Kelliher, M A; Gutierrez, A

2014-09-01

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.
Involvement of Bim in Photofrin-mediated photodynamically induced apoptosis.

PubMed

Wang, Xianwang; He, Xiaobing; Hu, Shujuan; Sun, Anbang; Lu, Chengbiao

2015-01-01

Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells. The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT-induced apoptosis was determined by RNAi. BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA-Bim. We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers. © 2015 S. Karger AG, Basel.
Spatial Dmbs Architecture for a Free and Open Source Bim

NASA Astrophysics Data System (ADS)

Logothetis, S.; Valari, E.; Karachaliou, E.; Stylianidis, E.

2017-08-01

Recent research on the field of Building Information Modelling (BIM) technology, revealed that except of a few, accessible and free BIM viewers there is a lack of Free & Open Source Software (FOSS) BIM software for the complete BIM process. With this in mind and considering BIM as the technological advancement of Computer-Aided Design (CAD) systems, the current work proposes the use of a FOSS CAD software in order to extend its capabilities and transform it gradually into a FOSS BIM platform. Towards this undertaking, a first approach on developing a spatial Database Management System (DBMS) able to store, organize and manage the overall amount of information within a single application, is presented.
Application of BIM technology in green scientific research office building

NASA Astrophysics Data System (ADS)

Ni, Xin; Sun, Jianhua; Wang, Bo

2017-05-01

BIM technology as a kind of information technology, has been along with the advancement of building industrialization application in domestic building industry gradually. Based on reasonable construction BIM model, using BIM technology platform, through collaborative design tools can effectively improve the design efficiency and design quality. Vanda northwest engineering design and research institute co., LTD., the scientific research office building project in combination with the practical situation of engineering using BIM technology, formed in the BIM model combined with related information according to the energy energy model (BEM) and the application of BIM technology in construction management stage made exploration, and the direct experience and the achievements gained by the architectural design part made a summary.
A review of BIM (Building Information Modeling) implementation in Indonesia construction industry

NASA Astrophysics Data System (ADS)

Suryadinata Telaga, Abdi

2018-05-01

Construction projects in Indonesia have been growing rapidly in the last three years. Therefore, construction management is very important to ensure completion of construction projects are within schedule and budget. Utilization of building information modeling (BIM) can increase the efficiency of a construction project. However, the implementation of BIM in Indonesia is still not known. This paper is intended to review the implementation of BIM in Indonesia through literature analysis. To find BIM articles in Indonesia, Firstly, searching was limited to English articles published in reputed journals or conferences. However the results were limited, then the search was expanded to the article using Indonesian languages that published in journal and conference. Based on the number of articles, the results showed that BIM research in Indonesia is still in a dearth. Furthermore, BIM study cases were conducted in a limited location and within a small population. Nevertheless, the literature shared the conclusion that BIM can increase project efficiency, but the implementation was hindered by high initial investment cost, inadequate human resources, small demand, and technology resistant. The research contributes to providing a current reported level of BIM implementation in Indonesia. In the future research to study of BIM implementation comprehensively in Indonesia is eminent.
The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.

PubMed

Rauzan, Muhammad; Chuah, Charles T H; Ko, Tun Kiat; Ong, S Tiong

2017-01-01

Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.
Best practices of Building Information Modelling (BIM) implementation in design phase for construction project

NASA Astrophysics Data System (ADS)

Kasim, N.; Zainal Abidin, N. A.; Zainal, R.; Sarpin, N.; Rahim, M. H. I. Abd; Saikah, M.

2017-11-01

Implementation of Building Information Modelling (BIM) was expected to bring improvement in current practices of Malaysian construction industry. In the design phase, there is a lack of a ready pool of skilled workers who are able to develop BIM strategic plan and effectively utilise it. These create boundaries for BIM nature in Malaysian construction industry specifically in the design phase to achieve its best practices. Therefore, the objectives of this research are to investigate the current practices of BIM implementation in the design phase as well as the best practices factors of BIM implementation in the design phase. The qualitative research approach is carried out through semi-structured interviews with the designers of different organisations which adopt BIM in the design phase. Data collection is analysed by executing content analysis method. From the findings, the best practices factors of BIM implementation in design phase such as the incentive for BIM training, formal approach to monitoring automated Level of Detailing (LOD), run a virtual meeting and improve Industry Foundation Class (IFC). Thus, best practices factors which lead to practices improvements in the design phase of project development which subsequently improves the implementation of BIM in the design phase of Malaysian construction industry.
Glucocorticoid-Mediated Repression of the Oncogenic microRNA Cluster miR-17∼92 Contributes to the Induction of Bim and Initiation of Apoptosis

PubMed Central

Molitoris, Jason K.; McColl, Karen S.

2011-01-01

Synthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17∼92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3′ untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17∼92 repression, resulting in increased Bim protein expression. Overexpression of miR-17∼92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR-17∼92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17∼92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17∼92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17∼92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17∼92 as a therapeutic target in leukemias and lymphomas. PMID:21239610
Integration of GIS and Bim for Indoor Geovisual Analytics

NASA Astrophysics Data System (ADS)

Wu, B.; Zhang, S.

2016-06-01

This paper presents an endeavour of integration of GIS (Geographical Information System) and BIM (Building Information Modelling) for indoor geovisual analytics. The merits of two types of technologies, GIS and BIM are firstly analysed in the context of indoor environment. GIS has well-developed capabilities of spatial analysis such as network analysis, while BIM has the advantages for indoor 3D modelling and dynamic simulation. This paper firstly investigates the important aspects for integrating GIS and BIM. Different data standards and formats such as the IFC (Industry Foundation Classes) and GML (Geography Markup Language) are discussed. Their merits and limitations in data transformation between GIS and BIM are analysed in terms of semantic and geometric information. An optimized approach for data exchange between GIS and BIM datasets is then proposed. After that, a strategy of using BIM for 3D indoor modelling, GIS for spatial analysis, and BIM again for visualization and dynamic simulation of the analysis results is presented. Based on the developments, this paper selects a typical problem, optimized indoor emergency evacuation, to demonstrate the integration of GIS and BIM for indoor geovisual analytics. The block Z of the Hong Kong Polytechnic University is selected as a test site. Detailed indoor and outdoor 3D models of the block Z are created using a BIM software Revit. The 3D models are transferred to a GIS software ArcGIS to carry out spatial analysis. Optimized evacuation plans considering dynamic constraints are generated based on network analysis in ArcGIS assuming there is a fire accident inside the building. The analysis results are then transferred back to BIM software for visualization and dynamic simulation. The developed methods and results are of significance to facilitate future development of GIS and BIM integrated solutions in various applications.
Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.

PubMed

Isobe, Kazutoshi; Hata, Yoshinobu; Tochigi, Naobumi; Kaburaki, Kyohei; Kobayashi, Hiroshi; Makino, Takashi; Otsuka, Hajime; Sato, Fumitomo; Ishida, Fumiaki; Kikuchi, Naoshi; Hirota, Nao; Sato, Keita; Sano, Go; Sugino, Keishi; Sakamoto, Susumu; Takai, Yujiro; Shibuya, Kazutoshi; Iyoda, Akira; Homma, Sakae

2014-04-01

Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in tumor response to treatment. To determine the clinical utility of detecting BIM deletion polymorphism in non-small-cell lung cancer positive for epidermal growth factor receptor (EGFR) mutation, we examined outcomes of patients with and without BIM alterations. We studied 70 patients with EGFR mutation-positive non-small-cell lung cancer who were treated with an EGFR tyrosine kinase inhibitor between January 2008 and January 2013. BIM deletion was analyzed by polymerase chain reaction in 58 samples of peripheral blood and 24 formalin-fixed paraffin-embedded slides of surgical specimens (20 of lung tissue and four of brain tissue); both blood and tissue specimens were available for 12 patients. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion. BIM deletion was present in 13 of 70 patients (18.6%). There were no significant differences between patients with and without BIM deletion in clinical characteristics, rate of response to EGFR tyrosine kinase inhibitor, or incidence of adverse events. Patients with BIM deletion had significantly shorter progression-free survival (PFS) than those without BIM deletion (median, 227 versus 533 days; p < 0.001). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (hazard ratio, 3.99; 95% confidence interval, 1.864-8.547; p < 0.001). Polymerase chain reaction successfully detected BIM deletion in samples of peripheral blood and formalin-fixed paraffin-embedded slides of surgical specimens. BIM deletion was the most important independent prognostic factor in shorter PFS.
Building Information Modeling (BIM): A Road Map for Implementation to Support MILCON Transformation and Civil Works Projects within the U.S. Army Corps of Engineers

DTIC Science & Technology

2006-10-01

benefit from BIM , but the data that can be gleaned from the BIM model will also feed many systems and users. What is Needed and What Must be...ER D C TR -0 6 -1 0 Building Information Modeling ( BIM ) A Road Map for Implementation To Support MILCON Transformation and Civil Works...compliant with National BIM Standard (NBIMS) 8 Centers of Standardization (COS) productive in BIM by 2008 All districts productive in NBIMS
The Pro-Apoptotic BH3-Only Protein Bim Interacts with Components of the Translocase of the Outer Mitochondrial Membrane (TOM)

PubMed Central

Frank, Daniel O.; Dengjel, Jörn; Wilfling, Florian; Kozjak-Pavlovic, Vera; Häcker, Georg; Weber, Arnim

2015-01-01

The pro-apoptotic Bcl-2-family protein Bim belongs to the BH3-only proteins known as initiators of apoptosis. Recent data show that Bim is constitutively inserted in the outer mitochondrial membrane via a C-terminal transmembrane anchor from where it can activate the effector of cytochrome c-release, Bax. To identify regulators of Bim-activity, we conducted a search for proteins interacting with Bim at mitochondria. We found an interaction of Bim with Tom70, Tom20 and more weakly with Tom40, all components of the Translocase of the Outer Membrane (TOM). In vitro import assays performed on tryptically digested yeast mitochondria showed reduced Bim insertion into the outer mitochondrial membrane (OMM) indicating that protein receptors may be involved in the import process. However, RNAi against components of TOM (Tom40, Tom70, Tom22 or Tom20) by siRNA, individually or in combination, did not consistently change the amount of Bim on HeLa mitochondria, either at steady state or upon de novo-induction. In support of this, the individual or combined knock-downs of TOM receptors also failed to alter the susceptibility of HeLa cells to Bim-induced apoptosis. In isolated yeast mitochondria, lack of Tom70 or the TOM-components Tom20 or Tom22 alone did not affect the import of Bim into the outer mitochondrial membrane. In yeast, expression of Bim can sensitize the cells to Bax-dependent killing. This sensitization was unaffected by the absence of Tom70 or by an experimental reduction in Tom40. Although thus the physiological role of the Bim-TOM-interaction remains unclear, TOM complex components do not seem to be essential for Bim insertion into the OMM. Nevertheless, this association should be noted and considered when the regulation of Bim in other cells and situations is investigated. PMID:25875815
Direct block by bisindolylmaleimide of rat Kv1.5 expressed in Chinese hamster ovary cells.

PubMed

Choi, B H; Choi, J S; Jeong, S W; Hahn, S J; Yoon, S H; Jo, Y H; Kim, M S

2000-05-01

The interaction of bisindolylmaleimide (BIM), widely used as a specific protein kinase C (PKC) inhibitor, with rat brain Kv1.5 (rKv1.5) channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. BIM (I) and its inactive analog, BIM (V), inhibited rKv1.5 currents at +50 mV in a reversible concentration-dependent manner with an apparent K(d) value of 0.38 and 1.70 microM, respectively. BIM (I) accelerated the decay rate of inactivation of rKv1.5 currents but did not significantly modify the kinetics of current activation. Other specific PKC inhibitors, chelerythrine and PKC 19-36, had no effect on rKv1.5 and did not prevent the inhibitory effect of BIM (I). The inhibition of rKv1.5 by BIM (I) and BIM (V) was highly voltage-dependent between -30 and 0 mV (voltage range of channel opening), suggesting that both drugs interact preferentially with the open state of the channel. The additional inhibition by BIM (I) displayed a voltage dependence (delta = 0.19) in the full activation voltage range positive to 0 mV, but was not shown in BIM (V) (delta = 0). The rate constants of association and dissociation for BIM (I) were 9.63 microM(-1) s(-1) and 5.82 s(-1), respectively. BIM (I) increased the time constant of deactivation of tail currents from 26. 35 to 45.79 ms, resulting in tail crossover phenomenon. BIM (I) had no effect on the voltage dependence of steady-state inactivation. BIM (I) produced use-dependent inhibition of rKv1.5, which was consistent with the slow recovery from inactivation in the presence of drug. These results suggest that BIM (I) directly inhibits rKv1.5 channels in a phosphorylation-independent, and state-, voltage-, time-, and use-dependent manner.
The pro-apoptotic BH3-only protein Bim interacts with components of the translocase of the outer mitochondrial membrane (TOM).

PubMed

Frank, Daniel O; Dengjel, Jörn; Wilfling, Florian; Kozjak-Pavlovic, Vera; Häcker, Georg; Weber, Arnim

2015-01-01

The pro-apoptotic Bcl-2-family protein Bim belongs to the BH3-only proteins known as initiators of apoptosis. Recent data show that Bim is constitutively inserted in the outer mitochondrial membrane via a C-terminal transmembrane anchor from where it can activate the effector of cytochrome c-release, Bax. To identify regulators of Bim-activity, we conducted a search for proteins interacting with Bim at mitochondria. We found an interaction of Bim with Tom70, Tom20 and more weakly with Tom40, all components of the Translocase of the Outer Membrane (TOM). In vitro import assays performed on tryptically digested yeast mitochondria showed reduced Bim insertion into the outer mitochondrial membrane (OMM) indicating that protein receptors may be involved in the import process. However, RNAi against components of TOM (Tom40, Tom70, Tom22 or Tom20) by siRNA, individually or in combination, did not consistently change the amount of Bim on HeLa mitochondria, either at steady state or upon de novo-induction. In support of this, the individual or combined knock-downs of TOM receptors also failed to alter the susceptibility of HeLa cells to Bim-induced apoptosis. In isolated yeast mitochondria, lack of Tom70 or the TOM-components Tom20 or Tom22 alone did not affect the import of Bim into the outer mitochondrial membrane. In yeast, expression of Bim can sensitize the cells to Bax-dependent killing. This sensitization was unaffected by the absence of Tom70 or by an experimental reduction in Tom40. Although thus the physiological role of the Bim-TOM-interaction remains unclear, TOM complex components do not seem to be essential for Bim insertion into the OMM. Nevertheless, this association should be noted and considered when the regulation of Bim in other cells and situations is investigated.
Identification of cis-Acting Elements and Splicing Factors Involved in the Regulation of BIM Pre-mRNA Splicing

PubMed Central

Juan, Wen Chun; Roca, Xavier; Ong, S. Tiong

2014-01-01

Aberrant changes in the expression of the pro-apoptotic protein, BCL-2-like 11 (BIM), can result in either impaired or excessive apoptosis, which can contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach to modulate apoptosis because BIM activity is partly determined by the alternative splicing of exons 3 or 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements and splicing factors involved in BIM alternative splicing, as a step to better understand the regulation of BIM expression. We analyzed a recently discovered 2,903-bp deletion polymorphism within BIM intron 2 that biased splicing towards exon 3, and which also impaired BIM-dependent apoptosis. We found that this region harbors multiple redundant cis-acting elements that repress exon 3 inclusion. Furthermore, we have isolated a 23-nt intronic splicing silencer at the 3′ end of the deletion that is important for excluding exon 3. We also show that PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. Collectively, these findings start building our understanding of the cis-acting elements and splicing factors that regulate BIM alternative splicing, and also suggest potential approaches to alter BIM splicing for therapeutic purposes. PMID:24743263

Identification of cis-acting elements and splicing factors involved in the regulation of BIM Pre-mRNA splicing.

PubMed

Juan, Wen Chun; Roca, Xavier; Ong, S Tiong

2014-01-01

Aberrant changes in the expression of the pro-apoptotic protein, BCL-2-like 11 (BIM), can result in either impaired or excessive apoptosis, which can contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach to modulate apoptosis because BIM activity is partly determined by the alternative splicing of exons 3 or 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements and splicing factors involved in BIM alternative splicing, as a step to better understand the regulation of BIM expression. We analyzed a recently discovered 2,903-bp deletion polymorphism within BIM intron 2 that biased splicing towards exon 3, and which also impaired BIM-dependent apoptosis. We found that this region harbors multiple redundant cis-acting elements that repress exon 3 inclusion. Furthermore, we have isolated a 23-nt intronic splicing silencer at the 3' end of the deletion that is important for excluding exon 3. We also show that PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. Collectively, these findings start building our understanding of the cis-acting elements and splicing factors that regulate BIM alternative splicing, and also suggest potential approaches to alter BIM splicing for therapeutic purposes.
Expanding uses of building information modeling in life-cycle construction projects.

PubMed

Hannele, Kerosuo; Reijo, Miettinen; Tarja, Mäki; Sami, Paavola; Jenni, Korpela; Teija, Rantala

2012-01-01

BIM is targeted at providing information about the entire building and a complete set of design documents and data stored in an integrated database. In this paper, we study the use of BIM in two life-cycle construction projects in Kuopio, Finland during 2011. The analysis of uses of BIM and their main problems will constitute a foundation for an intervention. We will focus on the following questions: (1) How different partners use the composite BIM model? (2) What are the major contradictions or problems in the BIM use? The preliminary findings reported in this study show that BIM has been adopted quite generally to design use but the old ways of collaboration seem to prevail, especially between designers and between designers and building sites. BIM has provided new means and demands for collaboration but expansive uses of BIM for providing new interactive processes across professional fields have not much come true.
BH3-only protein Bim is associated with the degree of Helicobacter pylori-induced gastritis and is localized to the mitochondria of inflammatory cells in the gastric mucosa.

PubMed

Akazawa, Yuko; Matsuda, Katsuya; Isomoto, Hajime; Matsushima, Kayoko; Kido, Yoko; Urabe, Shigetoshi; Yamaghchi, Naoyuki; Ohnita, Ken; Takeshima, Fuminao; Kondo, Hisayoshi; Tsugawa, Hitoshi; Suzuki, Hidekazu; Moss, Joel; Nakao, Kazuhiko; Nakashima, Masahiro

2015-09-01

BH3-only protein, Bim, is a pro-apoptotic protein that mediates mitochondria-dependent cell death. However, the role of Bim in Helicobacter pylori-associated gastritis remains unclear. This study aimed to assess the cellular localization of Bim and its possible role in H. pylori-induced gastritis. The study was conducted on biopsy specimens obtained from 80 patients who underwent upper gastrointestinal endoscopy (H. pylori-negative: n=30, positive: n=50). Association between Bim mRNA expression and severity of gastritis was evaluated and the localization of Bim was examined by immunofluorescence. Bim mRNA expression was positively correlated with the degree of gastritis, as defined by the Sydney system. Immunohistochemical analysis confirmed increased Bim expression in H. pylori-infected gastric mucosa compared with uninfected mucosa in both humans and mice. Bim localized in myeloperoxidase- and CD138-positive cells of H. pylori-infected lamina propria and submucosa of the gastric tract, indicating that this protein is predominantly expressed in neutrophils and plasma cells. In contrast, Bim did not localize in CD20-, CD3-, or CD68-positive cells. Bim was expressed in the mitochondria, where it was partially co-localized with activated Bax and cleaved-PARP. In conclusion, Bim is expressed in neutrophils and plasma cells in H. pylori-associated gastritis, where it may participate in the termination of inflammatory response by causing mitochondria-mediated apoptosis in specific leucocytes. Copyright © 2015 Elsevier GmbH. All rights reserved.
Dynein light chain 1 induces assembly of large Bim complexes on mitochondria that stabilize Mcl-1 and regulate apoptosis.

PubMed

Singh, Prafull Kumar; Roukounakis, Aristomenis; Frank, Daniel O; Kirschnek, Susanne; Das, Kushal Kumar; Neumann, Simon; Madl, Josef; Römer, Winfried; Zorzin, Carina; Borner, Christoph; Haimovici, Aladin; Garcia-Saez, Ana; Weber, Arnim; Häcker, Georg

2017-09-01

The Bcl-2 family protein Bim triggers mitochondrial apoptosis. Bim is expressed in nonapoptotic cells at the mitochondrial outer membrane, where it is activated by largely unknown mechanisms. We found that Bim is regulated by formation of large protein complexes containing dynein light chain 1 (DLC1). Bim rapidly inserted into cardiolipin-containing membranes in vitro and recruited DLC1 to the membrane. Bim binding to DLC1 induced the formation of large Bim complexes on lipid vesicles, on isolated mitochondria, and in intact cells. Native gel electrophoresis and gel filtration showed Bim-containing mitochondrial complexes of several hundred kilodaltons in all cells tested. Bim unable to form complexes was consistently more active than complexed Bim, which correlated with its substantially reduced binding to anti-apoptotic Bcl-2 proteins. At endogenous levels, Bim surprisingly bound only anti-apoptotic Mcl-1 but not Bcl-2 or Bcl-X L , recruiting only Mcl-1 into large complexes. Targeting of DLC1 by RNAi in human cell lines induced disassembly of Bim-Mcl-1 complexes and the proteasomal degradation of Mcl-1 and sensitized the cells to the Bcl-2/Bcl-X L inhibitor ABT-737. Regulation of apoptosis at mitochondria thus extends beyond the interaction of monomers of proapoptotic and anti-apoptotic Bcl-2 family members but involves more complex structures of proteins at the mitochondrial outer membrane, and targeting complexes may be a novel therapeutic strategy. © 2017 Singh et al.; Published by Cold Spring Harbor Laboratory Press.
Identifying critical success factors (CSFs) of implementing building information modeling (BIM) in Malaysian construction industry

NASA Astrophysics Data System (ADS)

Yaakob, Mazri; Ali, Wan Nur Athirah Wan; Radzuan, Kamaruddin

2016-08-01

Building Information Modeling (BIM) is defined as existing from the earliest concept to demolition and it involves creating and using an intelligent 3D model to inform and communicate project decisions. This research aims to identify the critical success factors (CSFs) of BIM implementation in Malaysian construction industry. A literature review was done to explore previous BIM studies on definitions and history of BIM, construction issues, application of BIM in construction projects as well as benefits of BIM. A series of interviews with multidisciplinary Malaysian construction experts will be conducted purposely for data collection process guided by the research design and methodology approach of this study. The analysis of qualitative data from the process will be combined with criteria identified in the literature review in order to identify the CSFs. Finally, the CSFs of BIM implementation will be validated by further Malaysian industrialists during a workshop. The validated CSFs can be used as a term of reference for both Malaysian practitioners and academics towards measuring BIM effectiveness level in their organizations.
Bim suppresses the development of SLE by limiting myeloid inflammatory responses.

PubMed

Tsai, FuNien; Homan, Philip J; Agrawal, Hemant; Misharin, Alexander V; Abdala-Valencia, Hiam; Haines, G Kenneth; Dominguez, Salina; Bloomfield, Christina L; Saber, Rana; Chang, Anthony; Mohan, Chandra; Hutcheson, Jack; Davidson, Anne; Budinger, G R Scott; Bouillet, Philippe; Dorfleutner, Andrea; Stehlik, Christian; Winter, Deborah R; Cuda, Carla M; Perlman, Harris

2017-12-04

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysM Cre Bim fl/fl ) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim -/- mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysM Cre Bim fl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysM Cre Bim fl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE. © 2017 Tsai et al.
The Epstein-Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim.

PubMed

Desbien, Anthony L; Kappler, John W; Marrack, Philippa

2009-04-07

Current knowledge suggests that the balance between life and death within a cell can be controlled by the stable engagement of Bcl-2-related proapoptotic proteins such as Bak, Bax, and Bim by survival proteins such as Bcl-2. BHRF1 is a prosurvival molecule from Epstein-Barr virus that has a high degree of homology to Bcl-2. To understand how BHRF1 blocks apoptosis, BHRF1 and mutants of BHRF1 were expressed in primary cells and an IL-2-dependent T cell line. BHRF1 bound the Executioner Bak and, when cells were cultured without cytokines, BHRF1 associated with Bim. A point mutation that lost the ability to bind Bak retained its ability to bind Bim and to protect cells. This result demonstrated that it was the capacity of BHRF1 to bind Bim, not Bak, that provided protection. Interestingly, the amount of Bim bound by BHRF1 was minimal when compared with the amount of Bim induced by apoptosis. Thus, BHRF1 does not act by simply absorbing the excess Bim produced while cells prepare for death. Rather, BHRF1 may act either by binding preferentially the most lethal form of Bim or by acting catalytically on Bim to block apoptosis.
Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice.

PubMed

Herold, M J; Stuchbery, R; Mérino, D; Willson, T; Strasser, A; Hildeman, D; Bouillet, P

2014-10-09

The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER, in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains (Rosa26-CreER and Vav-CreER) and will make these exciting new tools for studies on cell death and cancer available.
Bim Regulates Alloimmune-Mediated Vascular Injury Through Effects on T Cell Activation and Death

PubMed Central

von Rossum, Anna; Enns, Winnie; Shi, Yu P.; MacEwan, Grace E.; Malekesmaeli, Mehrnoush; Brinkman, Ryan; Choy, Jonathan C.

2014-01-01

Objective Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses and to also be required for antigen-induced T cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T cell responses in a model of vascular rejection. Approach and Results Bim was required for proliferation of CD4 and CD8 T cells, and for IL-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T cell activation whereas a complete elimination of Bim was required to prevent CD4 T cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim+/−, but not Bim−/−, graft recipients. T cell proliferation in response to allograft arteries was significantly reduced in both Bim+/− and Bim−/− mice, but cell death was attenuated only in Bim−/− animals. Conclusions Bim controls both T cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries. PMID:24700126
Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3.

PubMed

Koenig, M N; Naik, E; Rohrbeck, L; Herold, M J; Trounson, E; Bouillet, P; Thomas, T; Voss, A K; Strasser, A; Coultas, L

2014-11-01

The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim(-/-) primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17∼92 cluster. Bim mRNA levels were also elevated in miR-17∼92(+/-) endothelial cells cultured under steady-state conditions, suggesting that miR-17∼92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.
Dynein light chain 1 induces assembly of large Bim complexes on mitochondria that stabilize Mcl-1 and regulate apoptosis

PubMed Central

Singh, Prafull Kumar; Roukounakis, Aristomenis; Frank, Daniel O.; Kirschnek, Susanne; Das, Kushal Kumar; Neumann, Simon; Madl, Josef; Römer, Winfried; Zorzin, Carina; Borner, Christoph; Haimovici, Aladin; Garcia-Saez, Ana; Weber, Arnim; Häcker, Georg

2017-01-01

The Bcl-2 family protein Bim triggers mitochondrial apoptosis. Bim is expressed in nonapoptotic cells at the mitochondrial outer membrane, where it is activated by largely unknown mechanisms. We found that Bim is regulated by formation of large protein complexes containing dynein light chain 1 (DLC1). Bim rapidly inserted into cardiolipin-containing membranes in vitro and recruited DLC1 to the membrane. Bim binding to DLC1 induced the formation of large Bim complexes on lipid vesicles, on isolated mitochondria, and in intact cells. Native gel electrophoresis and gel filtration showed Bim-containing mitochondrial complexes of several hundred kilodaltons in all cells tested. Bim unable to form complexes was consistently more active than complexed Bim, which correlated with its substantially reduced binding to anti-apoptotic Bcl-2 proteins. At endogenous levels, Bim surprisingly bound only anti-apoptotic Mcl-1 but not Bcl-2 or Bcl-XL, recruiting only Mcl-1 into large complexes. Targeting of DLC1 by RNAi in human cell lines induced disassembly of Bim–Mcl-1 complexes and the proteasomal degradation of Mcl-1 and sensitized the cells to the Bcl-2/Bcl-XL inhibitor ABT-737. Regulation of apoptosis at mitochondria thus extends beyond the interaction of monomers of proapoptotic and anti-apoptotic Bcl-2 family members but involves more complex structures of proteins at the mitochondrial outer membrane, and targeting complexes may be a novel therapeutic strategy. PMID:28982759
The protein kinase C inhibitor, bisindolylmaleimide (I), inhibits voltage-dependent K+ channels in coronary arterial smooth muscle cells.

PubMed

Park, Won Sun; Son, Youn Kyoung; Ko, Eun A; Ko, Jae-Hong; Lee, Hyang Ae; Park, Kyoung Sun; Earm, Yung E

2005-06-17

We examined the effects of the protein kinase C (PKC) inhibitor, bisindolylmaleimide (BIM) (I), on voltage-dependent K+ (K(V)) channels in rabbit coronary arterial smooth muscle cells using whole-cell patch clamp technique. BIM (I) reversibly and dose-dependently inhibited the K(V) currents with an apparent Kd value of 0.27 microM. The inhibition of the K(V) current by BIM (I) was highly voltage-dependent between -30 and +10 mV (voltage range of channel activation), and the additive inhibition of the K(V) current by BIM (I) was voltage-dependence in the full activation voltage range. The rate constants of association and dissociation for BIM (I) were 18.4 microM(-1) s(-1) and 4.7 s(-1), respectively. BIM (I) had no effect on the steady-state activation and inactivation of K(V) channels. BIM (I) caused use-dependent inhibition of K(V) current, which was consistent with the slow recovery from inactivation in the presence of BIM (I) (recovery time constants were 856.95 +/- 282.6 ms for control, and 1806.38 +/- 110.0 ms for 300 nM BIM (I)). ATP-sensitive K+ (K(ATP)), inward rectifier K+ (K(IR)), Ca2+-activated K+ (BK(Ca)) channels, which regulate the membrane potential and arterial tone, were not affected by BIM (I). The PKC inhibitor, chelerythrine, and protein kinase A (PKA) inhibitor, PKA-IP, had little effect on the K(V) current and did not significantly alter the inhibitory effects of BIM (I) on the K(V) current. These results suggest that BIM (I) inhibits K(V) channels in a phosphorylation-independent, and voltage-, time- and use-dependent manner.
Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner.

PubMed

Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M; Strasser, Andreas; Heierhorst, Jörg

2018-01-01

The proapoptotic BH3-only protein BIM ( Bcl2l11 ) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre ) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre ) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim -deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro , conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc -driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions.
The MEK-ERK pathway negatively regulates bim expression through the 3' UTR in sympathetic neurons

PubMed Central

2011-01-01

Background Apoptosis plays a critical role during neuronal development and disease. Developing sympathetic neurons depend on nerve growth factor (NGF) for survival during the late embryonic and early postnatal period and die by apoptosis in its absence. The proapoptotic BH3-only protein Bim increases in level after NGF withdrawal and is required for NGF withdrawal-induced death. The regulation of Bim expression in neurons is complex and this study describes a new mechanism by which an NGF-activated signalling pathway regulates bim gene expression in sympathetic neurons. Results We report that U0126, an inhibitor of the prosurvival MEK-ERK pathway, increases bim mRNA levels in sympathetic neurons in the presence of NGF. We find that this effect is independent of PI3-K-Akt and JNK-c-Jun signalling and is not mediated by the promoter, first exon or first intron of the bim gene. By performing 3' RACE and microinjection experiments with a new bim-LUC+3'UTR reporter construct, we show that U0126 increases bim expression via the bim 3' UTR. We demonstrate that this effect does not involve a change in bim mRNA stability and by using PD184352, a specific MEK1/2-ERK1/2 inhibitor, we show that this mechanism involves the MEK1/2-ERK1/2 pathway. Finally, we demonstrate that inhibition of MEK/ERK signalling independently reduces cell survival in NGF-treated sympathetic neurons. Conclusions These results suggest that in sympathetic neurons, MEK-ERK signalling negatively regulates bim expression via the 3' UTR and that this regulation is likely to be at the level of transcription. This data provides further insight into the different mechanisms by which survival signalling pathways regulate bim expression in neurons. PMID:21762482
MiR-24 alleviates cardiomyocyte apoptosis after myocardial infarction via targeting BIM.

PubMed

Pan, L-J; Wang, X; Ling, Y; Gong, H

2017-07-01

Ischemia hypoxia induces cardiomyocyte (CM) apoptosis in the process of acute myocardial infarction (AMI). It was showed that pro-apoptosis factor BIM participates in regulating tumor cell apoptosis under ischemia or hypoxia condition, while its role in CM apoptosis after AMI is still unclear. It was revealed that miR-24 expression was significantly reduced in myocardial tissue after AMI. Bioinformatics analysis exhibits that miR-24 is targeted to the 3'-UTR of BIM. This study aims to investigate the role of miR-24 in mediating BIM expression and CM apoptosis. Dual-luciferase assay was used to confirm the targeted regulation between miR-24 and BIM. Cells were cultured under ischemia hypoxia for 12 h after transfection for 48 h. Cell apoptosis was tested by using flow cytometry. The caspase activity was detected by using spectrophotometry. Wistar rats were divided into four groups, including Sham, AMI, AMI + agomir-control, and AMI + agomir-24 groups. Cardiac function was evaluated by using echocardiography. CM apoptosis was determined by using TUNEL. Infarction area was measured by using evans blue staining. MiR-24 targeted suppressed BIM expression. MiR-24 mimic and/or si-BIM transfection significantly declined the BIM expression, inhibited caspase-9 and caspase-3 activities, and reduced cell apoptosis in H9C2 cells. MiR-24 expression was decreased, while BIM levels were up-regulated in myocardium after AMI. Agomir-24 injection down-regulated the BIM expression in myocardium, reduced CM apoptosis, narrowed infarction area, and improved cardiac function in rats. MiR-24 was reduced, whereas BIM was enhanced in the CM after AMI. MiR-24 up-regulation plays a critical role in decreasing BIM expression, reducing CM apoptosis, and improving cardiac function after AMI.
Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner

PubMed Central

Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M.; Strasser, Andreas; Heierhorst, Jörg

2018-01-01

The proapoptotic BH3-only protein BIM (Bcl2l11) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim-deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro, conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc-driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions. PMID:29623080
CRISPR analysis of bacteriophage-insensitive mutants (BIMs) of industrial Streptococcus thermophilus--implications for starter design.

PubMed

Mills, S; Griffin, C; Coffey, A; Meijer, W C; Hafkamp, B; Ross, R P

2010-03-01

An efficient approach for generation of bacteriophage-insensitive mutants (BIMs) of Streptococcus thermophilus starters was described in our laboratory [Mills et al. (2007) J Microbiol Methods70, 159-164]. The aim of this study was to analyse the phage resistance mechanism responsible for BIM formation. Three clustered regularly interspaced short palindromic repeat (CRISPR) regions have been identified in Strep. thermophilus, and Strep. thermophilus can integrate novel spacers into these loci in response to phage attack. Characterization of three sets of BIMs indicated that two sets had altered CRISPR1 and/or CRISPR3 loci. A range of BIMs of yoghurt starter CSK938 were generated with the same phage in different phage challenge experiments, and each acquired unique spacer regions ranging between one and four new spacers in CRISPR1. In addition, the BIM that acquired only one new spacer in CRISPR1 also acquired an additional spacer in CRISPR3. A fourth BIM, generated with a different phage, had two spacers deleted from CRISPR1 but acquired two spacers in CRISPR3. Analysis of the Mozzarella starter CSK939 and its associated BIMs indicated that formation of second generation BIMs does not lead to increases in spacer number but to alterations in spacer regions. BIMs of an exopolysaccharide (EPS)-producing strain that lost the ability to produce EPS did not harbour an altered CRISPR, suggesting that phage sensitivity may be related to the EPS-producing phenotype. Acquisition/deletion of new spacers in CRISPR loci in response to phage attack generates distinctly individual variants. It also demonstrates that other modifications may be responsible for the phage resistance of Strep. thermophilus BIMs. Isolation of individual BIMs that have unique spacers towards the leader region of the CRISPR locus may be a very useful approach for rotation strategies with the same starter backbone. Upon phage infection, BIMs 'in reserve' can be slotted into the rotation scheme.
Functional linkage between NOXA and Bim in mitochondrial apoptotic events.

PubMed

Han, Jie; Goldstein, Leslie A; Hou, Wen; Rabinowich, Hannah

2007-06-01

NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.
BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins.

PubMed

Weber, Arnim; Paschen, Stefan A; Heger, Klaus; Wilfling, Florian; Frankenberg, Tobias; Bauerschmitt, Heike; Seiffert, Barbara M; Kirschnek, Susanne; Wagner, Hermann; Häcker, Georg

2007-05-21

Release of apoptogenic proteins such as cytochrome c from mitochondria is regulated by pro- and anti-apoptotic Bcl-2 family proteins, with pro-apoptotic BH3-only proteins activating Bax and Bak. Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein Bim(S). Regulated expression of Bim(S) in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of Bim(S) showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, Bim(S) enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. Thus, cell death induction by a BH3-only protein can occur through a process that is independent of anti-apoptotic Bcl-2 proteins but requires mitochondrial targeting.
Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo

PubMed Central

Yu, Yu; Yu, Jing; Iclozan, Cristina; Kaosaard, Kane; Anasetti, Claudio; Yu, Xue-Zhong

2012-01-01

Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim-/- T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation. PMID:22432091

76 FR 23974 - Certain Pasta From Turkey: Notice of Preliminary Results of Antidumping Duty Administrative Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-29

... shareholder in BIM Birlesik Magazalar (BIM). BIM is owned 12 percent by Ulker Biskuvi, which is also an Ulker... Marsan's parent company and Birlik's parent company each own shares in BIM, a third party. See id., at 9...
Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex.

PubMed

Gomez-Bougie, Patricia; Oliver, Lisa; Le Gouill, Steven; Bataille, Régis; Amiot, Martine

2005-12-01

Multiple myeloma (MM) is a rapidly fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with MM but as yet its mechanisms of action are poorly documented. In the current study, we demonstrate that melphalan induces a drastic downregulation of Mcl-1L, Bcl-x(L) and BimEL in human melphalan-sensitive myeloma cells while the most potent proapoptotic isoforms, BimL and S, are affected to a lesser extent. Moreover, Mcl-1L and BimEL disappearance is associated with the generation of proapoptotic cleaved forms generated by a caspase cleavage. In myeloma cells, we have previously shown that Mcl-1 neutralizes the proapoptotic function of Bim and therefore, prevents the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex whereas the Bcl-2/Bim complex is not modified. The disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their proapoptotic function and leads to Bax activation and cytochrome c release. Thus, we can hypothesize that the cleaved 26 kDa proapoptotic Mcl-1 and the 19 and 12 kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis.
Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides

PubMed Central

Liu, Jun; Bhadra, Malini; Sinnakannu, Joanna Rajeswary; Yue, Wan Lin; Tan, Cheryl Weiqi; Rigo, Frank; Ong, S.Tiong; Roca, Xavier

2017-01-01

Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis. We sought to identify splice-switching antisense oligonucleotides (ASOs) that block exon 3 but enhance exon 4 splicing, and thereby resensitize BIM deletion-containing cancers to imatinib. First, we mapped multiple cis-acting splicing elements around BIM exon 3 by minigene mutations, and found an exonic splicing enhancer acting via SRSF1. Second, by a systematic ASO walk, we isolated ASOs that corrected the aberrant BIM splicing. Eight of 67 ASOs increased exon 4 levels in BIM deletion-containing cells, and restored imatinib-induced apoptosis and TKI sensitivity. This proof-of-principle study proves that resistant CML cells by BIM deletion polymorphism can be resensitized to imatinib via splice-switching BIM ASOs. Future optimizations might yield a therapeutic ASO as precision-medicine adjuvant treatment for BIM-polymorphism-associated TKI-resistant CML and other cancers. PMID:29100409
Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides.

PubMed

Liu, Jun; Bhadra, Malini; Sinnakannu, Joanna Rajeswary; Yue, Wan Lin; Tan, Cheryl Weiqi; Rigo, Frank; Ong, S Tiong; Roca, Xavier

2017-09-29

Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis. We sought to identify splice-switching antisense oligonucleotides (ASOs) that block exon 3 but enhance exon 4 splicing, and thereby resensitize BIM deletion-containing cancers to imatinib. First, we mapped multiple cis -acting splicing elements around BIM exon 3 by minigene mutations, and found an exonic splicing enhancer acting via SRSF1. Second, by a systematic ASO walk, we isolated ASOs that corrected the aberrant BIM splicing. Eight of 67 ASOs increased exon 4 levels in BIM deletion-containing cells, and restored imatinib-induced apoptosis and TKI sensitivity. This proof-of-principle study proves that resistant CML cells by BIM deletion polymorphism can be resensitized to imatinib via splice-switching BIM ASOs. Future optimizations might yield a therapeutic ASO as precision-medicine adjuvant treatment for BIM -polymorphism-associated TKI-resistant CML and other cancers.
FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons

PubMed Central

Gilley, Jonathan; Coffer, Paul J.; Ham, Jonathan

2003-01-01

Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal–induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons. PMID:12913110
BH3-only protein Bim predicts advanced stage of cutaneous melanoma.

PubMed

Gambichler, T; Rooms, I; Scholl, L; Stockfleth, E; Stücker, M; Sand, M

2016-11-01

Bim having strong pro-apoptotic effects belongs to the BH3-only proteins of the Bcl-2 protein family and contributes to survival pathways in cancer cells. We aimed to investigate Bim protein expression in cutaneous melanoma (CM). Bim protein expression was assessed by immunohistochemistry in primary and metastatic melanomas and correlated with clinical and histopathological features. The Bim immunoreactivity score of the primary melanomas investigated (4.6 ± 1.5) was significantly (P < 0.0001) higher than that observed in metastases (2.8 ± 1.1). Low Bim expression was significantly associated with primary nodular melanoma type (P = 0.005). Moreover, Bim expression was significantly inversely correlated with tumour thickness (r = -0.36; P = 0.0035), advanced stage of disease (stage III and IV; r = -0.60; P < 0.0001), disease relapse (r = -0.18; P = 0.034) and disease-related death (r = -0.19; P = 0.026). Advanced stage of disease was independently predicted by low Bim expression (P = 0.0010, odds ratio: 0.22, 95% CI: 0.10-0.56) on multivariate analysis; however, Bim was not shown to be an independent predictor for disease relapse (P = 0.40) and disease-related death (P = 0.77). Our data demonstrate that Bim protein expression is significantly inversely correlated with melanoma features that are associated with worse prognosis. We have shown that Bim protein expression in CM is an independent predictor for advanced disease confirming that this pro-apoptotic BH3-only protein might be a potent biomarker and promising therapeutic target. © 2016 European Academy of Dermatology and Venereology.
A Systematic Method of Integrating BIM and Sensor Technology for Sustainable Construction Design

NASA Astrophysics Data System (ADS)

Liu, Zhen; Deng, Zhiyu

2017-10-01

Building Information Modeling (BIM) has received lots of attention of construction field, and sensor technology was applied in construction data collection. This paper developed a method to integrate BIM and sensor technology for sustainable construction design. A brief literature review was conducted to clarify the current development of BIM and sensor technology; then a systematic method for integrating BIM and sensor technology to realize sustainable construction design was put forward; finally a brief discussion and conclusion was given.
BH3-only protein Bim is upregulated and mediates the apoptosis of cardiomyocytes under glucose and oxygen-deprivation conditions.

PubMed

Huang, Chahua; Li, Juxiang; Hong, Kui; Xia, Zhen; Xu, Yan; Cheng, Xiaoshu

2015-03-01

Bim is a potent pro-apoptotic BH3-only Bcl-2 member. However, the expression of Bim and its role in cardiac injury induced by ischemia remain unclear. H9c2 cells were subjected to a glucose and oxygen-deprived (GOD) condition in vitro, mimicking ischemia environment in vivo. GOD treatment augmented the expression of Bim and induced the apoptosis of H9c2 cells. Silencing of Bim by RNAi significantly attenuated GOD-induced cytotoxicity, suppressed mitochondrial membrane potential △Ψm loss, inhibited caspase 3 activation and reduced apoptosis. The data demonstrate that Bim is upregulated by GOD in a time-dependent manner in H9c2 cells, and enhances mitochondrial apoptosis dependent on the activation of caspase 3. Silencing of Bim may be a promising therapeutic strategy in ischemia related heart diseases. © 2014 International Federation for Cell Biology.
Common Object Library Description

DTIC Science & Technology

2012-08-01

Information Modeling ( BIM ) technology to be successful, it must be consistently applied across many projects, by many teams. The National Building Information ...distribution is unlimited. 13. SUPPLEMENTARY NOTES 14. ABSTRACT For Building Information Modeling ( BIM ) technology to be successful, it must be... BIM standards and for future research projects. 15. SUBJECT TERMS building information modeling ( BIM ), object
High glucose induces apoptosis via upregulation of Bim expression in proximal tubule epithelial cells.

PubMed

Zhang, Xiao-Qian; Dong, Jian-Jun; Cai, Tian; Shen, Xue; Zhou, Xiao-Jun; Liao, Lin

2017-04-11

Diabetic nephropathy is the primary cause of end-stage renal disease. Apoptosis of tubule epithelial cells is a major feature of diabetic nephropathy. The mechanisms of high glucose (HG) induced apoptosis are not fully understood. Here we demonstrated that, HG induced apoptosis via upregulating the expression of proapoptotic Bcl-2 homology domain 3 (BH3)-only protein Bim protein, but not bring a significant change in the baseline level of autophagy in HK2 cells. The increase of Bim expression was caused by the ugregulation of transcription factors, FOXO1 and FOXO3a. Bim expression initiates BAX/BAK-mediated mitochondria-dependent apoptosis. Silence of Bim by siRNA in HK2 cells prevented HG-induced apoptosis and also sensitized HK2 cells to autophagy during HG treatment. The autophagy inhibitor 3-MA increased the injury in Bim knockdown HK2 cells by retriggering apoptosis. The above results suggest a Bim-independent apoptosis pathway in HK2 cells, which normally could be inhibited by autophagy. Overall, our results indicate that HG induces apoptosis via up-regulation of Bim expression in proximal tubule epithelial cells.
CaMKII inhibition promotes neuronal apoptosis by transcriptionally upregulating Bim expression.

PubMed

Zhao, Yiwei; Zhu, Lin; Yu, Shaojun; Zhu, Jing; Wang, Chong

2016-09-28

The effects of Ca/calmodulin-dependent protein kinase II (CaMKII) on neuronal apoptosis are complex and contradictory, and the underlying mechanisms remain unclear. Bcl-2-interacting mediator of cell death (Bim) is an important proapoptotic protein under many physiological and pathophysiological conditions. However, there is no evidence that CaMKII and Bim are mechanistically linked in neuronal apoptosis. In this study, we showed that CaMKII inhibition by the inhibitors KN-62 and myristoylated autocamtide-2-related inhibitory peptide promoted apoptosis in cerebellar granule neurons in a dose-dependent manner. CaMKII inhibition increased Bim protein and messenger RNA levels. The expression of early growth response factor-1, a transcription factor of Bim, was also induced by CaMKII inhibitors. These data suggested that CaMKII repressed the transcriptional expression of Bim. Moreover, knockdown of Bim using small interfering RNAs attenuated the proapoptotic effects of CaMKII inhibition. Taken together, this is the first report to show that CaMKII inhibition transcriptionally upregulates Bim expression to promote neuronal apoptosis, providing new insights into the proapoptotic mechanism of CaMKII inhibition.
HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis

PubMed Central

Kennedy, Donna; Mnich, Katarzyna; Oommen, Deepu; Chakravarthy, Reka; Almeida-Souza, Leonardo; Krols, Michiel; Saveljeva, Svetlana; Doyle, Karen; Gupta, Sanjeev; Timmerman, Vincent; Janssens, Sophie; Gorman, Adrienne M; Samali, Afshin

2017-01-01

BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants. PMID:29048431
HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis.

PubMed

Kennedy, Donna; Mnich, Katarzyna; Oommen, Deepu; Chakravarthy, Reka; Almeida-Souza, Leonardo; Krols, Michiel; Saveljeva, Svetlana; Doyle, Karen; Gupta, Sanjeev; Timmerman, Vincent; Janssens, Sophie; Gorman, Adrienne M; Samali, Afshin

2017-08-31

BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants.
The germline BIM deletion polymorphism is not associated with the treatment efficacy of sorafenib in patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Chang, Yung-Lin; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2013-01-01

A germline BIM deletion polymorphism has been proposed to predict a poor treatment efficacy of certain kinase inhibitors. The current study aimed to explore whether the BIM deletion polymorphism predicts the treatment efficacy of sorafenib for advanced hepatocellular carcinoma (HCC). All patients who were enrolled in clinical trials to receive sorafenib-containing regimens as first-line therapy for advanced HCC and consented to providing peripheral blood samples were included. Polymerase chain reaction followed by gel electrophoresis was used to detect the germline BIM deletion polymorphism. A total of 89 patients were enrolled; 69 (77%) patients had chronic hepatitis B infection, and 18 (20%) had chronic hepatitis C infection. The heterozygous BIM deletion polymorphism was identified in 9 (10%) patients. Patients with and without the BIM deletion polymorphism had similar response rates (11 vs. 6%) and disease control rates (56 vs. 61%). The time to progression, progression-free survival, and overall survival were similar between patients with and without the BIM deletion polymorphism. After adjusting for basic clinicopathologic variables and treatment regimens, the BIM polymorphism still could not predict treatment outcomes. The BIM deletion polymorphism was not associated with the treatment efficacy of sorafenib for advanced HCC. © 2013 S. Karger AG, Basel.
Leukocyte Bim deficiency does not impact atherogenesis in ldlr -/- mice, despite a pronounced induction of autoimmune inflammation.

PubMed

Temmerman, Lieve; Westra, Marijke M; Bot, Ilze; van Vlijmen, Bart J M; van Bree, Niek; Bot, Martine; Habets, Kim L L; Keulers, Tom G H; van der Vlag, Johan; Cotter, Thomas G; van Berkel, Theo J C; Biessen, Erik A L

2017-06-08

Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim -/- or wild type bone marrow transplanted ldlr -/- mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim -/- transplanted mice displayed splenomegaly and overt lymphocytosis. CD4 + and CD8 + T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim -/- mice. Bim -/- mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim -/- mice.
The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.

PubMed

Weber, Arnim; Heinlein, Melanie; Dengjel, Jörn; Alber, Claudia; Singh, Prafull Kumar; Häcker, Georg

2016-05-01

Bim is a pro-apoptotic Bcl-2 family member of the BH3-only protein subgroup. Expression levels of Bim determine apoptosis susceptibility in non-malignant and in tumour cells. Bim protein expression is downregulated by proteasomal degradation following ERK-dependent phosphorylation and ubiquitination. Here, we report the identification of a deubiquitinase, Usp27x, that binds Bim upon its ERK-dependent phosphorylation and can upregulate its expression levels. Overexpression of Usp27x reduces ERK-dependent Bim ubiquitination, stabilizes phosphorylated Bim, and induces apoptosis in PMA-stimulated cells, as well as in tumour cells with a constitutively active Raf/ERK pathway. Loss of endogenous Usp27x enhances the Bim-degrading activity of oncogenic Raf. Overexpression of Usp27x induces low levels of apoptosis in melanoma and non-small cell lung cancer (NSCLC) cells and substantially enhances apoptosis induced in these cells by the inhibition of ERK signalling. Finally, deletion of Usp27x reduces apoptosis in NSCLC cells treated with an EGFR inhibitor. Thus, Usp27x can trigger via its proteolytic activity the deubiquitination of Bim and enhance its levels, counteracting the anti-apoptotic effects of ERK activity, and therefore acts as a tumour suppressor. © 2016 The Authors.
Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis.

PubMed

Han, Jie; Goldstein, Leslie A; Gastman, Brian R; Rabinowich, Hannah

2006-04-14

The current study demonstrates a novel cross-talk mechanism between the TRAIL receptor death signaling pathway and the mitochondria. This newly identified pathway is regulated at the mitochondrial outer membrane by a complex between the prosurvival Bcl-2 member, Mcl-1 and the BH3-only protein, Bim. Under non-apoptotic conditions, Bim is sequestered by Mcl-1. Direct degradation of Mcl-1 by TRAIL-activated caspase-8 or caspase-3 produces Mcl-1-free Bim that mediates a Bax-dependent apoptotic cascade. Using Mcl-1 or Bim RNAi, we demonstrate that a loss in Mcl-1 expression significantly enhances the mitochondrial apoptotic response to TRAIL that is now mediated by freed Bim. Whereas overexpression of Mcl-1 contributes to the preservation of the mitochondrial membrane potential, Mcl-1 knockdown facilitates the Bim-mediated dissipation of this potential. Loss of Mcl-1 contributes to an increased level of caspase activity downstream of the mitochondrial response to TRAIL. Furthermore, the Mcl-1 expression level at the mitochondrial outer membrane determines the release efficiency for the apoptogenic proteins cytochrome c, Smac, and HtrA2 in response to Bim. These are the first findings to demonstrate the involvement of Bim in the TRAIL-mediated mitochondrial cascade. They also suggest that Mcl-1 may serve as a direct substrate for TRAIL-activated caspases implying the existence of a novel TRAIL/caspase-8/Mcl-1/Bim communication mechanism between the extrinsic and the intrinsic apoptotic pathways.
Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells

PubMed Central

Liu, XueQiao

2014-01-01

Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens, such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. Varicella-zoster virus (VZV) induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of the proapoptotic proteins Bim and BAD but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduces their proapoptotic activity, this may prevent or delay apoptosis in VZV-infected cells. Phosphorylation of Bim but not BAD in VZV-infected cells was dependent on activation of the MEK/extracellular signal-regulated kinase (ERK) pathway. Cells knocked down for Bim showed delayed VZV plaque formation, resulting in longer survival of VZV-infected cells and increased replication of virus, compared with wild-type cells infected with virus. Conversely, overexpression of Bim resulted in earlier plaque formation, smaller plaques, reduced virus replication, and increased caspase 3 activity. Inhibition of caspase activity in VZV-infected cells overexpressing Bim restored levels of virus production similar to those seen with virus-infected wild-type cells. Previously we showed that VZV ORF12 activates ERK and inhibits apoptosis in virus-infected cells. Here we found that VZV ORF12 contributes to Bim and BAD phosphorylation. In summary, VZV triggers Bim phosphorylation; reduction of Bim levels results in longer survival of VZV-infected cells and increased VZV replication. PMID:24227856
BIM Gene Polymorphism Lowers the Efficacy of EGFR-TKIs in Advanced Nonsmall Cell Lung Cancer With Sensitive EGFR Mutations: A Systematic Review and Meta-Analysis.

PubMed

Huang, Wu Feng; Liu, Ai Hua; Zhao, Hai Jin; Dong, Hang Ming; Liu, Lai Yu; Cai, Shao Xi

2015-08-01

The strong association between bcl-2-like 11 (BIM) triggered apoptosis and the presence of epidermal growth factor receptor (EGFR) mutations has been proven in nonsmall cell lung cancer (NSCLC). However, the relationship between EGFR-tyrosine kinase inhibitor's (TKI's) efficacy and BIM polymorphism in NSCLC EGFR is still unclear.Electronic databases were searched for eligible literatures. Data on objective response rates (ORRs), disease control rates (DCRs), and progression-free survival (PFS) stratified by BIM polymorphism status were extracted and synthesized based on random-effect model. Subgroup and sensitivity analyses were conducted.A total of 6 studies that involved a total of 773 EGFR mutant advanced NSCLC patients after EGFR-TKI treatment were included. In overall, non-BIM polymorphism patients were associated with significant prolonged PFS (hazard ratio 0.63, 0.47-0.83, P = 0.001) compared to patients with BIM polymorphism. However, only marginal improvements without statistical significance in ORR (odds ratio [OR] 1.71, 0.91-3.24, P = 0.097) and DCR (OR 1.56, 0.85-2.89, P = 0.153) were observed. Subgroup analyses showed that the benefits of PFS in non-BIM polymorphism group were predominantly presented in pooled results of studies involving chemotherapy-naive and the others, and retrospective studies. Additionally, we failed to observe any significant benefit from patients without BIM polymorphism in every subgroup for ORR and DCR.For advanced NSCLC EGFR mutant patients, non-BIM polymorphism ones are associated with longer PFS than those with BIM polymorphism after EGFR-TKIs treatment. BIM polymorphism status should be considered an essential factor in studies regarding EGFR-targeted agents toward EGFR mutant patients.
BH3-only protein BIM: An emerging target in chemotherapy.

PubMed

Shukla, Shatrunajay; Saxena, Sugandh; Singh, Brijesh Kumar; Kakkar, Poonam

2017-12-01

BH3-only proteins constitute major proportion of pro-apoptotic members of B-cell lymphoma 2 (Bcl-2) family of apoptotic regulatory proteins and participate in embryonic development, tissue homeostasis and immunity. Absence of BH3-only proteins contributes to autoimmune disorders and tumorigenesis. Bim (Bcl-2 Interacting Mediator of cell death), most important member of BH3-only proteins, shares a BH3-only domain (9-16 aa) among 4 domains (BH1-BH4) of Bcl-2 family proteins and highly pro-apoptotic in nature. Bim initiates the intrinsic apoptotic pathway under both physiological and patho-physiological conditions. Reduction in Bim expression was found to be associated with tumor promotion and autoimmunity, while overexpression inhibited tumor growth and drug resistance as cancer cells suppress Bim expression and stability. Apart from its role in normal homeostasis, Bim has emerged as a central player in regulation of tumorigenesis, therefore gaining attention as a plausible target for chemotherapy. Regulation of Bim expression and stability is complicated and regulated at multiple levels viz. transcriptional, post-transcriptional, post-translational (preferably by phosphorylation and ubiquitination), epigenetic (by promoter acetylation or methylation) including miRNAs. Furthermore, control over Bim expression and stability may be exploited to enhance chemotherapeutic efficacy, overcome drug resistance and select anticancer drug regimen as various chemotherapeutic agents exploit Bim as an executioner of cell death. Owing to its potent anti-tumorigenic activity many BH3 mimetics e.g. ABT-737, ABT-263, obatoclax, AT-101and A-1210477 have been developed and entered in clinical trials. It is more likely that in near future strategies commanding Bim expression and stability ultimately lead to Bim based therapeutic regimen for cancer treatment. Copyright © 2017. Published by Elsevier GmbH.

Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.

PubMed

Tanimoto, Azusa; Takeuchi, Shinji; Arai, Sachiko; Fukuda, Koji; Yamada, Tadaaki; Roca, Xavier; Ong, S Tiong; Yano, Seiji

2017-06-15

Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR . ©2016 American Association for Cancer Research.
A Review of Application Building Information Modeling (BIM) During Pre-Construction Stage: Retrospective and Future Directions

NASA Astrophysics Data System (ADS)

Edra Nisa Lau, Santi; Zakaria, Rozana; Aminudin, Eeydzah; Saar, Chai Chang; Yusof, Aswadi; Fatihi Hafifi Che Wahid, Che Muhammad

2018-04-01

Pre-construction is one of the biggest areas of risk and uncertainty in construction project as it deals with subsurface ground conditions information. The amount of detail data needed in pre-construction especially for existing data modelling and site analysis should be sufficient enough to ensure that significant risks could not reasonably be anticipated. Current practicing method in interpreting data during this stage tasks reveal limitation. Construction industry faced many obstacles due to the depends on the traditional practice; paper-based document which missing and redundant data always happened. In recent years, there has been a shift in construction where people move to BIM application because of its potential to reduce the problem faced by infrastructure world. BIM has become a successful technology and widely popular in the construction world especially in developed countries because of its potential. Nowadays, people are moving one step ahead in BIM which is adoption of BIM during pre-construction stage. Thus, this paper review studies centered on BIM-integrated modelling during preconstruction stage. But there is lack of practical researches have been made during this stage. Although a large number of studies on BIM have been conducted in the past decade, a lack of consensus remains among researchers and practitioners regarding the applications of BIM during pre-construction stage, the availability of subsequent data integration tool for geotechnical activity. A comprehensive literature review was conducted for data collection and analysis. After in-depth review of journal articles widely cover the application of BIM, this study summarizes an overview and critical reflection of geotechnical data integration using BIM during pre-construction stage. The results are useful for the identification of research clusters and topics in the BIM community.
Molecular basis for the interplay of apoptosis and proliferation mediated by Bcl-xL:Bim interactions in pancreatic cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abrol, Ravinder, E-mail: abrol@wag.caltech.edu; Edderkaoui, Mouad; Goddard, William A.

2012-06-15

Highlights: Black-Right-Pointing-Pointer Direct role of Bcl-2 protein interactions in cell proliferation is not clear. Black-Right-Pointing-Pointer Designed Bcl-xL mutants show opposite effects on apoptosis and proliferation. Black-Right-Pointing-Pointer Disrupting Bcl-xL:Bim interaction increased apoptosis in pancreatic cancer. Black-Right-Pointing-Pointer Disrupting Bcl-xL:Bim interaction decreased proliferation in pancreatic cancer. Black-Right-Pointing-Pointer Bcl-xL:Bim interaction can control both apoptosis and proliferation. -- Abstract: A major mechanism through which cancer cells avoid apoptosis is by promoting the association of anti-apoptotic members of the pro-survival Bcl-2 protein family (like Bcl-2 and Bcl-xL) with BH{sub 3} domain-only proteins (like Bim and Bid). Apoptosis and cell proliferation have been shown to be linkedmore » for many cancers but the molecular basis for this link is far from understood. We have identified the Bcl-xL:Bim protein-protein interface as a direct regulator of proliferation and apoptosis in pancreatic cancer cells. We were able to predict and subsequently verify experimentally the effect of various Bcl-xL single-point mutants (at the position A142) on binding to Bim by structural analysis and computational modeling of the inter-residue interactions at the Bcl-xL:Bim protein-protein interface. The mutants A142N, A142Q, and A142Y decreased binding of Bim to Bcl-xL and A142S increased this binding. The Bcl-xL mutants, with decreased affinity for Bim, caused an increase in apoptosis and a corresponding decrease in cell proliferation. However, we could prevent these effects by introducing a small interfering RNA (siRNA) targeted at Bim. These results show a novel role played by the Bcl-xL:Bim interaction in regulating proliferation of pancreatic cancer cells at the expense of apoptosis. This study presents a physiologically relevant model of the Bcl-xL:Bim interface that can be used for rational therapeutic design for the inhibition of proliferation and cancer cell resistance to apoptosis.« less
Embedding intensity image into a binary hologram with strong noise resistant capability

NASA Astrophysics Data System (ADS)

Zhuang, Zhaoyong; Jiao, Shuming; Zou, Wenbin; Li, Xia

2017-11-01

A digital hologram can be employed as a host image for image watermarking applications to protect information security. Past research demonstrates that a gray level intensity image can be embedded into a binary Fresnel hologram by error diffusion method or bit truncation coding method. However, the fidelity of the retrieved watermark image from binary hologram is generally not satisfactory, especially when the binary hologram is contaminated with noise. To address this problem, we propose a JPEG-BCH encoding method in this paper. First, we employ the JPEG standard to compress the intensity image into a binary bit stream. Next, we encode the binary bit stream with BCH code to obtain error correction capability. Finally, the JPEG-BCH code is embedded into the binary hologram. By this way, the intensity image can be retrieved with high fidelity by a BCH-JPEG decoder even if the binary hologram suffers from serious noise contamination. Numerical simulation results show that the image quality of retrieved intensity image with our proposed method is superior to the state-of-the-art work reported.
77 FR 64102 - Frozen Warmwater Shrimp From the Socialist Republic of Vietnam: Amended Final Results and Partial...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-18

... of the request for review of BIM Seafood Joint Stock Company (``BIM Seafood''), the Department preliminarily rescinded this review with respect to BIM Seafood. Subsequent to the Final Results, the Department discovered that we had inadvertently failed to include the final rescission for BIM Seafood in the Final...
Assessing Students' Sentiments towards the Use of a Building Information Modelling (BIM) Learning Platform in a Construction Project Management Course

ERIC Educational Resources Information Center

Suwal, Sunil; Singh, Vishal

2018-01-01

Building Information Modelling (BIM) tools and processes are increasingly adopted and implemented in the construction industry. Consequently, BIM education is considered increasingly important in Architecture, Engineering and Construction (AEC) education. While most of the research and literature on BIM education in engineering studies has focused…
The US Army Corps of Engineers Roadmap for Life-Cycle Building Information Modeling (BIM)

DTIC Science & Technology

2012-11-01

Building Information Modeling ( BIM ) En gi ne er R es ea rc h an...Abstract Building Information Modeling ( BIM ) technology has rapidly gained ac- ceptance throughout the planning, architecture, engineering...the Industry Foundation Class (IFC) definitions to create vendor-neutral data exchanges for use in BIM software tools. Building Information Modeling
c-Cbl promotes T cell receptor-induced thymocyte apoptosis by activating the phosphatidylinositol 3-kinase/Akt pathway.

PubMed

Thien, Christine B F; Dagger, Samantha A; Steer, James H; Koentgen, Frank; Jansen, Elisa S; Scott, Clare L; Langdon, Wallace Y

2010-04-02

The ability of thymocytes to assess T cell receptor (TCR) signaling strength and initiate the appropriate downstream response is crucial for determining their fate. We have previously shown that a c-Cbl RING finger mutant knock-in mouse, in which the E3 ubiquitin ligase activity of c-Cbl is inactivated, is highly sensitive to TCR-induced death signals that cause thymic deletion. This high intensity signal involves the enhanced tyrosine phosphorylation of the mutant c-Cbl protein promoting a marked increase in the activation of Akt. Here we show that this high intensity signal in c-Cbl RING finger mutant thymocytes also promotes the enhanced induction of two mediators of TCR-directed thymocyte apoptosis, Nur77 and the pro-apoptotic Bcl-2 family member, Bim. In contrast, a knock-in mouse harboring a mutation at Tyr-737, the site in c-Cbl that activates phosphatidylinositol 3-kinase, shows reduced TCR-mediated responses including suppression of Akt activation, a reduced induction of Nur77 and Bim, and greater resistance to thymocyte death. These findings identify tyrosine-phosphorylated c-Cbl as a critical sensor of TCR signal strength that regulates the engagement of death-promoting signals.
Synthesis, crystal structure and cytotoxic activity of ruthenium(II) piano-stool complex with N,N-chelating ligand

NASA Astrophysics Data System (ADS)

Rogala, Patrycja; Jabłońska-Wawrzycka, Agnieszka; Kazimierczuk, Katarzyna; Borek, Agnieszka; Błażejczyk, Agnieszka; Wietrzyk, Joanna; Barszcz, Barbara

2016-12-01

A mononuclear compound of the general formula [(η6-p-cymene)RuIICl(2,2‧-PyBIm)]PF6 has been synthesized from a bidentate N,N-donor ligand, viz. 2,-(2‧-pyridyl)benzimidazole (2,2‧-PyBIm) and the corresponding chloro-complex [(η6-p-cymene)Ru(μ-Cl)Cl]2 (precursor). The isolated coordination compound was characterized by IR, UV-vis and 1H, 13C NMR spectroscopies. The single crystal X-ray analysis of the complex reveals that the asymmetric part of the unit cell consists of two symmetrically independent, [(η6-p-cymene)RuCl(2,2‧-PyBIm)]+ cationic complexes. Each cation exhibits a pseudo-octahedral three-legged piano-stool geometry, in which three "legs" are occupied by one chloride ion and two nitrogen donor atoms of the chelating ligand 2,2‧-PyBIm. The Hirshfeld surface analysis of obtained complex was determined, too. The ionic nature of the compound is identified by a strong band at around 830 cm-1 due to the νP-F stretching mode of the PF6- counter ion. The electronic spectrum of this monomeric complex displays high intensity bands in the ultraviolet region assignable to π→π*/n→π* transitions, as well as a band attributable to the metal-to-ligand charge transfer (MLCT) dπ(Ru)→π*(L) transition. Additionally, the complex has been screened for its cytotoxicity against three human cancer lines: non-small cell lung carcinoma (A549), colon adenocarcinoma (HT29) and breast adenocarcinoma (MCF-7) as well as normal mice fibroblast cells (BALB/3T3). The complex demonstrated a moderate antiproliferative activity against the cell lines tested.
Analysis of BIM (BCL-2 like 11 gene) deletion polymorphism in Chinese non-small cell lung cancer patients

PubMed Central

Zhong, Jia; Li, Zheng-Xiang; Zhao, Jun; Duan, Jian-Chun; Bai, Hua; An, Tong-Tong; Yang, Xiao-Dan; Wang, Jie

2014-01-01

Background Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. Methods The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. Results The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic-pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR-mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR-mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. Conclusion The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival. PMID:26767045
Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3

PubMed Central

Koenig, M N; Naik, E; Rohrbeck, L; Herold, M J; Trounson, E; Bouillet, P; Thomas, T; Voss, A K; Strasser, A; Coultas, L

2014-01-01

The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim−/− primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17∼92 cluster. Bim mRNA levels were also elevated in miR-17∼92+/− endothelial cells cultured under steady-state conditions, suggesting that miR-17∼92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells. PMID:24971484
RNA-Binding Protein Dnd1 Promotes Breast Cancer Apoptosis by Stabilizing the Bim mRNA in a miR-221 Binding Site.

PubMed

Cheng, Feng; Pan, Ying; Lu, Yi-Min; Zhu, Lei; Chen, Shuzheng

2017-01-01

RNA-binding proteins (RBPs) and miRNAs are capable of controlling processes in normal development and cancer. Both of them could determine RNA transcripts fate from synthesis to decay. One such RBP, Dead end (Dnd1), is essential for regulating germ-cell viability and suppresses the germ-cell tumors development, yet how it exerts its functions in breast cancer has remained unresolved. The level of Dnd1 was detected in 21 cancerous tissues paired with neighboring normal tissues by qRT-PCR. We further annotated TCGA (The Cancer Genome Atlas) mRNA expression profiles and found that the expression of Dnd1 and Bim is positively correlated ( p = 0.04). Patients with higher Dnd1 expression level had longer overall survival ( p = 0.0014) by KM Plotter tool. Dnd1 knockdown in MCF-7 cells decreased Bim expression levels and inhibited apoptosis. While knockdown of Dnd1 promoted the decay of Bim mRNA 3'UTR, the stability of Bim-5'UTR was not affected. In addition, mutation of miR-221-binding site in Bim-3'UTR canceled the effect of Dnd1 on Bim mRNA. Knockdown of Dnd1 in MCF-7 cells confirmed that Dnd1 antagonized miR-221-inhibitory effects on Bim expression. Overall, our findings indicate that Dnd1 facilitates apoptosis by increasing the expression of Bim via its competitive combining with miR-221 in Bim-3'UTR. The new function of Dnd1 may contribute to a vital role in breast cancer development.
Analysis of BIM (BCL-2 like 11 gene) deletion polymorphism in Chinese non-small cell lung cancer patients.

PubMed

Zhong, Jia; Li, Zheng-Xiang; Zhao, Jun; Duan, Jian-Chun; Bai, Hua; An, Tong-Tong; Yang, Xiao-Dan; Wang, Jie

2014-11-01

Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic-pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR-mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR-mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival.
Impact of the Bim Deletion Polymorphism on Survival Among Patients With Completely Resected Non-Small-Cell Lung Carcinoma.

PubMed

Atsumi, Jun; Shimizu, Kimihiro; Ohtaki, Yoichi; Kaira, Kyoichi; Kakegawa, Seiichi; Nagashima, Toshiteru; Enokida, Yasuaki; Nakazawa, Seshiru; Obayashi, Kai; Takase, Yoshiaki; Kawashima, Osamu; Kamiyoshihara, Mitsuhiro; Sugano, Masayuki; Ibe, Takashi; Igai, Hitoshi; Takeyoshi, Izumi

2016-02-01

A deletion polymorphism of the Bim gene has been reported to be a prognostic factor for patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the Bim deletion polymorphism on survival among patients with completely resected NSCLC. The Bim polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy. The Bim deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the Bim deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the Bim deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; P = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the Bim deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months v 26.9 months, respectively; P < .001). Multivariable analysis revealed that the Bim deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; P < .001). This trend remained apparent in subgroup analyses stratified by EGFR status, histology, and therapeutic modality. The Bim deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population.
Open Source Cloud-Based Technologies for Bim

NASA Astrophysics Data System (ADS)

Logothetis, S.; Karachaliou, E.; Valari, E.; Stylianidis, E.

2018-05-01

This paper presents a Cloud-based open source system for storing and processing data from a 3D survey approach. More specifically, we provide an online service for viewing, storing and analysing BIM. Cloud technologies were used to develop a web interface as a BIM data centre, which can handle large BIM data using a server. The server can be accessed by many users through various electronic devices anytime and anywhere so they can view online 3D models using browsers. Nowadays, the Cloud computing is engaged progressively in facilitating BIM-based collaboration between the multiple stakeholders and disciplinary groups for complicated Architectural, Engineering and Construction (AEC) projects. Besides, the development of Open Source Software (OSS) has been rapidly growing and their use tends to be united. Although BIM and Cloud technologies are extensively known and used, there is a lack of integrated open source Cloud-based platforms able to support all stages of BIM processes. The present research aims to create an open source Cloud-based BIM system that is able to handle geospatial data. In this effort, only open source tools will be used; from the starting point of creating the 3D model with FreeCAD to its online presentation through BIMserver. Python plug-ins will be developed to link the two software which will be distributed and freely available to a large community of professional for their use. The research work will be completed by benchmarking four Cloud-based BIM systems: Autodesk BIM 360, BIMserver, Graphisoft BIMcloud and Onuma System, which present remarkable results.
Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development.

PubMed

Cerqueira, Débora M; Bodnar, Andrew J; Phua, Yu Leng; Freer, Rachel; Hemker, Shelby L; Walensky, Loren D; Hukriede, Neil A; Ho, Jacqueline

2017-08-01

Low nephron endowment at birth has been associated with an increased risk for developing hypertension and chronic kidney disease. We demonstrated in an earlier study that conditional deletion of the microRNA (miRNA)-processing enzyme Dicer from nephron progenitors results in premature depletion of the progenitors and increased expression of the proapoptotic protein Bim (also known as Bcl-2L11). In this study, we generated a compound mouse model with conditional deletion of both Dicer and Bim , to determine the biologic significance of increased Bim expression in Dicer -deficient nephron progenitors. The loss of Bim partially restored the number of nephron progenitors and improved nephron formation. The number of progenitors undergoing apoptosis was significantly reduced in kidneys with loss of a single allele, or both alleles, of Bim compared to mutant kidneys. Furthermore, 2 miRNAs expressed in nephron progenitors ( miR-17 and miR-106b) regulated Bim levels in vitro and in vivo Together, these data suggest that miRNA-mediated regulation of Bim controls nephron progenitor survival during nephrogenesis, as one potential means of regulating nephron endowment.-Cerqueira, D. M., Bodnar, A. J., Phua, Y. L., Freer, R., Hemker, S. L., Walensky, L. D., Hukriede, N. A., Ho, J. Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development. © FASEB.
BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

PubMed

Karachaliou, Niki; Codony-Servat, Jordi; Teixidó, Cristina; Pilotto, Sara; Drozdowskyj, Ana; Codony-Servat, Carles; Giménez-Capitán, Ana; Molina-Vila, Miguel Angel; Bertrán-Alamillo, Jordi; Gervais, Radj; Massuti, Bartomeu; Morán, Teresa; Majem, Margarita; Felip, Enriqueta; Carcereny, Enric; García-Campelo, Rosario; Viteri, Santiago; González-Cao, María; Morales-Espinosa, Daniela; Verlicchi, Alberto; Crisetti, Elisabetta; Chaib, Imane; Santarpia, Mariacarmela; Luis Ramírez, José; Bosch-Barrera, Joaquim; Felipe Cardona, Andrés; de Marinis, Filippo; López-Vivanco, Guillermo; Miguel Sánchez, José; Vergnenegre, Alain; Sánchez Hernández, José Javier; Sperduti, Isabella; Bria, Emilio; Rosell, Rafael

2015-12-07

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

PubMed Central

Kurtulus, S; Sholl, A; Toe, J; Tripathi, P; Raynor, J; Li, K-P; Pellegrini, M; Hildeman, D A

2015-01-01

During the effector CD8+ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8+ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8+ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential. PMID:25124553
Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins.

PubMed

Kurtulus, S; Sholl, A; Toe, J; Tripathi, P; Raynor, J; Li, K-P; Pellegrini, M; Hildeman, D A

2015-01-01

During the effector CD8+ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8+ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8+ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.
Translating building information modeling to building energy modeling using model view definition.

PubMed

Jeong, WoonSeong; Kim, Jong Bum; Clayton, Mark J; Haberl, Jeff S; Yan, Wei

2014-01-01

This paper presents a new approach to translate between Building Information Modeling (BIM) and Building Energy Modeling (BEM) that uses Modelica, an object-oriented declarative, equation-based simulation environment. The approach (BIM2BEM) has been developed using a data modeling method to enable seamless model translations of building geometry, materials, and topology. Using data modeling, we created a Model View Definition (MVD) consisting of a process model and a class diagram. The process model demonstrates object-mapping between BIM and Modelica-based BEM (ModelicaBEM) and facilitates the definition of required information during model translations. The class diagram represents the information and object relationships to produce a class package intermediate between the BIM and BEM. The implementation of the intermediate class package enables system interface (Revit2Modelica) development for automatic BIM data translation into ModelicaBEM. In order to demonstrate and validate our approach, simulation result comparisons have been conducted via three test cases using (1) the BIM-based Modelica models generated from Revit2Modelica and (2) BEM models manually created using LBNL Modelica Buildings library. Our implementation shows that BIM2BEM (1) enables BIM models to be translated into ModelicaBEM models, (2) enables system interface development based on the MVD for thermal simulation, and (3) facilitates the reuse of original BIM data into building energy simulation without an import/export process.

Translating Building Information Modeling to Building Energy Modeling Using Model View Definition

PubMed Central

Kim, Jong Bum; Clayton, Mark J.; Haberl, Jeff S.

2014-01-01

This paper presents a new approach to translate between Building Information Modeling (BIM) and Building Energy Modeling (BEM) that uses Modelica, an object-oriented declarative, equation-based simulation environment. The approach (BIM2BEM) has been developed using a data modeling method to enable seamless model translations of building geometry, materials, and topology. Using data modeling, we created a Model View Definition (MVD) consisting of a process model and a class diagram. The process model demonstrates object-mapping between BIM and Modelica-based BEM (ModelicaBEM) and facilitates the definition of required information during model translations. The class diagram represents the information and object relationships to produce a class package intermediate between the BIM and BEM. The implementation of the intermediate class package enables system interface (Revit2Modelica) development for automatic BIM data translation into ModelicaBEM. In order to demonstrate and validate our approach, simulation result comparisons have been conducted via three test cases using (1) the BIM-based Modelica models generated from Revit2Modelica and (2) BEM models manually created using LBNL Modelica Buildings library. Our implementation shows that BIM2BEM (1) enables BIM models to be translated into ModelicaBEM models, (2) enables system interface development based on the MVD for thermal simulation, and (3) facilitates the reuse of original BIM data into building energy simulation without an import/export process. PMID:25309954
The NF-κB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells

PubMed Central

Bauer, Anette; Villunger, Andreas; Labi, Verena; Fischer, Silke F.; Strasser, Andreas; Wagner, Hermann; Schmid, Roland M.; Häcker, Georg

2006-01-01

Apoptosis of activated T cells is critical for the termination of immune responses. Here we show that adjuvant-stimulated dendritic cells secrete cytokines that prime activated T cells for survival and analyze the roles of the NF-κB regulator Bcl-3 and the proapoptotic Bcl-2 family members Bim and Puma. Bcl-3 overexpression increased survival, and activated bcl-3−/− T cells died abnormally rapidly. Cytokines from adjuvant-stimulated dendritic cells induced Bcl-3, but survival through cytokine priming was Bcl-3-independent. Apoptosis inhibition by Bcl-3 involved blockade of Bim activation, because Bim was overactivated in Bcl-3-deficient cells, and Bcl-3 failed to increase survival of bim−/− T cells. However, adjuvants increased survival also in Bim-deficient T cells. This Bim-independent death pathway is at least in part regulated by Puma, as shown by analysis of puma−/− and noxa−/− T cells. IL-1, IL-7, and IL-15 primed T cells for survival even in the absence of Bim or Puma. Our data define interrelations and a Bim-independent pathway to activated T cell death. PMID:16832056
Implementation of building information modeling in Malaysian construction industry

NASA Astrophysics Data System (ADS)

Memon, Aftab Hameed; Rahman, Ismail Abdul; Harman, Nur Melly Edora

2014-10-01

This study has assessed the implementation level of Building Information Modeling (BIM) in the construction industry of Malaysia. It also investigated several computer software packages facilitating BIM and challenges affecting its implementation. Data collection for this study was carried out using questionnaire survey among the construction practitioners. 95 completed forms of questionnaire received against 150 distributed questionnaire sets from consultant, contractor and client organizations were analyzed statistically. Analysis findings indicated that the level of implementation of BIM in the construction industry of Malaysia is very low. Average index method employed to assess the effectiveness of various software packages of BIM highlighted that Bentley construction, AutoCAD and ArchiCAD are three most popular and effective software packages. Major challenges to BIM implementation are it requires enhanced collaboration, add work to a designer, interoperability and needs enhanced collaboration. For improving the level of implementing BIM in Malaysian industry, it is recommended that a flexible training program of BIM for all practitioners must be created.
Loss of BIM increases mitochondrial oxygen consumption and lipid oxidation, reduces adiposity and improves insulin sensitivity in mice.

PubMed

Wali, Jibran A; Galic, Sandra; Tan, Christina Yr; Gurzov, Esteban N; Frazier, Ann E; Connor, Timothy; Ge, Jingjing; Pappas, Evan G; Stroud, David; Varanasi, L Chitra; Selck, Claudia; Ryan, Michael T; Thorburn, David R; Kemp, Bruce E; Krishnamurthy, Balasubramanian; Kay, Thomas Wh; McGee, Sean L; Thomas, Helen E

2018-01-01

BCL-2 proteins are known to engage each other to determine the fate of a cell after a death stimulus. However, their evolutionary conservation and the many other reported binding partners suggest an additional function not directly linked to apoptosis regulation. To identify such a function, we studied mice lacking the BH3-only protein BIM. BIM -/- cells had a higher mitochondrial oxygen consumption rate that was associated with higher mitochondrial complex IV activity. The consequences of increased oxygen consumption in BIM -/- mice were significantly lower body weights, reduced adiposity and lower hepatic lipid content. Consistent with reduced adiposity, BIM -/- mice had lower fasting blood glucose, improved insulin sensitivity and hepatic insulin signalling. Lipid oxidation was increased in BIM -/- mice, suggesting a mechanism for their metabolic phenotype. Our data suggest a role for BIM in regulating mitochondrial bioenergetics and metabolism and support the idea that regulation of metabolism and cell death are connected.
The dopamine-somatostatin chimeric compound BIM-23A760 exerts antiproliferative and cytotoxic effects in human non-functioning pituitary tumors by activating ERK1/2 and p38 pathways.

PubMed

Peverelli, Erika; Olgiati, Luca; Locatelli, Marco; Magni, Paolo; Fustini, Marco Faustini; Frank, Giorgio; Mantovani, Giovanna; Beck-Peccoz, Paolo; Spada, Anna; Lania, Andrea

2010-02-28

The study investigated the effects of the dopamine-somatostatin chimeric compound BIM-23A760 on cell proliferation and apoptosis in cultured cells from human non-functioning pituitary tumors (NFPTs). Both BIM-23A760 and the dopaminergic agonist BIM-53097 induced a significant inhibition of cell proliferation associated with increased p27 expression, together with a significant increase in caspase-3 activity. Conversely, null or marginal effects were elicited by somatostatin analogs. Moreover, BIM-23A760 and BIM-53097 induced ERK1/2 and p38 phosphorylation and the blockade of these pathways prevented both the antiproliferative and the pro-apoptotic effects of these drugs. In conclusions the chimeric compound BIM-23A760 is able to exert cytostatic and cytotoxic effects in NFPTs, these phenomena being mainly mediated by DR2D and involving ERK1/2 and p38 pathways activation. 2009 Elsevier Ireland Ltd. All rights reserved.
3D Documentation and BIM Modeling of Cultural Heritage Structures Using UAVs: The Case of the Foinikaria Church

NASA Astrophysics Data System (ADS)

Themistocleous, K.; Agapiou, A.; Hadjimitsis, D.

2016-10-01

The documentation of architectural cultural heritage sites has traditionally been expensive and labor-intensive. New innovative technologies, such as Unmanned Aerial Vehicles (UAVs), provide an affordable, reliable and straightforward method of capturing cultural heritage sites, thereby providing a more efficient and sustainable approach to documentation of cultural heritage structures. In this study, hundreds of images of the Panagia Chryseleousa church in Foinikaria, Cyprus were taken using a UAV with an attached high resolution camera. The images were processed to generate an accurate digital 3D model by using Structure in Motion techniques. Building Information Model (BIM) was then used to generate drawings of the church. The methodology described in the paper provides an accurate, simple and cost-effective method of documenting cultural heritage sites and generating digital 3D models using novel techniques and innovative methods.
Building Information Modelling for Cultural Heritage: A review

NASA Astrophysics Data System (ADS)

Logothetis, S.; Delinasiou, A.; Stylianidis, E.

2015-08-01

We discuss the evolution and state-of-the-art of the use of Building Information Modelling (BIM) in the field of culture heritage documentation. BIM is a hot theme involving different characteristics including principles, technology, even privacy rights for the cultural heritage objects. Modern documentation needs identified the potential of BIM in the recent years. Many architects, archaeologists, conservationists, engineers regard BIM as a disruptive force, changing the way professionals can document and manage a cultural heritage structure. The latest years, there are many developments in the BIM field while the developed technology and methods challenged the cultural heritage community in the documentation framework. In this review article, following a brief historic background for the BIM, we review the recent developments focusing in the cultural heritage documentation perspective.
Building Information Modeling (BIM) Primer. Report 1: Facility Life-Cycle Process and Technology Innovation

DTIC Science & Technology

2012-08-01

Building Information Modeling ( BIM ) Primer Report 1: Facility Life-cycle Process and Technology Innovation In fo...is unlimited. ERDC/ITL TR-12-2 August 2012 Building Information Modeling ( BIM ) Primer Report 1: Facility Life-cycle Process and Technology...and to enhance the quality of projects through the design, construction, and handover phases. Building Information Modeling ( BIM ) is a
Insulin-like Growth Factor 1 Rescues R28 Retinal Neurons from Apoptotic Death through ERK-mediated BimEL Phosphorylation Independent of Akt

PubMed Central

Kong, Dejuan; Gong, Lijie; Arnold, Edith; Shanmugam, Sumathi; Fort, Patrice E.; Gardner, Thomas W.; Abcouwer, Steven F.

2016-01-01

Insulin-like growth factor 1 (IGF-1) can provide long-term neurotrophic support by activation of Akt, inhibition of FoxO nuclear localization and suppression of Bim gene transcription in multiple neuronal systems. However, MEK/ERK activation can also promote neuron survival through phosphorylation of BimEL. We explored the contribution of the PI3K/Akt/FoxO and MEK/ERK/BimEL pathways in IGF-1 stimulated survival after serum deprivation (SD) of R28 cells differentiated to model retinal neurons. IGF-1 caused rapid activation of Akt leading to FoxO1/3-T32/T24 phosphorylation, and prevented FoxO1/3 nuclear translocation and Bim mRNA upregulation in response to SD. IGF-1 also caused MAPK/MEK pathway activation as indicated by ERK1/2-T202/Y204 and Bim-S65 phosphorylation. Overexpression of FoxO1 increased Bim mRNA expression and amplified the apoptotic response to SD without shifting the serum response curve. Inhibition of Akt activation with LY294002 or by Rictor knockdown did not block the protective effect of IGF-1, while inhibition of MEK activity with PD98059 prevented Bim phosphorylation and blocked IGF-1 protection. In addition, knockdown of Bim expression was protective during SD, while co-silencing of FoxO1 and Fox03 expression had little effect. Thus, the PI3K/Akt/FoxO pathway was not essential for protection from SD-induced apoptosis by IGF-1 in R28 cells. Instead, IGF-1 protection was dependent on activation of the MEK/ERK pathway leading to BimEL phosphorylation, which is known to prevent Bax/Bak oligomerization and activation of the intrinsic mitochondrial apoptosis pathway. These studies demonstrate the requirement of the MEK/ERK pathway in a model of retinal neuron cell survival and highlight the cell specificity for IGF-1 signaling in this response. PMID:27511131
Bimatoprost-Loaded Ocular Inserts as Sustained Release Drug Delivery Systems for Glaucoma Treatment: In Vitro and In Vivo Evaluation

PubMed Central

Franca, Juçara Ribeiro; Foureaux, Giselle; Fuscaldi, Leonardo Lima; Ribeiro, Tatiana Gomes; Rodrigues, Lívia Bomfim; Bravo, Renata; Castilho, Rachel Oliveira; Yoshida, Maria Irene; Cardoso, Valbert Nascimento; Fernandes, Simone Odília; Cronemberger, Sebastião; Ferreira, Anderson José; Faraco, André Augusto Gomes

2014-01-01

The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management. PMID:24788066
Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

PubMed Central

Ridinger-Saison, M; Evanno, E; Gallais, I; Rimmelé, P; Selimoglu-Buet, D; Sapharikas, E; Moreau-Gachelin, F; Guillouf, C

2013-01-01

Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. PMID:23852375
The apoptotic effect of simvastatin via the upregulation of BIM in nonsmall cell lung cancer cells.

PubMed

Lee, Hwa Young; Kim, In Kyoung; Lee, Hye In; Mo, Jin Young; Yeo, Chang Dong; Kang, Hyeon Hui; Moon, Hwa Sik; Lee, Sang Haak

2016-01-01

Statins are known to have pleiotropic effects that induce cell death in certain cancer cells. BIM is a member of the bcl-2 gene family, which promotes apoptotic cell death. This study investigated the hypothesis that simvastatin has pro-apoptotic effects in epidermal growth factor receptor (EGFR)-mutated lung cancer cell lines via the upregulation of the expression of the BIM protein. The cytotoxic effects of simvastatin on gefitinib-sensitive (HCC827, E716-A750del) and -resistant (H1975, T790M + L858R) nonsmall cell lung cancer (NSCLC) cells were compared. Cell proliferation and expression of apoptosis-related and EGFR downstream signaling proteins were evaluated. Expression of BIM was compared in H1975 cells after treatment with simvastatin or gefitinib. SiRNA-mediated BIM depletion was performed to confirm whether the cytotoxicity of simvastatin was mediated by the expression of BIM. H1975 cells showed significantly reduced viability compared with HCC827 cells after treatment with simvastatin (2 μM) for 48 hours. In simvastatin-treated H1975 cells, expression of pro-apoptotic proteins was increased and the phosphorylation of ERK 1/2 (p-ERK 1/2) was reduced. Expression of BIM was suppressed by gefitinib (1 μM) treatment in H1975 cells, but it was significantly increased by treatment with simvastatin. BIM depletion by siRNA transfection enhanced the viability of H1975 cells that received simvastatin treatment and increased their expression of anti-apoptotic proteins. Simvastatin restored the expression of BIM to induce apoptotic cell death in NSCLC cells harboring an EGFR-resistant mutation. Our study suggests the potential utility of simvastatin as a BIM-targeted treatment for NSCLC.
Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis.

PubMed

Ma, Ji-Yong; Yan, Hai-Jun; Gu, Wei

2015-01-01

BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC). However, accumulating evidences concerning the association between BIM deletion polymorphism and efficacy of EGFR-TKI and survival in EGFR-mutation-driven NSCLC patient reported contradictory results. A meta-analysis was conducted by combing six original eligible studies including 871 NSCLC patients. Our study showed that BIM deletion polymorphism was significantly associated with poor response to EGFR-TKI therapy in mutant EGFRNSCLC patients (P(h) = 0.309, P(z) = 0.001, OR = 0.39, 95% confidence interval (CI) = 0.23-0.67). Disease control rate (DCR) in mutant EGFRNSCLC patient with treatment of EGFR-TKI was significantly decreased in patients with BIM deletion polymorphism comparing to patients harbored BIM wild variant (P(h) = 0.583, P(Z) = 0.007, OR = 0.46, 95%CI = 0.25-0.85). EGFR mutation-derived NSCLC patient carrying BIM deletion polymorphism had a shorter progression-free survival (PFS; P(h) < 0.001, P(z) < 0.001, hazard ratio (HR) = 1.37, 95%CI = 1.09-1.71) and overall survival (OS; P(h) = 0.90, P(z) = 0.003, HR = 1.25, 95%CI = 1.08-1.45), than those harbored BIM wild variant. These results suggested that BIM deletion polymorphism might be a cause that contributes to primary EGFR-TKI resistance, and it could be used as a genetic predictor for EGFR-TKI outcome and an independent prognostic factor of EGFR mutation-driven NSCLC patient.
The BH3 α-Helical Mimic BH3-M6 Disrupts Bcl-XL, Bcl-2, and MCL-1 Protein-Protein Interactions with Bax, Bak, Bad, or Bim and Induces Apoptosis in a Bax- and Bim-dependent Manner*

PubMed Central

Kazi, Aslamuzzaman; Sun, Jiazhi; Doi, Kenichiro; Sung, Shen-Shu; Takahashi, Yoshinori; Yin, Hang; Rodriguez, Johanna M.; Becerril, Jorge; Berndt, Norbert; Hamilton, Andrew D.; Wang, Hong-Gang; Sebti, Saïd M.

2011-01-01

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-XL, and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-XL and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-XL, Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-XL/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-XL, Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612. PMID:21148306
The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.

PubMed

Kazi, Aslamuzzaman; Sun, Jiazhi; Doi, Kenichiro; Sung, Shen-Shu; Takahashi, Yoshinori; Yin, Hang; Rodriguez, Johanna M; Becerril, Jorge; Berndt, Norbert; Hamilton, Andrew D; Wang, Hong-Gang; Sebti, Saïd M

2011-03-18

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X(L), and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-X(L) and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X(L), Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-X(L)/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-X(L), Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612.
Clinical Implications of the BIM Deletion Polymorphism in Advanced Lung Adenocarcinoma Treated With Gefitinib.

PubMed

Yuan, Jupeng; Li, Bo; Zhang, Nasha; Zhu, Hui; Zhou, Liqing; Zhang, Li; Yang, Ming

2018-02-19

Proapoptotic protein Bcl-2-like 11 (BIM) is a crucial tumor suppressor gene in lung cancer development. A 2903-bp genomic deletion polymorphism is present in BIM intron 2, which alters RNA splicing and impairs the generation of the death-inducing isoform of BIM and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In the present study, we investigated the clinical implications of this genetic polymorphism in patients with advanced lung adenocarcinoma treated with gefitinib. After genotyping the BIM deletion polymorphism in 111 patients with stage IIIB or IV lung adenocarcinoma receiving gefitinib, the hazard ratio (HR) and 95% confidence interval (CI) for progression-free survival and overall survival were estimated using Cox proportional hazards models. Possession of ≥ 1 deletion allele of the BIM polymorphism was observed in 18.02% of the patients. The BIM deletion polymorphism was an independent indicator of a shorter PFS (7.5 months vs. 11.3 months; HR, 2.38; 95% CI, 1.30-4.34; P = .005) and shorter OS (9.9 months vs. 27.5 months; HR, 2.53; 95% CI, 1.37-4.65; P = .003). Additionally, patients carrying the BIM deletion allele were more likely to experience acquired gefitinib-resistant disease. Our results indicate that the BIM deletion polymorphism might be a promising germline biomarker for gefitinib treatment in Chinese patients with lung adenocarcinoma. Copyright © 2018 Elsevier Inc. All rights reserved.
Broadband Impedance Microscopy for Research on Complex Quantum Materials

DTIC Science & Technology

2016-02-08

function in various materials. Figure 2. Sensitivity limit of the broadband impedance microscope (BIM). Figure 3. Preliminary BIM data on YMnO3...2 Statement of the Problem The objective of this DURIP award is to construct a broadband impedance microscope (BIM) for frequency-dependent...platforms and specialized cantilever probes [1] in the PI’s lab, the BIM can now simultaneously obtain microscopic (10 – 100 nm) and quasi- spectroscopic
Emerging Challenges and Opportunities in Building Information Modeling for the US Army Installation Management Command

DTIC Science & Technology

2012-07-01

Information Modeling ( BIM ) is the process of generating and managing building data during a facility’s entire life cycle. New BIM standards for...cycle Building Information Modeling ( BIM ) as a new standard for building information data repositories can serve as the foun- dation for automation and... Building Information Modeling ( BIM ) is defined as “a digital representa- tion of physical and functional
Chlamydia Inhibit Host Cell Apoptosis by Degradation of Proapoptotic BH3-only Proteins

PubMed Central

Fischer, Silke F.; Vier, Juliane; Kirschnek, Susanne; Klos, Andreas; Hess, Simone; Ying, Songmin; Häcker, Georg

2004-01-01

Chlamydia are obligate intracellular bacteria that replicate in a vacuole inside a host cell. Chlamydial infection has been shown to protect the host cell against apoptotic stimuli. This is likely important for the ability of Chlamydia to reproduce in human cells. Here we show that resistance to apoptosis is conveyed by the destruction of the proapoptotic BH3-only proteins Bim/Bod, Puma, and Bad during infection. Apoptotic stimuli were blocked upstream of the mitochondrial activation of Bax/Bak. During infection with both species, Chlamydia trachomatis and Chlamydia pneumoniae, Bim protein gradually disappeared without noticeable changes in Bim mRNA. The disappearance was blocked by inhibitors of the proteasome. Infected cells retained sensitivity to Bim expressed by transfection, indicating functional relevance of the Bim disappearance. Fusion to Bim targeted the green fluorescent protein for destruction during infection. Analysis of truncation mutants showed that a short region of Bim containing the BH3 domain was sufficient for destruction during chlamydial infection. Like Bim, Puma and Bad proteins disappeared during infection. These results reveal a novel way by which microbes can interfere with the host cell's apoptotic machinery, and provide a molecular explanation of the cellular resistance to apoptosis during infection with Chlamydia. PMID:15452181
Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells

PubMed Central

Bodo, Juraj; Zhao, Xiaoxian; Durkin, Lisa; Souers, Andrew J.; Phillips, Darren C.; Smith, Mitchell R.; Hsi, Eric D.

2016-01-01

The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL. The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed. The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients. PMID:27661108

Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells.

PubMed

Bodo, Juraj; Zhao, Xiaoxian; Durkin, Lisa; Souers, Andrew J; Phillips, Darren C; Smith, Mitchell R; Hsi, Eric D

2016-10-25

The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed.The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients.
The inhibitory effect of BIM (I) on L-type Ca²⁺ channels in rat ventricular cells.

PubMed

Son, Youn Kyoung; Hong, Da Hye; Choi, Tae-Hoon; Choi, Seong Woo; Shin, Dong Hoon; Kim, Sung Joon; Jung, In Duk; Park, Yeong-Min; Jung, Won-Kyo; Kim, Dae-Joong; Choi, Il-Whan; Park, Won Sun

2012-06-22

We investigated the effect of a specific protein kinase C (PKC) inhibitor, bisindolylmaleimide I [BIM (I)], on L-type Ca(2+) channels in rat ventricular myocytes. BIM (I) alone inhibited the L-type Ca(2+) current in a concentration-dependent manner, with a K(d) value of 3.31 ± 0.25 μM, and a Hill coefficient of 2.34 ± 0.23. Inhibition was immediate after applying BIM (I) in the bath solution and then it partially washed out. The steady-state activation curve was not altered by applying 3μ M BIM (I), but the steady-state inactivation curve shifted to a more negative potential with a change in the slope factor. Other PKC inhibitors, PKC-IP and chelerythrine, showed no significant effects either on the L-type Ca(2+) current or on the inhibitory effect of BIM (I) on the L-type Ca(2+) current. The results suggest that the inhibitory effect of BIM (I) on the L-type Ca(2+) current is independent of the PKC pathway. Thus, our results should be considered in studies using BIM (I) to inhibit PKC activity and ion channel modulation. Copyright © 2012 Elsevier Inc. All rights reserved.
Practical Implementation of Semi-Automated As-Built Bim Creation for Complex Indoor Environments

NASA Astrophysics Data System (ADS)

Yoon, S.; Jung, J.; Heo, J.

2015-05-01

In recent days, for efficient management and operation of existing buildings, the importance of as-built BIM is emphasized in AEC/FM domain. However, fully automated as-built BIM creation is a tough issue since newly-constructed buildings are becoming more complex. To manage this problem, our research group has developed a semi-automated approach, focusing on productive 3D as-built BIM creation for complex indoor environments. In order to test its feasibility for a variety of complex indoor environments, we applied the developed approach to model the `Charlotte stairs' in Lotte World Mall, Korea. The approach includes 4 main phases: data acquisition, data pre-processing, geometric drawing, and as-built BIM creation. In the data acquisition phase, due to its complex structure, we moved the scanner location several times to obtain the entire point clouds of the test site. After which, data pre-processing phase entailing point-cloud registration, noise removal, and coordinate transformation was followed. The 3D geometric drawing was created using the RANSAC-based plane detection and boundary tracing methods. Finally, in order to create a semantically-rich BIM, the geometric drawing was imported into the commercial BIM software. The final as-built BIM confirmed that the feasibility of the proposed approach in the complex indoor environment.
Application of BIM Technology in Prefabricated Buildings

NASA Astrophysics Data System (ADS)

Zhanglin, Guo; Si, Gao; Jun-e, Liu

2017-08-01

The development of fabricated buildings has become the main trend of the developm ent of modern construction industry in China. As the main tool of building information, BIM (b uilding information modeling) has greatly promoted the development of construction industry. Based on the review of the papers about the fabricated buildings and BIM technology in recent years, this paper analyzes the advantages of fabricated buildings and BIM technology, then exp lores the application of BIM technology in fabricated buildings. It aims to realize the rationaliz ation and scientification of project lifecycle management in fabricated construction project, and finally form a coherent information platform in the fabricated building.
Impacts and benefits of implementing BIM on bridge infrastructure projects.

DOT National Transportation Integrated Search

2014-10-01

To date, BIM (Building Information Modeling) is not widely utilized in infrastructure asset management. : Benefits achieved through implementation in vertical construction, however, suggest that BIM represents : significant opportunity for gains in p...
Applications of building information model (BIM) in Malaysian construction industry

NASA Astrophysics Data System (ADS)

Tahir, M. M.; Haron, N. A.; Alias, A. H.; Al-Jumaa, A. T.; Muhammad, I. B.; Harun, A. N.

2017-12-01

Since the introduction of BIM in Malaysia in 2009, the technology adoption rate is slow when compared to other countries of the world. Most of the construction companies in Malaysia have an insight on the BIM concept but are yet to implement it in the management of their construction projects. By the year 2020, the Malaysian government will make BIM mandatory, this makes it important to carry out research on the possible applications of the technology. A qualitative method of enquiry was used for this study in Klang Valley using semistructured interview. The responses received were analysed using Principal component analysis (PCA). The result of the analysis showed that “quantity take-off and estimation”, “clash detection and coordination”, “integration and collaboration of stakeholders”, and “design and visualisation” as the main applications of BIM in Malaysia presently. The implication of this findings is that the Malaysian construction industry productivity is likely to increase to meet the demand of the population through the implementations of BIM. More also, BIM technology is regarded as the future of construction industry, which makes it very important for the industry.
Root causes occurrence of low BIM adoption in Malaysia: System dynamics modelling approach

NASA Astrophysics Data System (ADS)

Mamter, Shahela; Aziz, Abdul Rashid Abdul; Zulkepli, Jafri

2017-11-01

The global implementation of BIM in the construction field is increasing worldwide. Due to the advantages offered by BIM, its implementation is considered important in the construction projects. Nevertheless, the Construction Industry Transformation Plan has reported that the adoption of Building Information Modelling (BIM) in Malaysia is still low and it is estimated at only 10 percent adoption amongst construction stake players. The barriers influencing the occurrence of low adoption BIM in Malaysia have been studied by some researchers. However, these researchers did not investigate the root causes which might lead to the recurring of the barriers to BIM adoption. Root causes that immediately occurrence of barriers, also known as precipitants or trigger causes. This conceptual paper developed the causal loop diagram (CLD) which presents the relationship between the perceived variables using system dynamic modelling approach. The findings revealed a novelty validated diagrams that design the holistic dynamic relationship on the root causes occurrence of low BIM adoption. Nonetheless, the diagram subject to more empirical testing for its practicability and further refinement upon more results expected to emerge as the research progresses.
Apoptosis-Dependent and Apoptosis-Independent Functions Bim in Prostate Cancer Cells

DTIC Science & Technology

2004-03-01

AD_ Award Number: DAMD17-03-1-0146 TITLE: Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL...FUNDING NUMBERS Apoptosis-Dependent and Apoptosis-Independent Functions of DAMD17-03-1-0146 Bim in Prostate Cancer Cells 6. A UTHORs) Junwei Liu, M.D...extended cell survival have been implicated in prostate cancer (PCa) development and progression. We recently found that Bim , a BH3-only pro
The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.

PubMed

Liu, Rui; Zhang, Haiyang; Wang, Xia; Zhou, Likun; Li, Hongli; Deng, Ting; Qu, Yanjun; Duan, Jingjing; Bai, Ming; Ge, Shaohua; Ning, Tao; Zhang, Le; Huang, Dingzhi; Ba, Yi

2015-12-22

miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC.
An overview of BIM uptake in Asian developing countries

NASA Astrophysics Data System (ADS)

Ismail, Noor Akmal Adillah; Chiozzi, Maria; Drogemuller, Robin

2017-11-01

BIM is increasingly in demand within the construction industry internationally in recent years. The application of the technology reconciles several problems within the project teams such as delays, rework, miscommunication, and other related to inefficiencies that affect project success. While it is actively employed by the majority of the developed countries, however, BIM is not as advanced in most developing countries. Therefore, this paper reviews BIM uptake in some of the Asian developing countries and examines the extent to which it is implemented in these regions. Prevalent challenges were considered with recommendations towards addressing the issues of low level of BIM adoption that distinguishes the developing from the developed countries. This paper will provide some insights of how BIM is evolving within those countries considering the drivers and barriers in adopting the technology and how this is likely to change in the near future.
Bim from Laser SCANS… not Just for Buildings: Nurbs-Based Parametric Modeling of a Medieval Bridge

NASA Astrophysics Data System (ADS)

Barazzetti, L.; Banfi, F.; Brumana, R.; Previtali, M.; Roncoroni, F.

2016-06-01

Building Information Modelling is not limited to buildings. BIM technology includes civil infrastructures such as roads, dams, bridges, communications networks, water and wastewater networks and tunnels. This paper describes a novel methodology for the generation of a detailed BIM of a complex medieval bridge. The use of laser scans and images coupled with the development of algorithms able to handle irregular shapes allowed the creation of advanced parametric objects, which were assembled to obtain an accurate BIM. The lack of existing object libraries required the development of specific families for the different structural elements of the bridge. Finally, some applications aimed at assessing the stability and safety of the bridge are illustrated and discussed. The BIM of the bridge can incorporate this information towards a new "BIMonitoring" concept to preserve the geometric complexity provided by point clouds, obtaining a detailed BIM with object relationships and attributes.
Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells

PubMed Central

Heidari, N; Miller, A V; Hicks, M A; Marking, C B; Harada, H

2012-01-01

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex-induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex-induced BIM and apoptosis were decreased in cells harboring dominant-negative c-Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about −2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC-induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment. PMID:22825467
BIM-Mediated AKT Phosphorylation Is a Key Modulator of Arsenic Trioxide-Induced Apoptosis in Cisplatin-Sensitive and -Resistant Ovarian Cancer Cells

PubMed Central

Yuan, Zhu; Wang, Fang; Zhao, Zhiwei; Zhao, Xinyu; Qiu, Ji; Nie, Chunlai; Wei, Yuquan

2011-01-01

Background Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to the effective treatment of human ovarian cancer. Previous reports indicated that arsenic trioxide (ATO) induces cell apoptosis in both drug-sensitive and -resistant ovarian cancer cells. Principal Findings In this study, we determined the molecular mechanism of ATO-induced apoptosis in ovarian cancer cells. Our data demonstrated that ATO induced cell apoptosis by decreasing levels of phosphorylated AKT (p-AKT) and activating caspase-3 and caspase-9. Importantly, BIM played a critical role in ATO-induced apoptosis. The inhibition of BIM expression prevented AKT dephosphorylation and inhibited caspase-3 activation during cell apoptosis. However, surprisingly, gene silencing of AKT or FOXO3A had little effect on BIM expression and phosphorylation. Moreover, the activation of caspase-3 by ATO treatment improved AKT dephosphorylation, not only by cleaving the regulatory A subunit of protein phosphatase 2A (PP2A), but also by increasing its activation. Furthermore, our data indicated that the c-Jun N-terminal kinases (JNK) pathway is involved in the regulation of BIM expression. Conclusions We demonstrated the roles of BIM in ATO-induced apoptosis and the molecular mechanisms of BIM expression regulated by ATO during ovarian cancer cell apoptosis. Our findings suggest that BIM plays an important role in regulating p-AKT by activating caspase-3 and that BIM mediates the level of AKT phosphorylation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells. PMID:21655183
Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia.

PubMed

Soh, Sheila Xinxuan; Lim, Joshua Yew Suang; Huang, John W J; Jiang, Nan; Yeoh, Allen Eng Juh; Ong, S Tiong

2014-01-01

A broad range of anti-cancer agents, including glucocorticoids (GCs) and tyrosine kinase inhibitors (TKIs), kill cells by upregulating the pro-apoptotic BCL2 family member, BIM. A common germline deletion in the BIM gene was recently shown to favor the production of non-apoptotic BIM isoforms, and to predict inferior responses in TKI-treated chronic myeloid leukemia (CML) and EGFR-driven lung cancer patients. Given that both in vitro and in vivo GC resistance are predictive of adverse outcomes in acute lymphoblastic leukemia (ALL), we hypothesized that this polymorphism would mediate GC resistance, and serve as a biomarker of poor response in ALL. Accordingly, we used zinc finger nucleases to generate ALL cell lines with the BIM deletion, and confirmed the ability of the deletion to mediate GC resistance in vitro. In contrast to CML and lung cancer, the BIM deletion did not predict for poorer clinical outcome in a retrospective analysis of 411 pediatric ALL patients who were uniformly treated with GCs and chemotherapy. Underlying the lack of prognostic significance, we found that the chemotherapy agents used in our cohort (vincristine, L-asparaginase, and methotrexate) were each able to induce ALL cell death in a BIM-independent fashion, and resensitize BIM deletion-containing cells to GCs. Together, our work demonstrates how effective therapy can overcome intrinsic resistance in ALL patients, and suggests the potential of using combinations of drugs that work via divergent mechanisms of cell killing to surmount BIM deletion-mediated drug resistance in other cancers.
An experimental study on the coalescence process of binary droplets in oil under ultrasonic standing waves.

PubMed

Luo, Xiaoming; Cao, Juhang; He, Limin; Wang, Hongping; Yan, Haipeng; Qin, Yahua

2017-01-01

The coalescence process of binary droplets in oil under ultrasonic standing waves was investigated with high-speed photography. Three motion models of binary droplets in coalescence process were illustrated: (1) slight translational oscillation; (2) sinusoidal translational oscillation; (3) migration along with acoustic streaming. To reveal the droplets coalescence mechanisms, the influence of main factors (such as acoustic intensity, droplet size, viscosity and interfacial tension, etc) on the motion and coalescence of binary droplets was studied under ultrasonic standing waves. Results indicate that the shortest coalescence time is achieved when binary droplets show sinusoidal translational oscillation. The corresponding acoustic intensity in this case is the optimum acoustic intensity. Under the optimum acoustic intensity, drop size decrease will bring about coalescence time decrease by enhancing the binary droplets oscillation. Moreover, there is an optimum interfacial tension to achieve the shortest coalescence time. Copyright © 2016 Elsevier B.V. All rights reserved.
Identification and functional analysis of the BIM interactome; new clues on its possible involvement in Epstein-Barr Virus-associated diseases.

PubMed

Rouka, Erasmia; Kyriakou, Despoina

2015-12-01

Epigenetic deregulation is a common feature in the pathogenesis of Epstein-Barr Virus (EBV)-related lymphomas and carcinomas. Previous studies have demonstrated a strong association between EBV latency in B-cells and epigenetic silencing of the tumor suppressor gene BIM. This study aimed to the construction and functional analysis of the BIM interactome in order to identify novel host genes that may be targeted by EBV. Fifty-nine unique interactors were found to compose the BIM gene network. Ontological analysis at the pathway level highlighted infectious diseases along with neuropathologies. These results underline the possible interplay between the BIM interactome and EBV-associated disorders.
Application of BIM Technology in Building Water Supply and Drainage Design

NASA Astrophysics Data System (ADS)

Wei, Tianyun; Chen, Guiqing; Wang, Junde

2017-12-01

Through the application of BIM technology, the idea of building water supply and drainage designers can be related to the model, the various influencing factors to affect water supply and drainage design can be considered more comprehensively. BIM(Building information model) technology assist in improving the design process of building water supply and drainage, promoting the building water supply and drainage planning, enriching the building water supply and drainage design method, improving the water supply and drainage system design level and building quality. Combined with fuzzy comprehensive evaluation method to analyze the advantages of BIM technology in building water supply and drainage design. Therefore, application prospects of BIM technology are very worthy of promotion.
Exploitation and Benefits of BIM in Construction Project Management

NASA Astrophysics Data System (ADS)

Mesároš, Peter; Mandičák, Tomáš

2017-10-01

BIM is increasingly getting into the awareness in construction industry. BIM is the process of creating and data managing of the building during its life cycle. BIM became a part of management tools in modern construction companies. Construction projects have a number of participants. It means difficulty process of construction project management and a serious requirement for processing the huge amount of information including design, construction, time and cost parameters, economic efficiency and sustainability. Progressive information and communication technologies support cost management and management of construction project. One of them is Building Information Modelling. Aim of the paper is to examine the impact of BIM exploitation and benefits on construction project management in Slovak companies.
Mesh-To from Segmented Mesh Elements to Bim Model with Limited Parameters

NASA Astrophysics Data System (ADS)

Yang, X.; Koehl, M.; Grussenmeyer, P.

2018-05-01

Building Information Modelling (BIM) technique has been widely utilized in heritage documentation and comes to a general term Historical/Heritage BIM (HBIM). The current HBIM project mostly employs the scan-to-BIM process to manually create the geometric model from the point cloud. This paper explains how it is possible to shape from the mesh geometry with reduced human involvement during the modelling process. Aiming at unbuilt heritage, two case studies are handled in this study, including a ruined Roman stone architectural and a severely damaged abbey. The pipeline consists of solid element modelling based on documentation data using Autodesk Revit, a common BIM platform, and the successive modelling from these geometric primitives using Autodesk Dynamo, a visual programming built-in plugin tool in Revit. The BIM-based reconstruction enriches the classic visual model from computer graphics approaches with measurement, semantic and additional information. Dynamo is used to develop a semi-automated function to reduce the manual process, which builds the final BIM model from segmented parametric elements directly. The level of detail (LoD) of the final models is dramatically relevant with the manual involvement in the element creation. The proposed outline also presents two potential issues in the ongoing work: combining the ontology semantics with the parametric BIM model, and introducing the proposed pipeline into the as-built HBIM process.
The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL).

PubMed

Guo, Y; Schoell, M C; Freeman, R S

2009-04-23

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM(EL) and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM(EL) protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM(EL) protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC cells, and that destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.

Fusion of Terrestrial and Airborne Laser Data for 3D modeling Applications

NASA Astrophysics Data System (ADS)

Mohammed, Hani Mahmoud

This thesis deals with the 3D modeling phase of the as-built large BIM projects. Among several means of BIM data capturing, such as photogrammetric or range tools, laser scanners have been one of the most efficient and practical tool for a long time. They can generate point clouds with high resolution for 3D models that meet nowadays' market demands. The current 3D modeling projects of as-built BIMs are mainly focused on using one type of laser scanner data, such as Airborne or Terrestrial. According to the literatures, no significant (few) efforts were made towards the fusion of heterogeneous laser scanner data despite its importance. The importance of the fusion of heterogeneous data arises from the fact that no single type of laser data can provide all the information about BIM, especially for large BIM projects that are existing on a large area, such as university buildings, or Heritage places. Terrestrial laser scanners are able to map facades of buildings and other terrestrial objects. However, they lack the ability to map roofs or higher parts in the BIM project. Airborne laser scanner on the other hand, can map roofs of the buildings efficiently and can map only small part of the facades. Short range laser scanners can map the interiors of the BIM projects, while long range scanners are used for mapping wide exterior areas in BIM projects. In this thesis the long range laser scanner data obtained in the Stop-and-Go mapping mode, the short range laser scanner data, obtained in a fully static mapping mode, and the airborne laser data are all fused together to bring a complete effective solution for a large BIM project. Working towards the 3D modeling of BIM projects, the thesis framework starts with the registration of the data, where a new fast automatic registration algorithm were developed. The next step is to recognize the different objects in the BIM project (classification), and obtain 3D models for the buildings. The last step is the development of an occlusion removal algorithm to efficiently retain parts of the buildings occluded by surrounding objects such as trees, vehicles, or street poles.
Insulin-like growth factor 1 rescues R28 retinal neurons from apoptotic death through ERK-mediated BimEL phosphorylation independent of Akt.

PubMed

Kong, Dejuan; Gong, Lijie; Arnold, Edith; Shanmugam, Sumathi; Fort, Patrice E; Gardner, Thomas W; Abcouwer, Steven F

2016-10-01

Insulin-like growth factor 1 (IGF-1) can provide long-term neurotrophic support by activation of Akt, inhibition of FoxO nuclear localization and suppression of Bim gene transcription in multiple neuronal systems. However, MEK/ERK activation can also promote neuron survival through phosphorylation of BimEL. We explored the contribution of the PI3K/Akt/FoxO and MEK/ERK/BimEL pathways in IGF-1 stimulated survival after serum deprivation (SD) of R28 cells differentiated to model retinal neurons. IGF-1 caused rapid activation of Akt leading to FoxO1/3-T32/T24 phosphorylation, and prevented FoxO1/3 nuclear translocation and Bim mRNA upregulation in response to SD. IGF-1 also caused MAPK/MEK pathway activation as indicated by ERK1/2-T202/Y204 and Bim-S65 phosphorylation. Overexpression of FoxO1 increased Bim mRNA expression and amplified the apoptotic response to SD without shifting the serum response curve. Inhibition of Akt activation with LY294002 or by Rictor knockdown did not block the protective effect of IGF-1, while inhibition of MEK activity with PD98059 prevented Bim phosphorylation and blocked IGF-1 protection. In addition, knockdown of Bim expression was protective during SD, while co-silencing of FoxO1 and Fox03 expression had little effect. Thus, the PI3K/Akt/FoxO pathway was not essential for protection from SD-induced apoptosis by IGF-1 in R28 cells. Instead, IGF-1 protection was dependent on activation of the MEK/ERK pathway leading to BimEL phosphorylation, which is known to prevent Bax/Bak oligomerization and activation of the intrinsic mitochondrial apoptosis pathway. These studies demonstrate the requirement of the MEK/ERK pathway in a model of retinal neuron cell survival and highlight the cell specificity for IGF-1 signaling in this response. Copyright © 2016 Elsevier Ltd. All rights reserved.
Involvement of microRNA-181a and Bim in a rat model of retinal ischemia-reperfusion injury.

PubMed

He, Yu; Liu, Jin-Nan; Zhang, Jun-Jun; Fan, Wei

2016-01-01

To investigate the changes in the expression of microRNA-181a (miR-181a) and Bim in a rat model of retinal ischemia-reperfusion (RIR), to explore their target relationship in RIR and their involvement in regulating apoptosis of retinal ganglion cells (RGCs). Target gene prediction for miR-181a was performed with the aid of bioinformatics and Bim was identified as a potential target gene of miR-181a. A rat model of RIR was created by increasing the intraocular pressure. RGCs in the flatmounted retinas were labeled with Brn3, a marker for alive RGCs, by immunofluorescent staining. The changes in the number of RGCs after RIR were recorded. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of miR-181a in the retina. Bim/Brn3 double immunofluorescence was used to detect the localization of Bim. The expression of Bim in the retina was determined with the aids of Western blot and qRT-PCR. Compared with the negative control group, the density of RGCs was significantly lower in the ischemia/reperfusion (I/R)-24h and I/R-72h groups (P<0.001). The expression level of miR-181a started to decrease at 0h after RIR, and further decreased at 24h and 72h compared with the negative control group (P<0.001). Bim was significantly upregulated at 12h after RIR (P<0.05) and reached peak at 24, 72h compared with the negative control group (P<0.01). Pearson correlation analysis showed that the expression level of Bim was negatively correlated with the expression level of miR-181a and the density of RGCs. Bim may be a potential target gene of miR-181a. Both miR-181a and Bim are involved in RGCs death in RIR. RIR may promote RGCs apoptosis in the retina via downregulation of miR-181a and its inhibition on Bim expression.
Model-Driven Energy Intelligence

DTIC Science & Technology

2015-03-01

building information model ( BIM ) for operations...estimate of the potential impact on energy performance at Fort Jackson. 15. SUBJECT TERMS Building Information Modeling ( BIM ), Energy, ECMs, monitoring...dimensional AHU Air Handling Unit API Application Programming Interface BIM building information model BLCC Building Life Cycle Cost
The pro-apoptotic protein Bim is a convergence point for cAMP/protein kinase A- and glucocorticoid-promoted apoptosis of lymphoid cells.

PubMed

Zhang, Lingzhi; Insel, Paul A

2004-05-14

The mechanisms by which cAMP mediates apoptosis are not well understood. In the current studies, we used wild-type (WT) S49 T-lymphoma cells and the kin(-) variant (which lacks protein kinase A (PKA)) to examine cAMP/PKA-mediated apoptosis. The cAMP analog, 8-CPT-cAMP, increased phosphorylation of the cAMP response element-binding protein (CREB), activated caspase-3, and induced apoptosis in WT but not in kin(-) S49 cells. Using an array of 96 apoptosis-related genes, we found that treatment of WT cells with 8-CPT-cAMP for 24 h induced expression of mRNA for the pro-apoptotic gene, Bim. Real-time PCR analysis indicated that 8-CPT-cAMP increased Bim RNA in WT cells in <2 h and maintained this increase for >24 h. Bim protein expression increased in WT but not kin(-) cells treated with 8-CPT-cAMP or with the beta-adrenergic receptor agonist isoproterenol. Both apoptosis and Bim expression were reversible with removal of 8-CPT-cAMP after <6 h. The glucocorticoid dexamethasone also promoted apoptosis and Bim expression in S49 cells. In contrast, both UV light and anti-mouse Fas monoclonal antibody promoted apoptosis in S49 cells but did not induce Bim expression. 8-CPT-cAMP also induced Bim expression and enhanced dexamethasone-promoted apoptosis in human T-cell leukemia CEM-C7-14 (glucocorticoid-sensitive) and CEM-C1-15 (glucocorticoid-resistant) cells; increased Bim expression in 8-CPT-cAMP-treated CEM-C1-15 cells correlated with conversion of the cells from resistance to sensitivity to glucocorticoid-promoted apoptosis. Induction of Bim appears to be a key event in cAMP-promoted apoptosis in both murine and human T-cell lymphoma and leukemia cells and thus appears to be a convergence point for the killing of such cells by glucocorticoids and agents that elevate cAMP.
The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non-small cell lung cancer.

PubMed

Zhao, Mingchuan; Zhang, Yishi; Cai, Weijing; Li, Jiayu; Zhou, Fei; Cheng, Ningning; Ren, Ruixin; Zhao, Chao; Li, Xuefei; Ren, Shengxiang; Zhou, Caicun; Hirsch, Fred R

2014-08-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have EGFR mutations. Recent studies have indicated that some patients with positive mutations were refractory to EGFR TKIs if they harbored a B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (Bim) deletion polymorphism. The objective of the current work was to retrospectively study the Bim deletion polymorphism in Chinese patients with NSCLC and its correlation with the efficacy of EGFR TKIs. Distribution of the Bim polymorphism was detected using polymerase chain reaction analysis and direct sequencing of DNA from peripheral neutrophils in samples from 352 patients with NSCLC. Of the 352 patients, 166 who received TKI therapy and had an activating mutation identified were involved in further analysis. Progression-free survival (PFS) was the primary endpoint of the subsequent analyses, and the incidence of the Bim polymorphism and its relation to clinical benefit from EGFR TKIs also were investigated. In total, 45 of 352 patient samples (12.8%) had the Bim deletion polymorphism, which was distributed randomly with regard to various clinical characteristics. In patients with EGFR mutations who received treatment with TKIs, the median PFS and the median objective response rate were 4.7 months and 25%, respectively, for those with the Bim deletion polymorphism versus 11 months (P = .003) and 66% (P = .001), respectively, for those with wild-type Bim. Cox regression analysis identified Bim status (P = .016) and sex (P = .002) as independent factors predicting clinical benefit from EGFR TKIs in patients with EGFR-mutated NSCLC. The incidence of the Bim deletion polymorphism was approximately 13% in this study, and it was associated with a poor clinical response to EGFR TKIs in patients who had NSCLC with EGFR mutations. © 2014 American Cancer Society.
Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation.

PubMed

Chang, Yi; Hsu, Wen-Hsien; Yang, Wen-Bin; Jayakumar, Thanasekaran; Lee, Tzu-Yin; Sheu, Joen-Rong; Lu, Wan-Jung; Li, Jiun-Yi

2017-11-01

Antiplatelet agents have considerable benefits in the treatment of thromboembolic diseases; however, these agents still have substantial limitations due to their severe side-effects. In this study, the antiplatelet activity of three newly synthesized saccharide based benzimidazole derivatives, M3BIM, Malto-BIM and Melibio-BIM, in collagen and thrombin-stimulated human platelets in vitro was examined. Among the compounds tested, only compound M3BIM exerted concentration (20-60 µM)-dependent inhibitory effects against collagen (1 µg/ml) and thrombin (0.01 U/ml)-induced washed human platelet aggregation. Moreover, at a concentration of 60 µM, M3BIM distinctly abolished collagen-induced adenosine triphosphate (ATP) release and intracellular Ca2+ mobilization. Additionally, this compound attenuated the collagen-induced phosphorylation of p47, a marker of the activation of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK). However, Malto-BIM and Melibio-BIM were not effective in this regard. Moreover, the toxic effects of these compounds were evaluated using zebrafish embryo toxicity (ZET) assay, and the results revealed that all three compounds had no comparative cytotoxicity within the range of 25-200 µM. Overall, the results of this study provide evidence for the inhibitory effects of M3BIM on collagen-induced platelet aggregation in vitro compared to other imidazole derivatives. The presence of 1-imidazolyl moiety at one end with a longer chain length (three sugar moieties) may be mainly responsible for the observed effects of M3BIM. These results suggest that compound M3BIM may be used as a potential candidate for the treatment of aberrant platelet activation-related diseases as it inhibits the activation of p47 and p38 MAPK, and reduces ATP release and Ca2+ mobilization.
BIM: Enabling Sustainability and Asset Management through Knowledge Management

PubMed Central

2013-01-01

Building Information Modeling (BIM) is the use of virtual building information models to develop building design solutions and design documentation and to analyse construction processes. Recent advances in IT have enabled advanced knowledge management, which in turn facilitates sustainability and improves asset management in the civil construction industry. There are several important qualifiers and some disadvantages of the current suite of technologies. This paper outlines the benefits, enablers, and barriers associated with BIM and makes suggestions about how these issues may be addressed. The paper highlights the advantages of BIM, particularly the increased utility and speed, enhanced fault finding in all construction phases, and enhanced collaborations and visualisation of data. The paper additionally identifies a range of issues concerning the implementation of BIM as follows: IP, liability, risks, and contracts and the authenticity of users. Implementing BIM requires investment in new technology, skills training, and development of new ways of collaboration and Trade Practices concerns. However, when these challenges are overcome, BIM as a new information technology promises a new level of collaborative engineering knowledge management, designed to facilitate sustainability and asset management issues in design, construction, asset management practices, and eventually decommissioning for the civil engineering industry. PMID:24324392
Quantification of construction waste prevented by BIM-based design validation: Case studies in South Korea.

PubMed

Won, Jongsung; Cheng, Jack C P; Lee, Ghang

2016-03-01

Waste generated in construction and demolition processes comprised around 50% of the solid waste in South Korea in 2013. Many cases show that design validation based on building information modeling (BIM) is an effective means to reduce the amount of construction waste since construction waste is mainly generated due to improper design and unexpected changes in the design and construction phases. However, the amount of construction waste that could be avoided by adopting BIM-based design validation has been unknown. This paper aims to estimate the amount of construction waste prevented by a BIM-based design validation process based on the amount of construction waste that might be generated due to design errors. Two project cases in South Korea were studied in this paper, with 381 and 136 design errors detected, respectively during the BIM-based design validation. Each design error was categorized according to its cause and the likelihood of detection before construction. The case studies show that BIM-based design validation could prevent 4.3-15.2% of construction waste that might have been generated without using BIM. Copyright © 2015 Elsevier Ltd. All rights reserved.
BIM: enabling sustainability and asset management through knowledge management.

PubMed

Kivits, Robbert Anton; Furneaux, Craig

2013-11-10

Building Information Modeling (BIM) is the use of virtual building information models to develop building design solutions and design documentation and to analyse construction processes. Recent advances in IT have enabled advanced knowledge management, which in turn facilitates sustainability and improves asset management in the civil construction industry. There are several important qualifiers and some disadvantages of the current suite of technologies. This paper outlines the benefits, enablers, and barriers associated with BIM and makes suggestions about how these issues may be addressed. The paper highlights the advantages of BIM, particularly the increased utility and speed, enhanced fault finding in all construction phases, and enhanced collaborations and visualisation of data. The paper additionally identifies a range of issues concerning the implementation of BIM as follows: IP, liability, risks, and contracts and the authenticity of users. Implementing BIM requires investment in new technology, skills training, and development of new ways of collaboration and Trade Practices concerns. However, when these challenges are overcome, BIM as a new information technology promises a new level of collaborative engineering knowledge management, designed to facilitate sustainability and asset management issues in design, construction, asset management practices, and eventually decommissioning for the civil engineering industry.
Bim Automation: Advanced Modeling Generative Process for Complex Structures

NASA Astrophysics Data System (ADS)

Banfi, F.; Fai, S.; Brumana, R.

2017-08-01

The new paradigm of the complexity of modern and historic structures, which are characterised by complex forms, morphological and typological variables, is one of the greatest challenges for building information modelling (BIM). Generation of complex parametric models needs new scientific knowledge concerning new digital technologies. These elements are helpful to store a vast quantity of information during the life cycle of buildings (LCB). The latest developments of parametric applications do not provide advanced tools, resulting in time-consuming work for the generation of models. This paper presents a method capable of processing and creating complex parametric Building Information Models (BIM) with Non-Uniform to NURBS) with multiple levels of details (Mixed and ReverseLoD) based on accurate 3D photogrammetric and laser scanning surveys. Complex 3D elements are converted into parametric BIM software and finite element applications (BIM to FEA) using specific exchange formats and new modelling tools. The proposed approach has been applied to different case studies: the BIM of modern structure for the courtyard of West Block on Parliament Hill in Ottawa (Ontario) and the BIM of Masegra Castel in Sondrio (Italy), encouraging the dissemination and interaction of scientific results without losing information during the generative process.
Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2014-08-01

AWARD NUMBER: W81XWH-13-1-0227 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and...1Aug2013-31July2014 4. TITLE AND SUBTITLE Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to 5a. CONTRACT NUMBER...clinic. We had not had this capability when we applied for this award. We can now use these clinically relevant models to assess the expression of BIM
Using BIM Technology to Optimize the Traditional Interior Design Work Mode

NASA Astrophysics Data System (ADS)

Zhu, Ning Ke

2018-06-01

the development of BIM technology and application in the field of architecture design has produced results, but BIM technology and application in the field of interior design is still immaturity because of construction and decoration engineering separation. The article analyzes the problems that BIM technology lead to the interior design work mode optimization, from the 3D visualization work environment, real-time collaborative design mode, physical analysis design mode, information integration design mode state the application in interior design.
BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas

PubMed Central

Ibáñez-Costa, Alejandro; López-Sánchez, Laura M.; Gahete, Manuel D.; Rivero-Cortés, Esther; Vázquez-Borrego, Mari C.; Gálvez, María A.; de la Riva, Andrés; Venegas-Moreno, Eva; Jiménez-Reina, Luis; Moreno-Carazo, Alberto; Tinahones, Francisco J.; Maraver-Selfa, Silvia; Japón, Miguel A.; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Webb, Susan M.; Kineman, Rhonda D.; Culler, Michael D.; Castaño, Justo P.; Luque, Raúl M.

2017-01-01

Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3–5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760. PMID:28181484
Benefit Evaluation of Implementing BIM in Construction Projects

NASA Astrophysics Data System (ADS)

Chou, Hui-Yu; Chen, Pei-Yu

2017-10-01

Since 2014, public construction projects in Taiwan have progressively undertaken steps to promote the use of Building Information Modelling (BIM) technology, the use of BIM has therefore become a necessity for contractors. However, issues such as the high upfront costs relating to software and hardware setup and BIM user training, combined with the difficulties of incorporating BIM into existing workflow operations and management systems, remain a challenge to contractors. Consequently, the benefits stemming from the BIM implementation in turn will affect the activeness and enthusiasm of contractors to implement BIM. While there have been previous studies abroad where the benefits relating to BIM implementation had been calculated and quantified numerically, a benefit evaluation index would require considerations for regional industry practices and characteristics. This study established a benefit evaluation index and method for the implementation of BIM suitable for contractors in Taiwan. The three main principal indexes are: (1) RCR means the effects of reducing costs associated with rework; (2) SDR & DPR mean the effects of mitigating delays that occur due to construction interface coordination or rework, as well as the effects of reducing the penalty costs associated with overdue delivery; (3) AQE means the effects of improving the ability to estimate the amounts of building materials and resources. This study also performed a benefit evaluation calculation of a real world case study construction project using the first two established indexes. The results showed a 0.16% reduction in rework costs, a 6.49% reduction in delays that occur from construction interface coordination or rework, and a 5.0% reduction in penalty costs associated with overdue deliveries. The results demonstrated the applicability of the benefit evaluation index established in this study for real world construction projects.
[Retrospective Study of Efficacy in BIM Gene Polymorphism on First-line EGFR-TKIs Treatment for Advanced Lung Adenocarcinoma].

PubMed

Qian, Kun; Zhang, Yi; Zhi, Xiuyi

2017-08-20

The aim of this study is to detect the BIM polymorphism in 85 formalin-fixed and parrffin-embedded (FFPE) and some blood samples of advanced lung adenocarcinoma patients and study the relativity betweenthe BIM polymorphism and tyrosine kinase inhibitor (TKI). The correlation between BIM detection of different types of specimens was discussed. There were 85 patients who were diagnosed as advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) 19 or 21 exon mutation in thoracic surgery of Xuanwu Hospital from February 2013 to November 2014, all of who were received EGFR-TKI as first-line treatment in the study. FFPE and some blood were used to detect the BIM polymorphism. The objective response rate (ORR) and progression-free survival (PFS) of two groups were compared. According to smoking, sex, EGFR mutation and other factors, the single factor analysis was performed, and the correlation between paraffin samples and blood test BIM was compared. The ORR in BIM polymorphism and non-polymorphism groups was no significant differences (P>0.05). The median PFS in BIM polymorphism and non-polymorphism group was 7.1 months and 12.8 months, respectively (P=0.013). Univariate analysis the median PFS, women were longer than men (12.1 months vs 10.7 months, P=0.835); Non-smokers were longer than smokers (12.1 months vs 9.7 months, P=0.974). Group in EGFR exon 21 is longer than group in EGFR exon 19 (12.2 months vs 8.7 months, P=0.303). Detection of BIM gene polymorphism in lung cancer patients with EGFR-TKIs treatment might be helpful for predicting prognosis. But a large sample study is needed.
Bcl-2 Allows Effector and Memory CD8+ T Cells To Tolerate Higher Expression of Bim

PubMed Central

Kurtulus, Sema; Tripathi, Pulak; Moreno-Fernandez, Maria E.; Sholl, Allyson; Katz, Jonathan D.; Grimes, H. Leighton; Hildeman, David A.

2014-01-01

As acute infections resolve, most effector CD8+ T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8+ T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8+ T cells reported to have a longer lifespan (i.e., KLRG1lowCD127high) have increased levels of Bcl-2 compared with their shorter-lived KLRG1highCD127low counterparts. Surprisingly, we found that these effector KLRG1lowCD127high CD8+ T cells also had increased levels of Bim compared with KLRG1highCD127low cells. Similar effects were observed in memory cells, in which CD8+ central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8+ effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8+ T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8+ T cells. Finally, we found that Bim levels were significantly increased in effector CD8+ T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate. PMID:21451108
BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas.

PubMed

Ibáñez-Costa, Alejandro; López-Sánchez, Laura M; Gahete, Manuel D; Rivero-Cortés, Esther; Vázquez-Borrego, Mari C; Gálvez, María A; de la Riva, Andrés; Venegas-Moreno, Eva; Jiménez-Reina, Luis; Moreno-Carazo, Alberto; Tinahones, Francisco J; Maraver-Selfa, Silvia; Japón, Miguel A; García-Arnés, Juan A; Soto-Moreno, Alfonso; Webb, Susan M; Kineman, Rhonda D; Culler, Michael D; Castaño, Justo P; Luque, Raúl M

2017-02-09

Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D 2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca 2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3-5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca 2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca 2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca 2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D 2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D 2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.
Bim-Gis Integrated Geospatial Information Model Using Semantic Web and Rdf Graphs

NASA Astrophysics Data System (ADS)

Hor, A.-H.; Jadidi, A.; Sohn, G.

2016-06-01

In recent years, 3D virtual indoor/outdoor urban modelling becomes a key spatial information framework for many civil and engineering applications such as evacuation planning, emergency and facility management. For accomplishing such sophisticate decision tasks, there is a large demands for building multi-scale and multi-sourced 3D urban models. Currently, Building Information Model (BIM) and Geographical Information Systems (GIS) are broadly used as the modelling sources. However, data sharing and exchanging information between two modelling domains is still a huge challenge; while the syntactic or semantic approaches do not fully provide exchanging of rich semantic and geometric information of BIM into GIS or vice-versa. This paper proposes a novel approach for integrating BIM and GIS using semantic web technologies and Resources Description Framework (RDF) graphs. The novelty of the proposed solution comes from the benefits of integrating BIM and GIS technologies into one unified model, so-called Integrated Geospatial Information Model (IGIM). The proposed approach consists of three main modules: BIM-RDF and GIS-RDF graphs construction, integrating of two RDF graphs, and query of information through IGIM-RDF graph using SPARQL. The IGIM generates queries from both the BIM and GIS RDF graphs resulting a semantically integrated model with entities representing both BIM classes and GIS feature objects with respect to the target-client application. The linkage between BIM-RDF and GIS-RDF is achieved through SPARQL endpoints and defined by a query using set of datasets and entity classes with complementary properties, relationships and geometries. To validate the proposed approach and its performance, a case study was also tested using IGIM system design.
Research on odor interaction between aldehyde compounds via a partial differential equation (PDE) model.

PubMed

Yan, Luchun; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia

2015-01-28

In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures.

Energy-Saving Optimization of Water Supply Pumping Station Life Cycle Based on BIM Technology

NASA Astrophysics Data System (ADS)

Qun, Miao; Wang, Jiayuan; Liu, Chao

2017-12-01

In the urban water supply system, pump station is the main unit of energy consumption. In the background of pushing forward the informatization in China, using BIM technology in design, construction and operations of water supply pumping station, can break through the limitations of the traditional model and effectively achieve the goal of energy conservation and emissions reduction. This work researches the way to solve energy-saving optimization problems in the process of whole life cycle of water supply pumping station based on BIM technology, and put forward the feasible strategies of BIM application in order to realize the healthy and sustainable development goals by establishing the BIM model of water supply pumping station of Qingdao Guzhenkou water supply project.
Building Information Modelling: Challenges and Barriers in Implement of BIM for Interior Design Industry in Malaysia

NASA Astrophysics Data System (ADS)

Hamid, A. B. Abd; Taib, M. Z. Mohd; Razak, A. H. N. Abdul; Embi, M. R.

2018-04-01

Building Information Modelling (BIM) is an innovative approach that has developed crossways the global in architecture, engineering and construction (AEC) industry. The construction industry of Malaysia has undergone a rapid development and dynamic technology adoption in advance and methods between the players industry and stakeholders. Consequently, limited technologies and devices have not been successful as it should have been. This study will be emphasizing scenarios of challenges and barriers in adopting BIM in interior design industry in Malaysia. The study was emphasizing the challenges and barriers in BIM usage from the designer’s perspective. The data are collected through the questionnaires as to identifying the barriers, knowledge, readiness and awareness and distributed to interior design firms were selected randomly. The finding of this research is to examine the barriers and causes of variables BIM usage for interior design industry in Malaysia. The outcome of this study is to identify the constraint of adoption BIM in interior design industry compare to others players in same industry.
Minimizing delays in the Jordanian construction industry by adopting BIM technology

NASA Astrophysics Data System (ADS)

Btoush, M.; Harun, A. T.

2017-11-01

The Jordanian construction industry plays a significant role and contributes immensely to the gross domestic product (GDP) of the economy. However, the Jordanian public work and housing ministry and most industry players including engineers and contractors have reported that most of the projects experience delays which lead time and cost overruns, and extra efforts. The main causes of delays identified by researchers include poor scheduling and planning, change orders, site conditions, weather, late deliveries, incompetent technical staff. To address these challenges, the implementation of building information modelling (BIM) is paramount. This paper presents BIM as a powerful tool for reducing delays in Jordan construction projects. The paper focuses on two main parts; the first part involves the identification of the major causes of delays, and the second part is to accurately outline the roles and responsibilities of BIM specialist in construction projects. Finally, the paper matches the roles and responsibilities of BIM specialist and the causes of delays, and how the delays are addressed through BIM specialist.
Extended Maptree: a Representation of Fine-Grained Topology and Spatial Hierarchy of Bim

NASA Astrophysics Data System (ADS)

Wu, Y.; Shang, J.; Hu, X.; Zhou, Z.

2017-09-01

Spatial queries play significant roles in exchanging Building Information Modeling (BIM) data and integrating BIM with indoor spatial information. However, topological operators implemented for BIM spatial queries are limited to qualitative relations (e.g. touching, intersecting). To overcome this limitation, we propose an extended maptree model to represent the fine-grained topology and spatial hierarchy of indoor spaces. The model is based on a maptree which consists of combinatorial maps and an adjacency tree. Topological relations (e.g., adjacency, incidence, and covering) derived from BIM are represented explicitly and formally by extended maptrees, which can facilitate the spatial queries of BIM. To construct an extended maptree, we first use a solid model represented by vertical extrusion and boundary representation to generate the isolated 3-cells of combinatorial maps. Then, the spatial relationships defined in IFC are used to sew them together. Furthermore, the incremental edges of extended maptrees are labeled as removed 2-cells. Based on this, we can merge adjacent 3-cells according to the spatial hierarchy of IFC.
Hsp27 binding to the 3′UTR of bim mRNA prevents neuronal death during oxidative stress–induced injury: a novel cytoprotective mechanism

PubMed Central

Dávila, David; Jiménez-Mateos, Eva M.; Mooney, Claire M.; Velasco, Guillermo; Henshall, David C.; Prehn, Jochen H. M.

2014-01-01

Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cytoprotective and apoptosis-inducing signaling pathways. Cellular mechanisms that control apoptosis activation include the regulation of pro/antiapoptotic mRNAs through their 3′-untranslated region (UTR). This region holds binding elements for RNA-binding proteins, which can control mRNA translation. Here we demonstrate that heat shock protein 27 (Hsp27) prevents oxidative stress–induced cell death in cerebellar granule neurons by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2) correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition; however, it was associated with a specific increase in the levels of bim mRNA and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3′UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3′UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons. PMID:25187648
Evaluating the ready biodegradability of two poorly water-soluble substances: comparative approach of bioavailability improvement methods (BIMs).

PubMed

Sweetlove, Cyril; Chenèble, Jean-Charles; Barthel, Yves; Boualam, Marc; L'Haridon, Jacques; Thouand, Gérald

2016-09-01

Difficulties encountered in estimating the biodegradation of poorly water-soluble substances are often linked to their limited bioavailability to microorganisms. Many original bioavailability improvement methods (BIMs) have been described, but no global approach was proposed for a standardized comparison of these. The latter would be a valuable tool as part of a wider strategy for evaluating poorly water-soluble substances. The purpose of this study was to define an evaluation strategy following the assessment of different BIMs adapted to poorly water-soluble substances with ready biodegradability tests. The study was performed with two poorly water-soluble chemicals-a solid, anthraquinone, and a liquid, isodecyl neopentanoate-and five BIMs were compared to the direct addition method (reference method), i.e., (i) ultrasonic dispersion, (ii) adsorption onto silica gel, (iii) dispersion using an emulsifier, (iv) dispersion with silicone oil, and (v) dispersion with emulsifier and silicone oil. A two-phase evaluation strategy of solid and liquid chemicals was developed involving the selection of the most relevant BIMs for enhancing the biodegradability of tested substances. A description is given of a BIM classification ratio (R BIM), which enables a comparison to be made between the different test chemical sample preparation methods used in the various tests. Thereby, using this comparison, the BIMs giving rise to the greatest biodegradability were ultrasonic dispersion and dispersion with silicone oil or with silicone oil and emulsifier for the tested solid chemical, adsorption onto silica gel, and ultrasonic dispersion for the liquid one.
Optimizing Energy Consumption in Building Designs Using Building Information Model (BIM)

NASA Astrophysics Data System (ADS)

Egwunatum, Samuel; Joseph-Akwara, Esther; Akaigwe, Richard

2016-09-01

Given the ability of a Building Information Model (BIM) to serve as a multi-disciplinary data repository, this paper seeks to explore and exploit the sustainability value of Building Information Modelling/models in delivering buildings that require less energy for their operation, emit less CO2 and at the same time provide a comfortable living environment for their occupants. This objective was achieved by a critical and extensive review of the literature covering: (1) building energy consumption, (2) building energy performance and analysis, and (3) building information modeling and energy assessment. The literature cited in this paper showed that linking an energy analysis tool with a BIM model helped project design teams to predict and create optimized energy consumption. To validate this finding, an in-depth analysis was carried out on a completed BIM integrated construction project using the Arboleda Project in the Dominican Republic. The findings showed that the BIM-based energy analysis helped the design team achieve the world's first 103% positive energy building. From the research findings, the paper concludes that linking an energy analysis tool with a BIM model helps to expedite the energy analysis process, provide more detailed and accurate results as well as deliver energy-efficient buildings. The study further recommends that the adoption of a level 2 BIM and the integration of BIM in energy optimization analyse should be made compulsory for all projects irrespective of the method of procurement (government-funded or otherwise) or its size.
Historic Bim: a New Repository for Structural Health Monitoring

NASA Astrophysics Data System (ADS)

Banfi, F.; Barazzetti, L.; Previtali, M.; Roncoroni, F.

2017-05-01

Recent developments in Building Information Modelling (BIM) technologies are facilitating the management of historic complex structures using new applications. This paper proposes a generative method combining the morphological and typological aspects of the historic buildings (H-BIM), with a set of monitoring information. This combination of 3D digital survey, parametric modelling and monitoring datasets allows for the development of a system for archiving and visualizing structural health monitoring (SHM) data (Fig. 1). The availability of a BIM database allows one to integrate a different kind of data stored in different ways (e.g. reports, tables, graphs, etc.) with a representation directly connected to the 3D model of the structure with appropriate levels of detail (LoD). Data can be interactively accessed by selecting specific objects of the BIM, i.e. connecting the 3D position of the sensors installed with additional digital documentation. Such innovative BIM objects, which form a new BIM family for SHM, can be then reused in other projects, facilitating data archiving and exploitation of data acquired and processed. The application of advanced modeling techniques allows for the reduction of time and costs of the generation process, and support cooperation between different disciplines using a central workspace. However, it also reveals new challenges for parametric software and exchange formats. The case study presented is the medieval bridge Azzone Visconti in Lecco (Italy), in which multi-temporal vertical movements during load testing were integrated into H-BIM.
A Model Performance

ERIC Educational Resources Information Center

Thornton, Bradley D.; Smalley, Robert A.

2008-01-01

Building information modeling (BIM) uses three-dimensional modeling concepts, information technology and interoperable software to design, construct and operate a facility. However, BIM can be more than a tool for virtual modeling--it can provide schools with a 3-D walkthrough of a project while it still is on the electronic drawing board. BIM can…
Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2015-08-01

AWARD NUMBER: W81XWH-13-1-0226 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in...REPORT TYPE Annual 3. DATES COVERED 1 Aug 2014 - 31 Jul 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Deficient BIM Expression as a Mechanism of...the time of resistance. We are now using these patient-derived cell lines to assess BIM levels and apoptotic response to next-generation inhibitors
Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2015-08-01

AWARD NUMBER: W81XWH-13-1-0227 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in...TYPE Annual 3. DATES COVERED 1 Aug 2014 - 31 Jul 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Deficient BIM Expression as a Mechanism of Intrinsic...time of resistance. We are now using these patient-derived cell lines to assess BIM levels and apoptotic response to next-generation inhibitors. The
Utilization of building information modeling in infrastructure’s design and construction

NASA Astrophysics Data System (ADS)

Zak, Josef; Macadam, Helen

2017-09-01

Building Information Modeling (BIM) is a concept that has gained its place in the design, construction and maintenance of buildings in Czech Republic during recent years. This paper deals with description of usage, applications and potential benefits and disadvantages connected with implementation of BIM principles in the preparation and construction of infrastructure projects. Part of the paper describes the status of BIM implementation in Czech Republic, and there is a review of several virtual design and construction practices in Czech Republic. Examples of best practice are presented from current infrastructure projects. The paper further summarizes experiences with new technologies gained from the application of BIM related workflows. The focus is on the BIM model utilization for the machine control systems on site, quality assurance, quality management and construction management.
Mobile Laser Scanning for Indoor Modelling

NASA Astrophysics Data System (ADS)

Thomson, C.; Apostolopoulos, G.; Backes, D.; Boehm, J.

2013-10-01

The process of capturing and modelling buildings has gained increased focus in recent years with the rise of Building Information Modelling (BIM). At the heart of BIM is a process change for the construction and facilities management industries whereby a BIM aids more collaborative working through better information exchange, and as a part of the process Geomatic/Land Surveyors are not immune from the changes. Terrestrial laser scanning has been proscribed as the preferred method for rapidly capturing buildings for BIM geometry. This is a process change from a traditional measured building survey just with a total station and is aided by the increasing acceptance of point cloud data being integrated with parametric building models in BIM tools such as Autodesk Revit or Bentley Architecture. Pilot projects carried out previously by the authors to investigate the geometry capture and modelling of BIM confirmed the view of others that the process of data capture with static laser scan setups is slow and very involved requiring at least two people for efficiency. Indoor Mobile Mapping Systems (IMMS) present a possible solution to these issues especially in time saved. Therefore this paper investigates their application as a capture device for BIM geometry creation over traditional static methods through a fit-for-purpose test.
BH3-Only Protein BIM Mediates Heat Shock-Induced Apoptosis

PubMed Central

Mahajan, Indra M.; Chen, Miao-Der; Muro, Israel; Robertson, John D.; Wright, Casey W.; Bratton, Shawn B.

2014-01-01

Acute heat shock can induce apoptosis through a canonical pathway involving the upstream activation of caspase-2, followed by BID cleavage and stimulation of the intrinsic pathway. Herein, we report that the BH3-only protein BIM, rather than BID, is essential to heat shock-induced cell death. We observed that BIM-deficient cells were highly resistant to heat shock, exhibiting short and long-term survival equivalent to Bax−/−Bak−/− cells and better than either Bid−/− or dominant-negative caspase-9-expressing cells. Only Bim−/− and Bax−/−Bak−/− cells exhibited resistance to mitochondrial outer membrane permeabilization and loss of mitochondrial inner membrane potential. Moreover, while dimerized caspase-2 failed to induce apoptosis in Bid−/− cells, it readily did so in Bim−/− cells, implying that caspase-2 kills exclusively through BID, not BIM. Finally, BIM reportedly associates with MCL-1 following heat shock, and Mcl-1−/− cells were indeed sensitized to heat shock-induced apoptosis. However, pharmacological inhibition of BCL-2 and BCL-XL with ABT-737 also sensitized cells to heat shock, most likely through liberation of BIM. Thus, BIM mediates heat shock-induced apoptosis through a BAX/BAK-dependent pathway that is antagonized by antiapoptotic BCL-2 family members. PMID:24427286
The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia.

PubMed

Ko, Tun Kiat; Chin, Hui San; Chuah, Charles T H; Huang, John W J; Ng, King-Pan; Khaw, Seong Lin; Huang, David C S; Ong, S Tiong

2016-01-19

Both germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [1]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1-dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism.
PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2(+) breast cancer cells by inducing Bim.

PubMed

Park, Sun Hee; Ito, Koichi; Olcott, William; Katsyv, Igor; Halstead-Nussloch, Gwyneth; Irie, Hanna Y

2015-06-19

Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2(+) (Her2(+)) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibition is an effective strategy to inhibit growth and survival of Her2(+) breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2(+) breast cancer, either intrinsically or acquired after continuous drug exposure. To determine the effects of PTK6 inhibition on Lapatinib-resistant Her2(+) breast cancer cell lines (UACC893R1 and MDA-MB-453), we used short hairpin ribonucleic acid (shRNA) vectors to downregulate PTK6 expression. We determined the effects of PTK6 downregulation on growth and survival in vitro and in vivo, as well as the mechanisms responsible for these effects. Lapatinib treatment of "sensitive" Her2(+) cells induces apoptotic cell death and enhances transcript and protein levels of Bim, a pro-apoptotic Bcl2 family member. In contrast, treatment of relatively "resistant" Her2(+) cells fails to induce Bim or enhance levels of cleaved, poly-ADP ribose polymerase (PARP). Downregulation of PTK6 expression in these "resistant" cells enhances Bim expression, resulting in apoptotic cell death. PTK6 downregulation impairs growth of these cells in in vitro 3-D Matrigel(TM) cultures, and also inhibits growth of Her2(+) primary tumor xenografts. Bim expression is critical for apoptosis induced by PTK6 downregulation, as co-expression of Bim shRNA rescued these cells from PTK6 shRNA-induced death. The regulation of Bim by PTK6 is not via changes in Erk/MAPK or Akt signaling, two pathways known to regulate Bim expression. Rather, PTK6 downregulation activates p38, and pharmacological inhibition of p38 activity prevents PTK6 shRNA-induced Bim expression and partially rescues cells from apoptosis. PTK6 downregulation induces apoptosis of Lapatinib-resistant Her2(+) breast cancer cells by enhancing Bim expression via p38 activation. As Bim expression is a critical biomarker for response to many targeted therapies, PTK6 inhibition may offer a therapeutic approach to treating patients with Her2 targeted therapy-resistant breast cancers.
Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer.

PubMed

Zhang, Limin; Jiang, Tao; Li, Xuefei; Wang, Yan; Zhao, Chao; Zhao, Sha; Xi, Lei; Zhang, Shijia; Liu, Xiaozhen; Jia, Yijun; Yang, Hui; Shi, Jinpeng; Su, Chunxia; Ren, Shengxiang; Zhou, Caicun

2017-08-01

The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib. A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated. The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]). The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927-35. © 2017 American Cancer Society. © 2017 American Cancer Society.
GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis.

PubMed

Yin, Heng; Zhu, Qing; Liu, Manran; Tu, Gang; Li, Qing; Yuan, Jie; Wen, Siyang; Yang, Guanglun

2017-10-01

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING ﬁnger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM-sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM-resistance in ER-positive breast cancer cells.
Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells.

PubMed

Kim, Kyung Ok; Hsu, Anny C; Lee, Heon Goo; Patel, Neel; Chandhanayingyong, Chandhanarat; Hickernell, Thomas; Lee, Francis Young-In

2014-06-01

Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro-apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14-3-3ϵ protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14-3-3ϵ mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14-3-3ϵ using siRNA. The 14-3-3ϵ gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14-3-3ϵ is required for Bim expression and that it has an anti-cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14-3-3ϵ may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
Combination of erlotinib and EGCG induces apoptosis of head and neck cancers through posttranscriptional regulation of Bim and Bcl-2.

PubMed

Haque, Abedul; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Saba, Nabil F; Khuri, Fadlo R; Shin, Dong M; Ruhul Amin, A R M

2015-07-01

Combinatorial approaches using two or more compounds are gaining increasing attention for cancer therapy. We have previously reported that the combination of the EGFR-TKI erlotinib and epigallocatechin-3-gallate (EGCG) exhibited synergistic chemopreventive effects in head and neck cancers by inducing the expression of Bim, p21, p27, and by inhibiting the phosphorylation of ERK and AKT and expression of Bcl-2. In the current study, we further investigated the mechanism of regulation of Bim, Bcl-2, p21 and p27, and their role in apoptosis. shRNA-mediated silencing of Bim significantly inhibited apoptosis induced by the combination of erlotinib and EGCG (p = 0.005). On the other hand, overexpression of Bcl-2 markedly protected cells from apoptosis (p = 0.003), whereas overexpression of constitutively active AKT only minimally protected cells from apoptosis induced by the combination of the two compounds. Analysis of mRNA expression by RT-PCR revealed that erlotinib, EGCG and their combination had no significant effects on the mRNA expression of Bim, p21, p27 or Bcl-2 suggesting the post-transcriptional regulation of these molecules. Furthermore, we found that erlotinib or the combination of EGCG and erlotinib inhibited the phosphorylation of Bim and stabilized Bim after inhibition of protein translation by cycloheximide. Taken together, our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the posttranscriptional level.

Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.

PubMed

He, Xiaoping; Khurana, Ashwani; Roy, Debarshi; Kaufmann, Scott; Shridhar, Viji

2014-10-15

The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression. © 2014 UICC.
78 FR 40063 - Airworthiness Directives; Erickson Air-Crane Incorporated Helicopters (Type Certificate...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... Sikorsky Model S-64E helicopters. The AD requires repetitive checks of the Blade Inspection Method (BIM... and check procedures for BIM blades installed on the Model S-64F helicopters. Several blade spars with a crack emanating from corrosion pits and other damage have been found because of BIM pressure...
Application Analysis of BIM Technology in Metro Rail Transit

NASA Astrophysics Data System (ADS)

Liu, Bei; Sun, Xianbin

2018-03-01

With the rapid development of urban roads, especially the construction of subway rail transit, it is an effective way to alleviate urban traffic congestion. There are limited site space, complex resource allocation, tight schedule, underground pipeline complex engineering problems. BIM technology, three-dimensional visualization, parameterization, virtual simulation and many other advantages can effectively solve these technical problems. Based on the project of Shenzhen Metro Line 9, BIM technology is innovatively researched throughout the lifecycle of BIM technology in the context of the metro rail transit project rarely used at this stage. The model information file is imported into Navisworks for four-dimensional animation simulation to determine the optimum construction scheme of the shield machine. Subway construction management application platform based on BIM and private cloud technology, the use of cameras and sensors to achieve electronic integration, dynamic monitoring of the operation and maintenance of underground facilities. Make full use of the many advantages of BIM technology to improve the engineering quality and construction efficiency of the subway rail transit project and to complete the operation and maintenance.
AMP kinase–mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

PubMed Central

Concannon, Caoimhín G.; Tuffy, Liam P.; Weisová, Petronela; Bonner, Helena P.; Dávila, David; Bonner, Caroline; Devocelle, Marc C.; Strasser, Andreas; Ward, Manus W.

2010-01-01

Excitotoxicity after glutamate receptor overactivation induces disturbances in cellular ion gradients, resulting in necrosis or apoptosis. Excitotoxic necrosis is triggered by rapid, irreversible ATP depletion, whereas the ability to recover cellular bioenergetics is suggested to be necessary for the activation of excitotoxic apoptosis. In this study, we demonstrate that even a transient decrease in cellular bioenergetics and an associated activation of adenosine monophosphate–activated protein kinase (AMPK) is necessary for the activation of excitotoxic apoptosis. We show that the Bcl-2 homology domain 3 (BH3)–only protein Bim, a proapoptotic Bcl-2 family member, is activated in multiple excitotoxicity paradigms, mediates excitotoxic apoptosis, and inhibits delayed Ca2+ deregulation, mitochondrial depolarization, and apoptosis-inducing factor translocation. We demonstrate that bim activation required the activation of AMPK and that prolonged AMPK activation is sufficient to induce bim gene expression and to trigger a bim-dependent cell death. Collectively, our data demonstrate that AMPK activation and the BH3-only protein Bim couple transient energy depletion to stress-induced neuronal apoptosis. PMID:20351066
BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency

PubMed Central

Ren, Decheng; Sun, Juan; Mao, Liqun; Ye, Honggang

2014-01-01

Irs2-deficient mice develop type 2–like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes. PMID:24760140
Bim-mediated apoptosis is not necessary for thymic negative selection to ubiquitous self-antigens.

PubMed

Hu, Qian; Sader, Alyssa; Parkman, Julia C; Baldwin, Troy A

2009-12-15

T cell education in the thymus is critical for establishing a functional, yet self-tolerant, T cell repertoire. Negative selection is a key process in enforcing self-tolerance. There are many questions that surround the mechanism of negative selection, but it is currently held that apoptosis initiated by Bim and/or Nur77 is critical for negative selection. Recent studies, however, have questioned the necessity of Bim in maintaining both central and peripheral T cell tolerance. To reconcile these apparently contradictory findings, we examined the role of Bim in negative selection in the well-characterized, physiological HY(cd4) mouse model. We found that while Bim expression was required for CD4(+)CD8(+) double-positive thymocyte apoptosis, it was not required for negative selection. Furthermore, Bim deficiency did not alter the frequency or affinity of male reactive cells that escape negative selection in an oligoclonal repertoire. Collectively, these studies indicate that negative selection occurs efficiently in the absence of apoptosis and suggest that the current paradigm of negative selection requiring apoptosis be revisited.
The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim.

PubMed

Aira, Lazaro E; Villa, Elodie; Colosetti, Pascal; Gamas, Parvati; Signetti, Laurie; Obba, Sandrine; Proics, Emma; Gautier, Fabien; Bailly-Maitre, Béatrice; Jacquel, Arnaud; Robert, Guillaume; Luciano, Frédéric; Juin, Philippe P; Ricci, Jean-Ehrland; Auberger, Patrick; Marchetti, Sandrine

2018-04-01

Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lyn, which results in an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptotic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells.
Avian reovirus S1133-induced apoptosis is associated with Bip/GRP79-mediated Bim translocation to the endoplasmic reticulum.

PubMed

Lin, Ping-Yuan; Liu, Hung-Jen; Chang, Ching-Dong; Chen, Yo-Chia; Chang, Chi-I; Shih, Wen-Ling

2015-04-01

In this study the mechanism of avian reovirus (ARV) S1133-induced pathogenesis was investigated, with a focus on the contribution of ER stress to apoptosis. Our results showed that upregulation of the ER stress response protein, as well as caspase-3 activation, occurred in ARV S1133-infected cultured cells and in SPF White Leghorn chicks organs. Upon infection, Bim was translocated specifically to the ER, but not mitochondria, in the middle to late infectious stages. In addition, ARV S1133 induced JNK phosphorylation and promoted JNK-Bim complex formation, which correlated with the Bim translocation and apoptosis induction that was observed at the same time point. Knockdown of BiP/GRP78 by siRNA and inhibition of BiP/GRP78 using EGCG both abolished the formation of the JNK-Bim complex, caspase-3 activation, and subsequent apoptosis induction by ARV S1133 efficiently. These results suggest that BiP/GRP78 played critical roles and works upstream of JNK-Bim in response to the ARV S1133-mediated apoptosis process.
Burning invariant manifolds for reaction fronts in three-dimensional fluid flows

NASA Astrophysics Data System (ADS)

Mitchell, Kevin; Solomon, Tom

2017-11-01

The geometry of reaction fronts that propagate in fully three-dimensional (3D) fluid flows is studied using the tools of dynamical systems theory. The evolution of an infinitesimal front element is modeled as a six-dimensional ODE-three dimensions for the position of the front element and three for the orientation of its unit normal. This generalizes an earlier approach to understanding front propagation in two-dimensional (2D) fluid flows. As in 2D, the 3D system exhibits prominent burning invariant manifolds (BIMs). In 3D, BIMs are two-dimensional dynamically defined surfaces that form one-way barriers to the propagation of reaction fronts within the fluid. Due to the third dimension, BIMs in 3D exhibit a richer topology than their cousins in 2D. In particular, whereas BIMs in both 2D and 3D can originate from fixed points of the dynamics, BIMs in 3D can also originate from limit cycles. Such BIMs form robust tube-like channels that guide and constrain the evolution of the front within the bulk of the fluid. Supported by NSF Grant CMMI-1201236.
Developing mobile- and BIM-based integrated visual facility maintenance management system.

PubMed

Lin, Yu-Cheng; Su, Yu-Chih

2013-01-01

Facility maintenance management (FMM) has become an important topic for research on the operation phase of the construction life cycle. Managing FMM effectively is extremely difficult owing to various factors and environments. One of the difficulties is the performance of 2D graphics when depicting maintenance service. Building information modeling (BIM) uses precise geometry and relevant data to support the maintenance service of facilities depicted in 3D object-oriented CAD. This paper proposes a new and practical methodology with application to FMM using BIM technology. Using BIM technology, this study proposes a BIM-based facility maintenance management (BIMFMM) system for maintenance staff in the operation and maintenance phase. The BIMFMM system is then applied in selected case study of a commercial building project in Taiwan to verify the proposed methodology and demonstrate its effectiveness in FMM practice. Using the BIMFMM system, maintenance staff can access and review 3D BIM models for updating related maintenance records in a digital format. Moreover, this study presents a generic system architecture and its implementation. The combined results demonstrate that a BIMFMM-like system can be an effective visual FMM tool.
Overview of Building Information Modelling (BIM) adoption factors for construction organisations

NASA Astrophysics Data System (ADS)

Mohammad, W. N. S. Wan; Abdullah, M. R.; Ismail, S.; Takim, R.

2018-04-01

Improvement and innovation in building visualization, project coordination and communication are the major benefits generated by Building Information Modelling (BIM) for construction organisations. Thus, as many firms across the world would adopt BIM, however they do not know the clear direction in which path they are moving as there is no specific reference available for them to refer to. Hence, the paper seeks to identify the factors of BIM adoption from previous research. The methodology used in this paper is based on literature review from various sources such as conference articles and journals. Then, the findings were analysed using content analysis. The findings show that there are 24 factors found from literature that influence the adoption of BIM and four (4) factors such as vendor, organisational vision, knowledge, and implementation plan are among the least factors mentioned by previous researchers.
Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-induced apoptosis through upregulation of Bim expression.

PubMed

Seo, Seung Un; Woo, Seon Min; Min, Kyoung-Jin; Kwon, Taeg Kyu

2018-04-15

Inhibition of cathespsin S not only inhibits invasion and angiogenesis, but also induces apoptosis and autophagy in cancer cells. In present study, we revealed that pharmacological inhibitor [Z-FL-COCHO (ZFL)] of cathepsin S up-regulates pro-apoptotic protein Bim expression at the posttranslational levels. These effects were not associated with MAPKs and AMPK signal pathways. Interestingly, pretreatment with the chemical chaperones (TUDCA and PBA) and knockdown of protein phosphatase 2A (PP2A) markedly inhibited ZFL-induced Bim upregulation. ZFL enhances oxaliplatin-mediated apoptosis through ER stress-induced Bim upregulation in cancer cells. Collectively, our results suggest that inhibition of cathepsin S-induced Bim upregulation contribute to anti-cancer drug-induced apoptotic cell death in renal carcinoma Caki cells. Copyright © 2018 Elsevier Inc. All rights reserved.
Bim and Bmf in tissue homeostasis and malignant disease

PubMed Central

Piñon, JD; Labi, V; Egle, A; Villunger, A

2012-01-01

Among all BH3-only proteins known to date, most information is available on the biological role and function of Bim (Bcl-2 interacting mediator of cell death)/BOD (Bcl-2 related ovarian death agonist), whereas little is still known about its closest relative, Bcl-2 modifying factor (Bmf). Although Bim has been implicated in the regulation of cell death induction in multiple cell types and tissues in response to a large number of stimuli, including growth factor or cytokine deprivation, calcium flux, ligation of antigen receptors on T and B cells, glucocorticoid or loss of adhesion, Bmf seems to play a more restricted role by supporting Bim in some of these cell death processes. This review aims to highlight similarities between Bim and Bmf function in apoptosis signaling and their role in normal development and disease. PMID:19641506
c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1.

PubMed

Campone, Mario; Noël, Bélinda; Couriaud, Cécile; Grau, Morgan; Guillemin, Yannis; Gautier, Fabien; Gouraud, Wilfried; Charbonnel, Catherine; Campion, Loïc; Jézéquel, Pascal; Braun, Frédérique; Barré, Benjamin; Coqueret, Olivier; Barillé-Nion, Sophie; Juin, Philippe

2011-09-07

Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells. We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data. We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors. This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.
Exploratory cohort study and meta-analysis of BIM deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors

PubMed Central

Sun, Si; Yu, Hui; Wang, Huijie; Zhao, Xinmin; Zhao, Xintai; Wu, Xianghua; Qiao, Jie; Chang, Jianhua; Wang, Jialei

2017-01-01

Background Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive EGFR mutations were refractory to EGFR-TKIs if they harbored a BIM deletion polymorphism. The purpose of this study was to investigate whether BIM polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients. Patients and methods A cohort of advanced NSCLC patients with EGFR mutations and treated with EGFR-TKIs (gefitinib or erlotinib) were recruited. We drew peripheral blood to determinate BIM deletion status and then compared patients’ clinical outcomes according to the BIM deletion status. Additionally, we electronically searched eligible cohort studies and conducted a meta-analysis to pool event risk. Results The exploratory cohort study included 140 patients. Patients with and without the BIM deletion polymorphism had similar objective response rates (ORRs, 48.5 vs 63.0%, P=0.16), disease control rate (DCR, 93.9 vs 97.0%, P=0.60) and adverse reactions. Similar progression-free survival (PFS) and overall survival (OS) were noted in overall population (P=0.27 for PFS and P=0.61 for OS) and prespecified patient subgroups. The meta-analysis included 10 eligible cohort studies involving 1,317 NSCLC patients. It showed the positive BIM deletion was associated with shorter PFS (hazard ratio =1.45; P=0.02). Nonsignificant differences existed for ORR, DCR and OS. Conclusion The expanded meta-analysis results demonstrated the positive BIM deletion predicts shorter PFS in NSCLC patients after treatment with EGFR-TKIs while other clinical measures do not. A large multicenter well-designed cohort study involving other concurrent genetic alterations is warranted. PMID:28435285
The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR-Mutant Non-Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors.

PubMed

Lee, Ji Yun; Ku, Bo Mi; Lim, Sung Hee; Lee, Min-Young; Kim, Haesu; Kim, Moonjin; Kim, Sungmin; Jung, Hyun Ae; Sun, Jong-Mu; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung-Ju

2015-06-01

A germline BIM deletion polymorphism has been proposed to predict poor treatment response to certain kinase inhibitors. The purpose of this study was to explore whether the BIM deletion polymorphism predicts treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in Korean patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Peripheral blood samples from a total of 205 patients with EGFR-mutant NSCLC who were treated with EGFR TKIs between July 2008 and April 2013 were included. The incidence of BIM deletions in these samples was detected by polymerase chain reaction. We compared the clinical outcomes in patients with and without the polymorphism after treatment with EGFR TKIs (gefitinib or erlotinib). The BIM deletion polymorphism was present in 15.6% (32 of 205) of patients. One patient was homozygous for the deletion, and the remaining 31 had heterozygous deletions. The majority of patients were younger than 65 years (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar objective response rates (91 vs. 84%, p = 0.585). Progression-free survival and overall survival did not differ significantly between patients with and without the BIM deletion polymorphism (median progression-free survival 12 vs. 11 months, p = 0.160; median overall survival 31 vs. 30 months, p = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including Eastern Cooperative Oncology Group performance status 0-1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients. It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR-mutant NSCLC patients.
Exploratory cohort study and meta-analysis of BIM deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.

PubMed

Sun, Si; Yu, Hui; Wang, Huijie; Zhao, Xinmin; Zhao, Xintai; Wu, Xianghua; Qiao, Jie; Chang, Jianhua; Wang, Jialei

2017-01-01

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR ) mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive EGFR mutations were refractory to EGFR-TKIs if they harbored a BIM deletion polymorphism. The purpose of this study was to investigate whether BIM polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients. A cohort of advanced NSCLC patients with EGFR mutations and treated with EGFR-TKIs (gefitinib or erlotinib) were recruited. We drew peripheral blood to determinate BIM deletion status and then compared patients' clinical outcomes according to the BIM deletion status. Additionally, we electronically searched eligible cohort studies and conducted a meta-analysis to pool event risk. The exploratory cohort study included 140 patients. Patients with and without the BIM deletion polymorphism had similar objective response rates (ORRs, 48.5 vs 63.0%, P =0.16), disease control rate (DCR, 93.9 vs 97.0%, P =0.60) and adverse reactions. Similar progression-free survival (PFS) and overall survival (OS) were noted in overall population ( P =0.27 for PFS and P =0.61 for OS) and prespecified patient subgroups. The meta-analysis included 10 eligible cohort studies involving 1,317 NSCLC patients. It showed the positive BIM deletion was associated with shorter PFS (hazard ratio =1.45; P =0.02). Nonsignificant differences existed for ORR, DCR and OS. The expanded meta-analysis results demonstrated the positive BIM deletion predicts shorter PFS in NSCLC patients after treatment with EGFR-TKIs while other clinical measures do not. A large multicenter well-designed cohort study involving other concurrent genetic alterations is warranted.
Combustion Properties of Amino-Substituted Guanidinium 4,4',5,5'-Tetranitro-2,2'-biimidazolate(N4BIM) Salts

DOE PAGES

Tappan, Bryce C.; Chavez, David E.

2014-12-02

This paper describes the combustion properties of the amino-substituted guanidinium 4,4’,5,5’-tetranitro-2,2’-biimidazolate (N4BIM) series, including the bis-mono, di and triaminoguanidinium salts. These salts are of interest as propellant ingredient additives, and in particular, the bis-triaminoguanidinium salt of N4BIM displays excellent burn rate and combustion behavior. Our combustion studies have shown that TAGN4-BIM displays a fast burning rate and has the lowest pressure dependence exponent yet measured for a triaminoguanidinium salt.
Sulforaphane Induced Apoptosis via Promotion of Mitochondrial Fusion and ERK1/2-Mediated 26S Proteasome Degradation of Novel Pro-survival Bim and Upregulation of Bax in Human Non-Small Cell Lung Cancer Cells.

PubMed

Geng, Yang; Zhou, Yan; Wu, Sai; Hu, Yabin; Lin, Kai; Wang, Yalin; Zheng, Zhongnan; Wu, Wei

2017-01-01

Previous studies in our laboratory showed that sulforaphane (SFN) induced apoptosis by sustained activation of extracellular regulated protein kinases 1/2 (ERK1/2). However, the underlying mechanisms associated with SFN-induced apoptosis and downstream cascades which are modulated by ERK1/2 were not elucidated. Herein we demonstrated for the first time that alteration of mitochondrial dynamics contributed to SFN-induced apoptosis in human non-small cell lung cancer (NSCLC) cells. Reports showed that protein Bim not only induced apoptosis but also promoted proliferation under certain circumstances. We found that Bim was related to cell growth in NSCLC cells. Pro-survival Bim downregulation was shown to induce apoptosis in response to SFN. Further, Using the ERK1/2 inhibitor, PD98059, we found that SFN upregulated Bax and downregulated Bim through the ERK1/2-dependent signaling pathway. Furthermore, SFN activated ERK1/2 to increase 26S proteasome activity to degrade Bim, while the proteasome inhibitor MG132 reversed this effect. Therefore, SFN phosphorylated ERK1/2 and activated the proteasome system leading to the degradation of Bim, which contributed to apoptosis in NSCLC cells. These findings provided a novel insight into SFN-related therapeutics in cancer treatment.
Phase I study of combined therapy with vorinostat and gefitinib to treat BIM deletion polymorphism-associated resistance in EGFR-mutant lung cancer (VICTROY-J): a study protocol.

PubMed

Takeuchi, Shinji; Yoshimura, Kenichi; Fujiwara, Tadami; Ando, Masahiko; Shimizu, Shinobu; Nagase, Katsuhiko; Hasegawa, Yoshinori; Takahashi, Toshiaki; Katakami, Nobuyuki; Inoue, Akira; Yano, Seiji

2017-01-01

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR-mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400 mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism. J. Med. Invest. 64: 321-325, August, 2017.

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

PubMed

Song, Kyung-A; Niederst, Matthew J; Lochmann, Timothy L; Hata, Aaron N; Kitai, Hidenori; Ham, Jungoh; Floros, Konstantinos V; Hicks, Mark A; Hu, Haichuan; Mulvey, Hillary E; Drier, Yotam; Heisey, Daniel A R; Hughes, Mark T; Patel, Neha U; Lockerman, Elizabeth L; Garcia, Angel; Gillepsie, Shawn; Archibald, Hannah L; Gomez-Caraballo, Maria; Nulton, Tara J; Windle, Brad E; Piotrowska, Zofia; Sahingur, Sinem E; Taylor, Shirley M; Dozmorov, Mikhail; Sequist, Lecia V; Bernstein, Bradley; Ebi, Hiromichi; Engelman, Jeffrey A; Faber, Anthony C

2018-01-01

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR -mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR -mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR -mutant lung cancers, as it was also observed in KRAS -mutant lung cancers and large datasets, including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR . ©2017 American Association for Cancer Research.
The relationship between BIM deletion polymorphism and clinical significance of epidermal growth factor receptor-mutated non-small cell lung cancer patients with epidermal growth factor receptor-tyrosine kinase inhibitor therapy: a meta-analysis.

PubMed

Zou, Qian; Zhan, Ping; Lv, Tangfeng; Song, Yong

2015-12-01

BIM deletion polymorphism is a germline that might lead to little or no BH3 expression, which affects epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) related apoptosis. Recent studies show that BIM deletion polymorphism might be a critical factor leading to the resistance of EGFR-TKIs in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. Thus, a meta-analysis was conducted by combing seven original eligible studies including 778 NSCLC patients to investigate a steady and reliable conclusion. Our study indicated that BIM deletion polymorphism was significantly associated with the poor objective response rate (ORR) of EGFR-TKIs in EGFR-mutated NSCLC patients [odds ratios (OR) =0.55, 95% confidence interval (CI), 0.33-0.92]. And disease control rate (DCR) in EGFR-mutate NSCLC patients treated with EGFR-TKIs was significantly decreased in patients with BIM deletion polymorphism (OR=0.55, 95% CI, 0.27-1.12). Moreover, the progression-free survival (PFS) of patients with BIM deletion polymorphism is shorter. These findings suggested that BIM deletion polymorphism might be a genetic cause of intrinsic resistance to TKI therapy and it could be emerged as an independent predictor to identify patients who would benefit from TKI targeted therapy in EGFR-mutated NSCLC.
76 FR 50254 - Notice of Lodging of Consent Decree Under the Comprehensive Environmental Response, Compensation...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-12

..., 2011, a proposed Consent Decree in United States and Commonwealth of Massachusetts v. BIM Investment... Healthcare Group LP, W.R. Grace & Co.-Conn., BIM Investment Corporation, and Shaffer Realty Nominee Trust.... BIM Investment Corp. et al., D.J. Ref. No. 90-11-3-09667/1. During the public comment period, the...
78 FR 69987 - Airworthiness Directives; Erickson Air-Crane Incorporated Helicopters (Type Certificate...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-22

... to require recurring checks of the Blade Inspection Method (BIM) indicator on each blade to determine whether the BIM indicator is signifying that the blade pressure may have been compromised by a blade crack... check procedures for BIM blades installed on the Model S-64E and S-64F helicopters. Several blade spars...
Ontology for Life-Cycle Modeling of Electrical Distribution Systems: Model View Definition

DTIC Science & Technology

2013-06-01

building information models ( BIM ) at the coordinated design stage of building construction. 1.3 Approach To...standard for exchanging Building Information Modeling ( BIM ) data, which defines hundreds of classes for common use in software, currently supported by...specifications, Construction Operations Building in- formation exchange (COBie), Building Information Modeling ( BIM ) 16. SECURITY CLASSIFICATION OF:
Hsp27 binding to the 3'UTR of bim mRNA prevents neuronal death during oxidative stress-induced injury: a novel cytoprotective mechanism.

PubMed

Dávila, David; Jiménez-Mateos, Eva M; Mooney, Claire M; Velasco, Guillermo; Henshall, David C; Prehn, Jochen H M

2014-11-01

Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cytoprotective and apoptosis-inducing signaling pathways. Cellular mechanisms that control apoptosis activation include the regulation of pro/antiapoptotic mRNAs through their 3'-untranslated region (UTR). This region holds binding elements for RNA-binding proteins, which can control mRNA translation. Here we demonstrate that heat shock protein 27 (Hsp27) prevents oxidative stress-induced cell death in cerebellar granule neurons by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2) correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition; however, it was associated with a specific increase in the levels of bim mRNA and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3'UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3'UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons. © 2014 Dávila et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
High BIM mRNA levels are associated with longer survival in advanced gastric cancer.

PubMed

Wu, Nandie; Huang, Ying; Zou, Zhengyun; Gimenez-Capitan, Ana; Yu, Lixia; Hu, Wenjing; Zhu, Lijing; Sun, Xia; Sanchez, Jose Javier; Guan, Wenxian; Liu, Baorui; Rosell, Rafael; Wei, Jia

2017-03-01

Chemotherapy drugs, including 5-fluorouracil (5-FU), oxaliplatin and docetaxel, are commonly used in the treatment of gastric cancer (GC). Apoptosis-relevant genes may be associated with drug resistance. In the present study, the messenger RNA (mRNA) expression levels of B-cell lymphoma 2 interacting mediator of cell death (BIM), astrocyte elevated gene-1 (AEG-1) and AXL receptor tyrosine kinase (AXL) were investigated in 131 advanced GC samples, and the expression levels of these genes were correlated with patients' overall survival (OS). All 131 patients received first-line FOLFOX combination chemotherapy with folinic acid and 5-FU, in which 56 patients were further treated with second-line docetaxel-based chemotherapy. A correlation between the mRNA expression levels of BIM and AEG-1 was observed ( r s =0.30; P=0.002). There was no association between the mRNA expression levels of any of the individual genes analyzed and OS in patients only receiving first-line FOLFOX chemotherapy. In a subgroup of patients receiving docetaxel-based second-line chemotherapy, those with high or intermediate levels of BIM exhibited a median OS of 18.2 months [95% confidence interval (CI), 12.8-23.6], compared with 9.6 months (95% CI, 8.9-10.3) in patients with low BIM levels (P=0.008). However, there was no correlation between the mRNA expression levels of AEG-1 or AXL and OS. The risk of mortality was higher in patients with low BIM mRNA levels than in those with high or intermediate BIM mRNA levels (hazard ratio, 2.61; 95% CI, 1.21-5.62; P=0.010). Therefore, BIM may be considered as a biomarker to identify whether patients could benefit from docetaxel-based second-line chemotherapy in GC.
miR-34a increases cisplatin sensitivity of osteosarcoma cells in vitro through up-regulation of c-Myc and Bim signal.

PubMed

Li, Qi-Cai; Xu, Haiyan; Wang, Xiaohui; Wang, Ting; Wu, Jiang

2017-12-12

Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. Recently, increasing evidence has suggested decreased expression of miR-34a is observed in a number of cancer types, including human osteosarcoma, and decreased miR-34a is involved in drug resistance. However, the underlying molecular mechanisms of decreased miR-34a on cisplatin chemoresistance in osteosarcoma has not been reported. Osteosarcoma U2OS cells were transfected with miR-34a mimics for 48 h, then the cells were treated with 3.0 μm cisplatin for 24 h. Using siRNA targeting c-Myc and Bim to examine the relation between miR-34a, c-Myc and Bim expression exposure to cisplatin on cisplatin-induced apoptosis. Treatment of U2OS cells with cisplatin induced cell apoptosis by upregulation of c-Myc -dependent Bim expression; Osteosarcoma U2OS cells transfected with miR-34a mimics (miR-34a/U2OS) induced cell apoptosis and inhibited cell survival, and increased the sensitivity of U2OS cells to cisplatin. U2OS cells transfected with miR-34a mimics upregulated the protein expression of c-Myc and Bim. Targeting c-Myc downregulated the expression of Bim in the miR-34a/U2OS cells. In addition, Targeting Bim reversed the chemeresistance of miR-34a/U2OS cells to cisplatin. Our data indicated that miR-34a enhanced the sensitivity to cisplatin by upregulation of c-Myc and Bim pathway.
Further evidence from functional studies for somatostatin receptor heterogeneity in guinea-pig isolated ileum, vas deferens and right atrium.

PubMed Central

Feniuk, W.; Dimech, J.; Jarvie, E. M.; Humphrey, P. P.

1995-01-01

1. Somatostatin (SRIF) causes a concentration-dependent inhibition of neurotransmission in guinea-pig ileum and vas deferens as well as negative inotropy in guinea-pig isolated right atrium. The SRIF receptors mediating these effects have now been further characterized by use of the peptides BIM-23027, BIM-23056 and L-362855, reported as selective for the recombinant SRIF receptor types, sst2, sst3 and sst5, respectively. 2. BIM-23027 was a highly potent agonist at causing an inhibition of neurotransmission in the guinea-pig ileum (EC50 value 1.9 nM), being about 3 times more potent than SRIF (EC50 value 6.8 nM). In contrast, in both guinea-pig vas deferens and right atrial preparations, BIM-23027 was a relatively weak agonist being at least 30-100 times weaker than SRIF. In guinea-pig atria, BIM-23027 (3 microM) antagonized the negative inotropic action of SRIF28 (apparent pKB = 5.9 +/- 0.1) but had no effect on the negative inotropic action of cyclohexyladenosine. 3. The inhibitory effect of BIM-23027 in the guinea-pig ileum was readily desensitized. Prior exposure to BIM-23027 (0.3 microM) markedly attenuated the inhibitory effect of SRIF but had no effect on the inhibitory action of clonidine suggesting that BIM-23027 and SRIF act via a common receptor mechanism. 4. L-362855 caused a concentration-dependent inhibition of neurotransmission in both the guinea-pig ileum and vas deferens as well as causing negative inotropy in the guinea-pig atrium but was at least 30-100 times weaker than SRIF. In guinea-pig isolated atria, L-362855 (3 microM) did not antagonize the negative inotropic action of SRIF28.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582529
Adoption of Building Information Modelling in project planning risk management

NASA Astrophysics Data System (ADS)

Mering, M. M.; Aminudin, E.; Chai, C. S.; Zakaria, R.; Tan, C. S.; Lee, Y. Y.; Redzuan, A. A.

2017-11-01

An efficient and effective risk management required a systematic and proper methodology besides knowledge and experience. However, if the risk management is not discussed from the starting of the project, this duty is notably complicated and no longer efficient. This paper presents the adoption of Building Information Modelling (BIM) in project planning risk management. The objectives is to identify the traditional risk management practices and its function, besides, determine the best function of BIM in risk management and investigating the efficiency of adopting BIM-based risk management during the project planning phase. In order to obtain data, a quantitative approach is adopted in this research. Based on data analysis, the lack of compliance with project requirements and failure to recognise risk and develop responses to opportunity are the risks occurred when traditional risk management is implemented. When using BIM in project planning, it works as the tracking of cost control and cash flow give impact on the project cycle to be completed on time. 5D cost estimation or cash flow modeling benefit risk management in planning, controlling and managing budget and cost reasonably. There were two factors that mostly benefit a BIM-based technology which were formwork plan with integrated fall plan and design for safety model check. By adopting risk management, potential risks linked with a project and acknowledging to those risks can be identified to reduce them to an acceptable extent. This means recognizing potential risks and avoiding threat by reducing their negative effects. The BIM-based risk management can enhance the planning process of construction projects. It benefits the construction players in various aspects. It is important to know the application of BIM-based risk management as it can be a lesson learnt to others to implement BIM and increase the quality of the project.
Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim.

PubMed

Ren, Xiaoxia; Zhao, Wenjing; Du, Yongxing; Zhang, Taiping; You, Lei; Zhao, Yupei

2016-12-01

Gemcitabine is a commonly used chemotherapy drug in pancreatic cancer. The function of activator protein 1 (AP-1) is cell-specific, and its function depends on the expression of other complex members. In the present study, we added gemcitabine to the media of Panc-1 and SW1990 cells at clinically achieved concentrations (10 µM). Compared with constitutive c-Fos expression, c-Jun expression increased in a dose-dependent manner upon gemcitabine treatment. c-Jun overexpression increased gemcitabine-induced apoptosis through Bim activation, while cell apoptosis and Bim expression decreased following c-Jun knockdown. Furthermore, gemcitabine-induced apoptosis and Bim levels decreased when c-Jun phosphorylation was blocked by SP600125. Our findings suggest that c-Jun, which is a member of the AP-1 complex, functions in gemcitabine-induced apoptosis by regulating its downstream target Bim in pancreatic cancer cells.
Parametric Workflow (BIM) for the Repair Construction of Traditional Historic Architecture in Taiwan

NASA Astrophysics Data System (ADS)

Ma, Y.-P.; Hsu, C. C.; Lin, M.-C.; Tsai, Z.-W.; Chen, J.-Y.

2015-08-01

In Taiwan, numerous existing traditional buildings are constructed with wooden structures, brick structures, and stone structures. This paper will focus on the Taiwan traditional historic architecture and target the traditional wooden structure buildings as the design proposition and process the BIM workflow for modeling complex wooden combination geometry, integrating with more traditional 2D documents and for visualizing repair construction assumptions within the 3D model representation. The goal of this article is to explore the current problems to overcome in wooden historic building conservation, and introduce the BIM technology in the case of conserving, documenting, managing, and creating full engineering drawings and information for effectively support historic conservation. Although BIM is mostly oriented to current construction praxis, there have been some attempts to investigate its applicability in historic conservation projects. This article also illustrates the importance and advantages of using BIM workflow in repair construction process, when comparing with generic workflow.
Application of BIM technology in green building material management system

NASA Astrophysics Data System (ADS)

Zhineng, Tong

2018-06-01

The current green building materials management system in China's construction industry is not perfect, and there are still many shortcomings. Active construction of green building materials management system based on BIM technology, combined with the characteristics of green building materials and its relationship with BIM technology application, is urgently needed to better realize the scientific management of green building materials.
Getting Started and Working with Building Information Modeling

ERIC Educational Resources Information Center

Smith, Dana K.

2009-01-01

This article will assume that one has heard of Building Information Modeling or BIM but has not developed a strategy as to how to get the most out of it. The National BIM Standard (NBIMS) has defined BIM as a digital representation of physical and functional characteristics of a facility. As such, it serves as a shared knowledge resource for…
75 FR 45666 - Notice of Lodging of Consent Decree Under the Comprehensive Environmental Response, Compensation...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-03

..., a proposed Consent Decree in United States v. BIM Investment Corp. et al., Civil Action No. 1:10-cv... Settling Defendants--BIM Investment Corporation, Shaffer Realty Nominee Trust, Tyco Healthcare Group LP... refer to United States v. BIM Investment Corp. et al., D.J. Ref. No. 90-11-3- 09667. The Consent Decree...
Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells

DTIC Science & Technology

2005-03-01

Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Dr. Dean Tang...SUBTITLE 5a. CONTRACT NUMBER Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells 5b. GRANT NUMBER DAMD17-03-1...Unlimited 13. SUPPLEMENTARY NOTES Original contains colored plates: ALL DTIC reproductions will be in black and white. 14. ABSTRACT
Pokemon silencing leads to Bim-mediated anoikis of human hepatoma cell QGY7703.

PubMed

Liu, Kun; Liu, Feng; Zhang, Nannan; Liu, Shiying; Jiang, Yuyang

2012-01-01

Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.
Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

PubMed Central

Liu, Kun; Liu, Feng; Zhang, Nannan; Liu, Shiying; Jiang, Yuyang

2012-01-01

Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer. PMID:22754333
Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage

PubMed Central

Badmann, A; Keough, A; Kaufmann, T; Bouillet, P; Brunner, T; Corazza, N

2011-01-01

Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis-inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro-apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim-deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death. PMID:21654829
Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma

PubMed Central

Li, Min; Zhang, Chao; Liu, Li-Li; Fu, Jia; Jin, Jie-Tian; Luo, Rong-Zhen; Zhang, Chris Zhiyi; Yun, Jing-Ping

2015-01-01

Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389–2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214–2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim. PMID:25788265

Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis

PubMed Central

Li, Chenggang; Li, Na; Liu, Xiaolei; Zhang, Erik Y.; Sun, Yang; Masuda, Kouhei; Li, Jing; Sun, Julia; Morrison, Tasha; Li, Xiangke; Chen, Yuanguang; Wang, Jiang; Karim, Nagla A.; Zhang, Yi; Blenis, John; Reginato, Mauricio J.; Henske, Elizabeth P.; Yu, Jane J.

2016-01-01

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearing TSC2 mutations migrate to the lungs, proliferate, and cause cystic remodeling. The female predominance indicates that estrogen plays a critical role in LAM pathogenesis, and we have proposed that estrogen promotes LAM cell metastasis by inhibition of anoikis. We report here that estrogen increased LAM patient–derived cells’ resistance to anoikis in vitro, accompanied by decreased accumulation of the proapoptotic protein Bim, an activator of anoikis. The resistance to anoikis was reversed by the proteasome inhibitor, bortezomib. Treatment of LAM patient–derived cells with estrogen plus bortezomib promoted anoikis compared with estrogen alone. Depletion of Bim by siRNA in TSC2-deficient cells resulted in anoikis resistance. Treatment of mice with bortezomib reduced estrogen-promoted lung colonization of TSC2-deficient cells. Importantly, molecular depletion of Bim by siRNA in Tsc2-deficient cells increased lung colonization in a mouse model. Collectively, these data indicate that Bim plays a key role in estrogen-enhanced survival of LAM patient–derived cells under detached conditions that occur with dissemination. Thus, targeting Bim may be a plausible future treatment strategy in patients with LAM. PMID:27882343
Structure-Function Relationship of the Bik1-Bim1 Complex.

PubMed

Stangier, Marcel M; Kumar, Anil; Chen, Xiuzhen; Farcas, Ana-Maria; Barral, Yves; Steinmetz, Michel O

2018-04-03

In budding yeast, the microtubule plus-end tracking proteins Bik1 (CLIP-170) and Bim1 (EB1) form a complex that interacts with partners involved in spindle positioning, including Stu2 and Kar9. Here, we show that the CAP-Gly and coiled-coil domains of Bik1 interact with the C-terminal ETF peptide of Bim1 and the C-terminal tail region of Stu2, respectively. The crystal structures of the CAP-Gly domain of Bik1 (Bik1CG) alone and in complex with an ETF peptide revealed unique, functionally relevant CAP-Gly elements, establishing Bik1CG as a specific C-terminal phenylalanine recognition domain. Unlike the mammalian CLIP-170-EB1 complex, Bik1-Bim1 forms ternary complexes with the EB1-binding motifs SxIP and LxxPTPh, which are present in diverse proteins, including Kar9. Perturbation of the Bik1-Bim1 interaction in vivo affected Bik1 localization and astral microtubule length. Our results provide insight into the role of the Bik1-Bim1 interaction for cell division, and demonstrate that the CLIP-170-EB1 module is evolutionarily flexible. Copyright © 2018 Elsevier Ltd. All rights reserved.
Developing Mobile- and BIM-Based Integrated Visual Facility Maintenance Management System

PubMed Central

Su, Yu-Chih

2013-01-01

Facility maintenance management (FMM) has become an important topic for research on the operation phase of the construction life cycle. Managing FMM effectively is extremely difficult owing to various factors and environments. One of the difficulties is the performance of 2D graphics when depicting maintenance service. Building information modeling (BIM) uses precise geometry and relevant data to support the maintenance service of facilities depicted in 3D object-oriented CAD. This paper proposes a new and practical methodology with application to FMM using BIM technology. Using BIM technology, this study proposes a BIM-based facility maintenance management (BIMFMM) system for maintenance staff in the operation and maintenance phase. The BIMFMM system is then applied in selected case study of a commercial building project in Taiwan to verify the proposed methodology and demonstrate its effectiveness in FMM practice. Using the BIMFMM system, maintenance staff can access and review 3D BIM models for updating related maintenance records in a digital format. Moreover, this study presents a generic system architecture and its implementation. The combined results demonstrate that a BIMFMM-like system can be an effective visual FMM tool. PMID:24227995
JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis, and Insulin Resistance in Obesity.

PubMed

Litwak, Sara A; Pang, Lokman; Galic, Sandra; Igoillo-Esteve, Mariana; Stanley, William J; Turatsinze, Jean-Valery; Loh, Kim; Thomas, Helen E; Sharma, Arpeeta; Trepo, Eric; Moreno, Christophe; Gough, Daniel J; Eizirik, Decio L; de Haan, Judy B; Gurzov, Esteban N

2017-12-01

The members of the BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. It remains unclear, however, whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. In this study, we report that fat accumulation in the liver increases c-Jun N-terminal kinase-dependent BCL-2 interacting mediator of cell death (BIM) expression in hepatocytes. To determine the consequences of hepatic BIM deficiency in diet-induced obesity, we generated liver-specific BIM-knockout (BLKO) mice. BLKO mice had lower hepatic lipid content, increased insulin signaling, and improved global glucose metabolism. Consistent with these findings, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Mechanistically, BIM deficiency improved mitochondrial function and decreased oxidative stress and oxidation of protein tyrosine phosphatases, and ameliorated activation of peroxisome proliferator-activated receptor γ/sterol regulatory element-binding protein 1/CD36 in hepatocytes from high fat-fed mice. Importantly, short-term knockdown of BIM rescued obese mice from insulin resistance, evidenced by reduced fat accumulation and improved insulin sensitivity. Our data indicate that BIM is an important regulator of liver dysfunction in obesity and a novel therapeutic target for restoring hepatocyte function. © 2017 by the American Diabetes Association.
Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins.

PubMed

Antignani, A; Segal, D; Simon, N; Kreitman, R J; Huang, D; FitzGerald, D J

2017-08-31

Protein synthesis is crucial for regulating cell homeostasis and, when unrestricted, it can lead to tumorigenesis. Immunotoxins derived from Pseudomonas exotoxin are antibody-toxin fusion proteins that inhibit protein synthesis of mammalian cells via ADP-ribosylation of the eukaryotic elongation factor-2. Here we investigate the role of the Bcl-2 family proteins in the response of cancer cells to immunotoxin challenge. Besides the well-known reduction of the prosurvival Bcl-2 family member, Mcl-1, following inhibition of protein synthesis, we show for the first time that immunotoxins also reduce the levels of selected proapoptotic BH-3-only proteins. Among these, only Bim protein levels correlated with the ability of immunotoxins to induce an apoptotic response. To support our findings, we verified that a Bim knockout completely abolished immunotoxin-mediated apoptosis. Further, mice bearing either wild-type or Bid knockout tumors responded to immunotoxin treatment with a decrease in growth kinetics, whereas mice engrafted with Bim knockout tumors showed no reduction in tumor size or prolongation of survival following immunotoxin treatment. From these results, we conclude that Bim expression is a major susceptibility factor for tumor cell death and, as such, constitutes a potential biomarker that could be evaluated before immunotoxin treatment. In support of this hypothesis, clinically, we analyzed patient cells before immunotoxin treatment and report that samples of hairy cell leukemia with high levels of Bim protein responded with a greater decrease in leukemic cell count compared with those samples expressing a low level of Bim.
Bim and Gis: when Parametric Modeling Meets Geospatial Data

NASA Astrophysics Data System (ADS)

Barazzetti, L.; Banfi, F.

2017-12-01

Geospatial data have a crucial role in several projects related to infrastructures and land management. GIS software are able to perform advanced geospatial analyses, but they lack several instruments and tools for parametric modelling typically available in BIM. At the same time, BIM software designed for buildings have limited tools to handle geospatial data. As things stand at the moment, BIM and GIS could appear as complementary solutions, notwithstanding research work is currently under development to ensure a better level of interoperability, especially at the scale of the building. On the other hand, the transition from the local (building) scale to the infrastructure (where geospatial data cannot be neglected) has already demonstrated that parametric modelling integrated with geoinformation is a powerful tool to simplify and speed up some phases of the design workflow. This paper reviews such mixed approaches with both simulated and real examples, demonstrating that integration is already a reality at specific scales, which are not dominated by "pure" GIS or BIM. The paper will also demonstrate that some traditional operations carried out with GIS software are also available in parametric modelling software for BIM, such as transformation between reference systems, DEM generation, feature extraction, and geospatial queries. A real case study is illustrated and discussed to show the advantage of a combined use of both technologies. BIM and GIS integration can generate greater usage of geospatial data in the AECOO (Architecture, Engineering, Construction, Owner and Operator) industry, as well as new solutions for parametric modelling with additional geoinformation.
Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

PubMed Central

Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic applications, such as for cachexia and anorexia. PMID:23515849
Trichonomas vaginalis metalloproteinase induces apoptosis of SiHa cells through disrupting the Mcl-1/Bim and Bcl-xL/Bim complexes.

PubMed

Quan, Juan-Hua; Kang, Byung-Hun; Cha, Guang-Ho; Zhou, Wei; Koh, Young-Bok; Yang, Jung-Bo; Yoo, Heon-Jong; Lee, Min-A; Ryu, Jae-Sook; Noh, Heung-Tae; Kwon, Jaeyul; Lee, Young-Ha

2014-01-01

To elucidate the roles of metalloproteinases and the Bcl-2 family of proteins in Trichovaginalis. vaginalis-induced apoptosis in human cervical cancer cells (SiHa cells) and vaginal epithelial cells (MS74 cells), SiHa cells and MS74 cells were incubated with live T. vaginalis, T. vaginalis excretory and secretory products (ESP), and T. vaginalis lysates, either with or without the specific metalloproteinase inhibitor 1,10-phenanthroline (1,10-PT), and examined apoptotic events and Bcl-2 signaling. The live T. vaginalis and the T. vaginalis ESP induced the release of cytochrome c into the cytosol, the activation of caspase-3 and caspase-9, and the cleavage of PARP. Additionally, the live T. vaginalis, but not the T. vaginalis lysate, induced the cleavage of the proapoptotic Bim protein. The live T. vaginalis and the T. vaginalis ESP, but not the T. vaginalis lysate, induced the dose-dependent cleavage of the antiapoptotic Bcl-xL and Mcl-1 proteins and decreased the association levels of Bcl-xL/Bim and Mcl-1/Bim complexes. We performed gelatin zymography and casein-hydrolysis assays on the live T. vaginalis and the T. vaginalis ESP to identify the apoptosis-inducing factor. Both the live T. vaginalis and the ESP contained high levels of metalloproteinases, of which activities were significantly inhibited by 1,10-PT treatment. Furthermore, the 1,10-PT blocked the cleavage of Bcl-xL, Mcl-1, PARP, caspase-3, and caspase-9, as well as the release of cytochrome c into the cytosol, and it significantly increased the association levels of the Bcl-xL/Bim and Mcl-1/Bim protein complexes, returning them to normal levels. Our results demonstrate that T. vaginalis induces mitochondria-dependent apoptosis in SiHa cells through the dissociation of Bcl-xL/Bim and Mcl-1/Bim complexes and that the apoptosis is blocked by the metalloproteinase inhibitor 1,10-PT. These results expand our understanding of the role of metalloproteinases in T. vaginalis-induced apoptosis and the signaling pathway in trichomoniasis of the cervicovaginal epithelial cells.
Trichonomas vaginalis Metalloproteinase Induces Apoptosis of SiHa Cells through Disrupting the Mcl-1/Bim and Bcl-xL/Bim Complexes

PubMed Central

Zhou, Wei; Koh, Young-Bok; Yang, Jung-Bo; Yoo, Heon-Jong; Lee, Min-A; Ryu, Jae-Sook; Noh, Heung-Tae; Kwon, Jaeyul; Lee, Young-Ha

2014-01-01

To elucidate the roles of metalloproteinases and the Bcl-2 family of proteins in Trichovaginalis. vaginalis-induced apoptosis in human cervical cancer cells (SiHa cells) and vaginal epithelial cells (MS74 cells), SiHa cells and MS74 cells were incubated with live T. vaginalis, T. vaginalis excretory and secretory products (ESP), and T. vaginalis lysates, either with or without the specific metalloproteinase inhibitor 1,10-phenanthroline (1,10-PT), and examined apoptotic events and Bcl-2 signaling. The live T. vaginalis and the T. vaginalis ESP induced the release of cytochrome c into the cytosol, the activation of caspase-3 and caspase-9, and the cleavage of PARP. Additionally, the live T. vaginalis, but not the T. vaginalis lysate, induced the cleavage of the proapoptotic Bim protein. The live T. vaginalis and the T. vaginalis ESP, but not the T. vaginalis lysate, induced the dose-dependent cleavage of the antiapoptotic Bcl-xL and Mcl-1 proteins and decreased the association levels of Bcl-xL/Bim and Mcl-1/Bim complexes. We performed gelatin zymography and casein-hydrolysis assays on the live T. vaginalis and the T. vaginalis ESP to identify the apoptosis-inducing factor. Both the live T. vaginalis and the ESP contained high levels of metalloproteinases, of which activities were significantly inhibited by 1,10-PT treatment. Furthermore, the 1,10-PT blocked the cleavage of Bcl-xL, Mcl-1, PARP, caspase-3, and caspase-9, as well as the release of cytochrome c into the cytosol, and it significantly increased the association levels of the Bcl-xL/Bim and Mcl-1/Bim protein complexes, returning them to normal levels. Our results demonstrate that T. vaginalis induces mitochondria-dependent apoptosis in SiHa cells through the dissociation of Bcl-xL/Bim and Mcl-1/Bim complexes and that the apoptosis is blocked by the metalloproteinase inhibitor 1,10-PT. These results expand our understanding of the role of metalloproteinases in T. vaginalis-induced apoptosis and the signaling pathway in trichomoniasis of the cervicovaginal epithelial cells. PMID:25343522
Learning moment-based fast local binary descriptor

NASA Astrophysics Data System (ADS)

Bellarbi, Abdelkader; Zenati, Nadia; Otmane, Samir; Belghit, Hayet

2017-03-01

Recently, binary descriptors have attracted significant attention due to their speed and low memory consumption; however, using intensity differences to calculate the binary descriptive vector is not efficient enough. We propose an approach to binary description called POLAR_MOBIL, in which we perform binary tests between geometrical and statistical information using moments in the patch instead of the classical intensity binary test. In addition, we introduce a learning technique used to select an optimized set of binary tests with low correlation and high variance. This approach offers high distinctiveness against affine transformations and appearance changes. An extensive evaluation on well-known benchmark datasets reveals the robustness and the effectiveness of the proposed descriptor, as well as its good performance in terms of low computation complexity when compared with state-of-the-art real-time local descriptors.
From BIM to GIS at the Smithsonian Institution

NASA Astrophysics Data System (ADS)

Günther-Diringer, Detlef

2018-05-01

BIM-files (Building Information Models) are in modern architecture and building management a basic prerequisite for successful creation of construction engineering projects. At the facilities department of the Smithsonian Institution more than six hundred buildings were maintained. All facilities were digital available in an ESRI ArcGIS-environment with connection to the database information about single rooms with the usage and further maintenance information. These data are organization wide available by an intranet viewer, but only in a two-dimensional representation. Goal of the carried out project was the development of a workflow from available BIM-models to the given GIS-structure. The test-environment were the BIM-models of the buildings of the Smithsonian museums along the Washington Mall. Based on new software editions of Autodesk Revit, FME and ArcGIS Pro the workflow from BIM to the GIS-data structure of the Smithsonian was successfully developed and may be applied for the setup of the future 3D intranet viewer.
Integrating Building Information Modeling and Health and Safety for Onsite Construction

PubMed Central

Ganah, Abdulkadir; John, Godfaurd A.

2014-01-01

Background Health and safety (H&S) on a construction site can either make or break a contractor, if not properly managed. The usage of Building Information Modeling (BIM) for H&S on construction execution has the potential to augment practitioner understanding of their sites, and by so doing reduce the probability of accidents. This research explores BIM usage within the construction industry in relation to H&S communication. Methods In addition to an extensive literature review, a questionnaire survey was conducted to gather information on the embedment of H&S planning with the BIM environment for site practitioners. Results The analysis of responses indicated that BIM will enhance the current approach of H&S planning for construction site personnel. Conclusion From the survey, toolbox talk will have to be integrated with the BIM environment, because it is the predominantly used procedure for enhancing H&S issues within construction sites. The advantage is that personnel can visually understand H&S issues as work progresses during the toolbox talk onsite. PMID:25830069
Building information modelling review with potential applications in tunnel engineering of China.

PubMed

Zhou, Weihong; Qin, Haiyang; Qiu, Junling; Fan, Haobo; Lai, Jinxing; Wang, Ke; Wang, Lixin

2017-08-01

Building information modelling (BIM) can be applied to tunnel engineering to address a number of problems, including complex structure, extensive design, long construction cycle and increased security risks. To promote the development of tunnel engineering in China, this paper combines actual cases, including the Xingu mountain tunnel and the Shigu Mountain tunnel, to systematically analyse BIM applications in tunnel engineering in China. The results indicate that BIM technology in tunnel engineering is currently mainly applied during the design stage rather than during construction and operation stages. The application of BIM technology in tunnel engineering covers many problems, such as a lack of standards, incompatibility of different software, disorganized management, complex combination with GIS (Geographic Information System), low utilization rate and poor awareness. In this study, through summary of related research results and engineering cases, suggestions are introduced and an outlook for the BIM application in tunnel engineering in China is presented, which provides guidance for design optimization, construction standards and later operation maintenance.
Characterizing the role of the microtubule binding protein Bim1 in Cryptococcus neoformans

PubMed Central

Staudt, Mark W.; Kruzel, Emilia K.; Shimizu, Kiminori; Hull, Christina M.

2010-01-01

During sexual development the human fungal pathogen Cryptococcus neoformans undergoes a developmental transition from yeast-form growth to filamentous growth. This transition requires cellular restructuring to form a filamentous dikaryon. Dikaryotic growth also requires tightly controlled nuclear migration to ensure faithful replication and dissemination of genetic material to spore progeny. Although the gross morphological changes that take place during dikaryotic growth are largely known, the molecular underpinnings that control this process are uncharacterized. Here we identify and characterize a C. neoformans homolog of the Saccharomyces cerevisiae BIM1 gene, and establish the importance of BIM1 for proper filamentous growth of C. neoformans. Deletion of BIM1 leads to truncated sexual development filaments, a severe defect in diploid formation, and a block in monokaryotic fruiting. Our findings lead to a model consistent with a critical role for BIM1 in both filament integrity and nuclear congression that is mediated through the microtubule cytoskeleton. PMID:20044015
BIM based virtual environment for fire emergency evacuation.

PubMed

Wang, Bin; Li, Haijiang; Rezgui, Yacine; Bradley, Alex; Ong, Hoang N

2014-01-01

Recent building emergency management research has highlighted the need for the effective utilization of dynamically changing building information. BIM (building information modelling) can play a significant role in this process due to its comprehensive and standardized data format and integrated process. This paper introduces a BIM based virtual environment supported by virtual reality (VR) and a serious game engine to address several key issues for building emergency management, for example, timely two-way information updating and better emergency awareness training. The focus of this paper lies on how to utilize BIM as a comprehensive building information provider to work with virtual reality technologies to build an adaptable immersive serious game environment to provide real-time fire evacuation guidance. The innovation lies on the seamless integration between BIM and a serious game based virtual reality (VR) environment aiming at practical problem solving by leveraging state-of-the-art computing technologies. The system has been tested for its robustness and functionality against the development requirements, and the results showed promising potential to support more effective emergency management.
Building information modelling review with potential applications in tunnel engineering of China

PubMed Central

Zhou, Weihong; Qin, Haiyang; Fan, Haobo; Lai, Jinxing; Wang, Ke; Wang, Lixin

2017-01-01

Building information modelling (BIM) can be applied to tunnel engineering to address a number of problems, including complex structure, extensive design, long construction cycle and increased security risks. To promote the development of tunnel engineering in China, this paper combines actual cases, including the Xingu mountain tunnel and the Shigu Mountain tunnel, to systematically analyse BIM applications in tunnel engineering in China. The results indicate that BIM technology in tunnel engineering is currently mainly applied during the design stage rather than during construction and operation stages. The application of BIM technology in tunnel engineering covers many problems, such as a lack of standards, incompatibility of different software, disorganized management, complex combination with GIS (Geographic Information System), low utilization rate and poor awareness. In this study, through summary of related research results and engineering cases, suggestions are introduced and an outlook for the BIM application in tunnel engineering in China is presented, which provides guidance for design optimization, construction standards and later operation maintenance. PMID:28878970
Integrating building information modeling and health and safety for onsite construction.

PubMed

Ganah, Abdulkadir; John, Godfaurd A

2015-03-01

Health and safety (H&S) on a construction site can either make or break a contractor, if not properly managed. The usage of Building Information Modeling (BIM) for H&S on construction execution has the potential to augment practitioner understanding of their sites, and by so doing reduce the probability of accidents. This research explores BIM usage within the construction industry in relation to H&S communication. In addition to an extensive literature review, a questionnaire survey was conducted to gather information on the embedment of H&S planning with the BIM environment for site practitioners. The analysis of responses indicated that BIM will enhance the current approach of H&S planning for construction site personnel. From the survey, toolbox talk will have to be integrated with the BIM environment, because it is the predominantly used procedure for enhancing H&S issues within construction sites. The advantage is that personnel can visually understand H&S issues as work progresses during the toolbox talk onsite.
Towards AN Integration of GIS and Bim Data: what are the Geometric and Topological Issues?

NASA Astrophysics Data System (ADS)

Arroyo Ohori, K.; Biljecki, F.; Diakité, A.; Krijnen, T.; Ledoux, H.; Stoter, J.

2017-10-01

Geographic information and building information modelling both model buildings and infrastructure, but the way in which they are modelled is usually complimentary and BIM-GIS integration is widely considered as a way forward for both domains. For one, more detailed BIM data can feed more general GIS data and GIS data can provide the context that is necessary to BIM data. While previous studies have focused on the theoretical aspects of such an integration at a schema level, in this paper we focus on explaining the geometric and topological issues we have found while trying to develop software to realise such an integration in practice and at a data level. In our preliminary results, which are presented here, we have found that many issues for such an integration remain: handling the geometric and topological problems in BIM models, dealing with bad georeferencing and figuring out the best way to convert data between IFC and CityGML are all open issues.
Building information modelling review with potential applications in tunnel engineering of China

NASA Astrophysics Data System (ADS)

Zhou, Weihong; Qin, Haiyang; Qiu, Junling; Fan, Haobo; Lai, Jinxing; Wang, Ke; Wang, Lixin

2017-08-01

Building information modelling (BIM) can be applied to tunnel engineering to address a number of problems, including complex structure, extensive design, long construction cycle and increased security risks. To promote the development of tunnel engineering in China, this paper combines actual cases, including the Xingu mountain tunnel and the Shigu Mountain tunnel, to systematically analyse BIM applications in tunnel engineering in China. The results indicate that BIM technology in tunnel engineering is currently mainly applied during the design stage rather than during construction and operation stages. The application of BIM technology in tunnel engineering covers many problems, such as a lack of standards, incompatibility of different software, disorganized management, complex combination with GIS (Geographic Information System), low utilization rate and poor awareness. In this study, through summary of related research results and engineering cases, suggestions are introduced and an outlook for the BIM application in tunnel engineering in China is presented, which provides guidance for design optimization, construction standards and later operation maintenance.
Gestation and breastfeeding in schistosomotic mothers differently modulate the immune response of adult offspring to postnatal Schistosoma mansoni infection

PubMed Central

Santos, Patrícia d‘Emery Alves; de Lorena, Virgínia Maria Barros; Fernandes, Érica de Souza; Sales, Iana Rafaela Fernandes; do Nascimento, Wheverton Ricardo Correia; Gomes, Yara de Miranda; Albuquerque, Mônica Camelo Pessoa de Azevedo; Costa, Vlaudia Maria Assis; de Souza, Valdênia Maria Oliveira

2016-01-01

Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants. PMID:26872339

Gestation and breastfeeding in schistosomotic mothers differently modulate the immune response of adult offspring to postnatal Schistosoma mansoni infection.

PubMed

Santos, Patrícia d'Emery Alves; Lorena, Virgínia Maria Barros de; Fernandes, Érica de Souza; Sales, Iana Rafaela Fernandes; Nascimento, Wheverton Ricardo Correia do; Gomes, Yara de Miranda; Albuquerque, Mônica Camelo Pessoa de Azevedo; Costa, Vlaudia Maria Assis; Souza, Valdênia Maria Oliveira de

2016-02-01

Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.
A major role for Bim in regulatory T cell homeostasis.

PubMed

Chougnet, Claire A; Tripathi, Pulak; Lages, Celine S; Raynor, Jana; Sholl, Allyson; Fink, Pamela; Plas, David R; Hildeman, David A

2011-01-01

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the proapoptotic molecule Bim compared with Treg from young mice. Furthermore, in the absence of Bim, Treg accumulate rapidly, accounting for >25% of the CD4(+) T cell compartment by 6 mo of age. Additionally, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bim(lo) Treg. Collectively, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts.
Developing Mobile BIM/2D Barcode-Based Automated Facility Management System

PubMed Central

Chen, Yen-Pei

2014-01-01

Facility management (FM) has become an important topic in research on the operation and maintenance phase. Managing the work of FM effectively is extremely difficult owing to the variety of environments. One of the difficulties is the performance of two-dimensional (2D) graphics when depicting facilities. Building information modeling (BIM) uses precise geometry and relevant data to support the facilities depicted in three-dimensional (3D) object-oriented computer-aided design (CAD). This paper proposes a new and practical methodology with application to FM that uses an integrated 2D barcode and the BIM approach. Using 2D barcode and BIM technologies, this study proposes a mobile automated BIM-based facility management (BIMFM) system for FM staff in the operation and maintenance phase. The mobile automated BIMFM system is then applied in a selected case study of a commercial building project in Taiwan to verify the proposed methodology and demonstrate its effectiveness in FM practice. The combined results demonstrate that a BIMFM-like system can be an effective mobile automated FM tool. The advantage of the mobile automated BIMFM system lies not only in improving FM work efficiency for the FM staff but also in facilitating FM updates and transfers in the BIM environment. PMID:25250373
Developing mobile BIM/2D barcode-based automated facility management system.

PubMed

Lin, Yu-Cheng; Su, Yu-Chih; Chen, Yen-Pei

2014-01-01

Facility management (FM) has become an important topic in research on the operation and maintenance phase. Managing the work of FM effectively is extremely difficult owing to the variety of environments. One of the difficulties is the performance of two-dimensional (2D) graphics when depicting facilities. Building information modeling (BIM) uses precise geometry and relevant data to support the facilities depicted in three-dimensional (3D) object-oriented computer-aided design (CAD). This paper proposes a new and practical methodology with application to FM that uses an integrated 2D barcode and the BIM approach. Using 2D barcode and BIM technologies, this study proposes a mobile automated BIM-based facility management (BIMFM) system for FM staff in the operation and maintenance phase. The mobile automated BIMFM system is then applied in a selected case study of a commercial building project in Taiwan to verify the proposed methodology and demonstrate its effectiveness in FM practice. The combined results demonstrate that a BIMFM-like system can be an effective mobile automated FM tool. The advantage of the mobile automated BIMFM system lies not only in improving FM work efficiency for the FM staff but also in facilitating FM updates and transfers in the BIM environment.
Toxoplasma gondii infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax.

PubMed

Hippe, Diana; Weber, Arnim; Zhou, Liying; Chang, Donald C; Häcker, Georg; Lüder, Carsten G K

2009-10-01

In order to accomplish their life style, intracellular pathogens, including the apicomplexan Toxoplasma gondii, subvert the innate apoptotic response of infected host cells. However, the precise mechanisms of parasite interference with the mitochondrial apoptotic pathway remain unknown. Here, we used the conditional expression of the BH3-only protein Bim(S) to pinpoint the interaction of T. gondii with the intrinsic pathway of apoptosis. Infection of epithelial cells with T. gondii dose-dependently abrogated Bim(S)-triggered release of cytochrome c from host-cell mitochondria into the cytosol, induction of activity of caspases 3, 7 and 9, and chromatin condensation. Furthermore, inhibition of apoptosis in parasite-infected lymphocytes counteracted death of Toxoplasma-infected host cells. Although total cellular levels and mitochondrial targeting of Bim(S) was not altered by the infection, the activation of pro-apoptotic effector proteins Bax and Bak was strongly impaired. Inhibition of Bax and Bak activation by T. gondii was seen with regard to their conformational changes, the cytosol-to-mitochondria targeting and the oligomerization of Bax but not their cellular protein levels. Blockade of Bax and Bak activation was not mediated by the upregulation of anti-apoptotic Bcl-2-like proteins following infection. Further, the BH3-mimetic ABT-737 failed to overcome the Toxoplasma-imposed inhibition of Bim(S)-triggered apoptosis. These results indicate that T. gondii targets activation of pro-apoptotic Bax and Bak to inhibit the apoptogenic function of mitochondria and to increase host-cell viability.
Mitochondrial ATF2 translocation contributes to apoptosis induction and BRAF inhibitor resistance in melanoma through the interaction of Bim with VDAC1.

PubMed

Gao, Zongwei; Shang, Qingjuan; Liu, Zhaoyun; Deng, Chun; Guo, Chunbao

2015-11-03

The mitochondrial accumulation of ATF2 is involved in tumor suppressor activities via cytochrome c release in melanoma cells. However, the signaling pathways that connect mitochondrial ATF2 accumulation and cytochrome c release are not well documented. Several melanoma cell lines, B16F10, K1735M2, A375 and A375-R1, were treated with paclitaxel and vemurafenib to test the function of mitochondrial ATF2 and its connection to Bim and voltage-dependent anion channel 1 (VDAC1). Immunoprecipitation analysis was performed to investigate the functional interaction between the involved proteins. VDAC1 oligomerization was evaluated using an EGS-based crosslinking assay. The expression and migration of ATF2 to the mitochondria accounted for paclitaxel stimuli and acquired resistance to BRAF inhibitors. Mitochondrial ATF2 facilitated Bim stabilization through the inhibition of its degradation by the proteasome, thereby promoting cytochrome c release and inducing apoptosis in B16F10 and A375 cells. Studies using B16F10 and A375 cells genetically modified for ATF2 indicated that mitochondrial ATF2 was able to dissociate Bim from the Mcl-1/Bim complex to trigger VDAC1 oligomerization. Immunoprecipitation analysis revealed that Bim interacts with VDAC1, and this interaction was remarkably enhanced during apoptosis. These results reveal that mitochondrial ATF2 is associated with the induction of apoptosis and BRAF inhibitor resistance through Bim activation, which might suggest potential novel therapies for the targeted induction of apoptosis in melanoma therapy.
IL-15 regulates Bcl-2 family members Bim and Mcl-1 through JAK/STAT and PI3K/AKT pathways in T cells.

PubMed

Shenoy, Aparna R; Kirschnek, Susanne; Häcker, Georg

2014-08-01

Maintenance of T cells is determined by their survival capacity, which is regulated by Bcl-2 proteins. Cytokines signalling through the common gamma chains such as IL-2, IL-7 and IL-15 are important for T-cell survival but how these cytokines determine the expression of Bcl-2-family proteins is not clear. We report signalling events of cytokines that regulate expression of two key Bcl-2 proteins, pro-apoptotic Bim and anti-apoptotic Mcl-1, in resting C57BL/6 mouse T cells. IL-2, IL-7 and IL-15 inhibited apoptosis but paradoxically induced the expression of Bim, countered by concomitant induction of Mcl-1. Bim induction by IL-15 was found at the mRNA and protein levels and depended on both JAK/STAT and PI3K signals. A new STAT5-binding site was identified in the Bim promoter, which was occupied by STAT5 upon IL-15 stimulation. Although it also depended on JAK/STAT- and PI3K signalling, Mcl-1 regulation was independent of Mcl-1 mRNA levels and of regulation of protein stability, suggesting translational regulation. Concurrent CD3 signals inhibited some of the IL-7 effect but not the IL-15 effect on Bcl-2 proteins. The data suggest that cytokines induce Bim and prime T cells for apoptosis, but also inhibit apoptosis by stabilising Mcl-1. Later downregulation of short-lived Mcl-1 may induce efficient, Bim-dependent apoptosis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Mitochondrial ATF2 translocation contributes to apoptosis induction and BRAF inhibitor resistance in melanoma through the interaction of Bim with VDAC1

PubMed Central

Deng, Chun; Guo, Chunbao

2015-01-01

Background The mitochondrial accumulation of ATF2 is involved in tumor suppressor activities via cytochrome c release in melanoma cells. However, the signaling pathways that connect mitochondrial ATF2 accumulation and cytochrome c release are not well documented. Methods Several melanoma cell lines, B16F10, K1735M2, A375 and A375-R1, were treated with paclitaxel and vemurafenib to test the function of mitochondrial ATF2 and its connection to Bim and voltage-dependent anion channel 1 (VDAC1). Immunoprecipitation analysis was performed to investigate the functional interaction between the involved proteins. VDAC1 oligomerization was evaluated using an EGS-based crosslinking assay. Results The expression and migration of ATF2 to the mitochondria accounted for paclitaxel stimuli and acquired resistance to BRAF inhibitors. Mitochondrial ATF2 facilitated Bim stabilization through the inhibition of its degradation by the proteasome, thereby promoting cytochrome c release and inducing apoptosis in B16F10 and A375 cells. Studies using B16F10 and A375 cells genetically modified for ATF2 indicated that mitochondrial ATF2 was able to dissociate Bim from the Mcl-1/Bim complex to trigger VDAC1 oligomerization. Immunoprecipitation analysis revealed that Bim interacts with VDAC1, and this interaction was remarkably enhanced during apoptosis. Conclusion These results reveal that mitochondrial ATF2 is associated with the induction of apoptosis and BRAF inhibitor resistance through Bim activation, which might suggest potential novel therapies for the targeted induction of apoptosis in melanoma therapy. PMID:26462148
BIM-Based Timber Structures Refurbishment of the Immovable Heritage Listed Buildings

NASA Astrophysics Data System (ADS)

Henek, Vladan; Venkrbec, Václav

2017-12-01

The use of Building information model (BIM) design tools is no longer an exception, but a common issue. When designing new buildings or complex renovations using BIM, the benefits have already been repeatedly published. The essence of BIM is to create a multidimensional geometric model of a planned building electronically on a computer, supplemented with the necessary information in advance of the construction process. Refurbishment is a specific process that combines both - new structures and demolished structures, or structures that need to be dismantled, repaired, and then returned to the original position. Often it can be historically valuable part of the building. BIM-based repairs and refurbishments of the constructions, especially complicated repairs of the structures of roof trusses of immovable heritage listed buildings, have not yet been credibly presented. However, the use of BIM tools may be advantageous in this area, because user can quickly response to the necessary changes that may be needed during refurbishments, but also in connection with the quick assessment and cost estimation of any unexpected additional works. The paper deals with the use of BIM in the field of repairs and refurbishment of the buildings in general. The emphasis on monumentally protected elements was priority. Advantage of the proposal research is demonstrated on case study of the refurbishment of the immovable heritage listed truss roof. According to this study, this construction was realized in the Czech Republic. Case study consists of 3D modelled truss parts and the connected technological workflow base. The project work was carried out in one common model environment.
Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2-interacting mediator knock-out mice.

PubMed

Wang, Y M; Zhang, G Y; Wang, Y; Hu, M; Zhou, J J; Sawyer, A; Cao, Q; Wang, Y; Zheng, G; Lee, V W S; Harris, D C H; Alexander, S I

2017-05-01

Regulatory T cells (T regs ) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of T regs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of T regs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of T regs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2-interacting mediator (Bim) knock-out mice by transient depleting T regs . Bim is a pro-apoptotic member of the B cell lymphoma 2 (Bcl-2) family. Bim knock-out (Bim -/- ) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that T reg depletion in Bim -/- mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild-type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17α, interferon (IFN)-γ and tumour necrosis factor (TNF)-α were increased significantly after T reg depletion in Bim -/- mice. This study demonstrates that transient depletion of T regs leads to enhanced self-reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim-deficient mice. © 2017 British Society for Immunology.
Scan-To Output Validation: Towards a Standardized Geometric Quality Assessment of Building Information Models Based on Point Clouds

NASA Astrophysics Data System (ADS)

Bonduel, M.; Bassier, M.; Vergauwen, M.; Pauwels, P.; Klein, R.

2017-11-01

The use of Building Information Modeling (BIM) for existing buildings based on point clouds is increasing. Standardized geometric quality assessment of the BIMs is needed to make them more reliable and thus reusable for future users. First, available literature on the subject is studied. Next, an initial proposal for a standardized geometric quality assessment is presented. Finally, this method is tested and evaluated with a case study. The number of specifications on BIM relating to existing buildings is limited. The Levels of Accuracy (LOA) specification of the USIBD provides definitions and suggestions regarding geometric model accuracy, but lacks a standardized assessment method. A deviation analysis is found to be dependent on (1) the used mathematical model, (2) the density of the point clouds and (3) the order of comparison. Results of the analysis can be graphical and numerical. An analysis on macro (building) and micro (BIM object) scale is necessary. On macro scale, the complete model is compared to the original point cloud and vice versa to get an overview of the general model quality. The graphical results show occluded zones and non-modeled objects respectively. Colored point clouds are derived from this analysis and integrated in the BIM. On micro scale, the relevant surface parts are extracted per BIM object and compared to the complete point cloud. Occluded zones are extracted based on a maximum deviation. What remains is classified according to the LOA specification. The numerical results are integrated in the BIM with the use of object parameters.
The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism.

PubMed

Zaanan, Aziz; Okamoto, Koichi; Kawakami, Hisato; Khazaie, Khashayarsha; Huang, Shengbing; Sinicrope, Frank A

2015-09-25

In colorectal cancers with oncogenic GTPase Kras (KRAS) mutations, inhibition of downstream MEK/ERK signaling has shown limited efficacy, in part because of failure to induce a robust apoptotic response. We studied the mechanism of apoptosis resistance in mutant KRAS cells and sought to enhance the efficacy of a KRAS-specific MEK/ERK inhibitor, GDC-0623. GDC-0623 was shown to potently up-regulate BIM expression to a greater extent versus other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cancer cells. ERK silencing enhanced BIM up-regulation by GDC-0623 that was due to its loss of phosphorylation at Ser(69), confirmed by a BIM-EL phosphorylation-defective mutant (S69G) that increased protein stability and blocked BIM induction. Despite BIM and BIK induction, the isogenic KRAS mutant versus wild-type cells remained resistant to GDC-0623-induced apoptosis, in part because of up-regulation of BCL-XL. KRAS knockdown by a doxycycline-inducible shRNA attenuated BCL-XL expression. BCL-XL knockdown sensitized KRAS mutant cells to GDC-0623-mediated apoptosis, as did the BH3 mimetic ABT-263. GDC-0623 plus ABT-263 induced a synergistic apoptosis by a mechanism that includes release of BIM from its sequestration by BCL-XL. Furthermore, mutant KRAS activated p-STAT3 (Tyr(705)) in the absence of IL-6 secretion, and STAT3 knockdown reduced BCL-XL mRNA and protein expression. These data suggest that BCL-XL up-regulation by STAT3 contributes to mutant KRAS-mediated apoptosis resistance. Such resistance can be overcome by potent BIM induction and concurrent BCL-XL antagonism to enable a synergistic apoptotic response. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death.

PubMed

Liu, Zhaoyun; Luo, Qianfu; Guo, Chunbao

2015-01-01

ATF2 mediated cytochrome c release is the formation of a channel with some unknown factors larger than that of the individual proteins. BHS-only proteins (BH3s), such as Bim, could induce BAX and VDAC, forming a new channel. According to this facts, we can speculated that there is possible signal relationship with BH3s and ATF2, which is associated with mitochondrial-based death programs. The growth inhibitory effects of mitochondrial ATF2 were tested in cancer cell lines B16F10, A549, EG7, and LL2. Apoptosis was measured by flow cytometry. The effects of ATF2 and levels of apoptosis regulatory proteins were measured by Western blotting. The interaction of proteins were evaluated by immunoprecipitation analysis. The in vivo antitumor activity of mitochondrial ATF2 were tested in xenograft B16F10 models. Genotoxic stress enabled mitochondrial ATF2 accumulation, perturbing the HK1-VDAC1 complex, increasing mitochondrial permeability, and promoting apoptosis. ATF2 inhibition strongly reduced the conformational activation of Bim, suggesting that Bim acts downstream of ATF2. Although Bim downregulation had no effect on ATF2 activation, Bim knockdown abolished VDAC1 activation; the failure of VDAC1 activation in Bim-depleted cells could be reversed by the BH3-only protein mimic ABT-737. We also demonstrate that silencing of ATF2 in B16F10 cells increases both the incidence and prevalence of tumor xenografts in vivo, whereas stably mitochondrial ATF2 transfection inhibited B16F10 tumor xenografts growth. Altogether, these results show that ATF2 is a component of the apoptosis machinery that involves a hierarchical contribution of ATF2, Bim, and VDAC1. Our data offer new insight into the mechanism of mitochondrial ATF2 in mitochondrial apoptosis.
A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

PubMed

Soh, Sheila X; Siddiqui, Fahad J; Allen, John C; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A; Chin, Tan-Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lu, Shun; Isobe, Kazutoshi; Lee, Jih-Hsiang; Yang, James C; Zhao, Mingchuan; Zhou, Caicun; Lee, June-Koo; Lee, Se-Hoon; Lee, Ji Yun; Ahn, Myung-Ju; Tan, Tira J; Tan, Daniel S; Tan, Eng-Huat; Ong, S Tiong; Lim, Wan-Teck

2017-06-20

A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.
Phenotypic, fermentation characterization, and resistance mechanism analysis of bacteriophage-resistant mutants of Lactobacillus delbrueckii ssp. bulgaricus isolated from traditional Chinese dairy products.

PubMed

Deng, Kaibo; Fang, Wei; Zheng, Baodong; Miao, Song; Huo, Guicheng

2018-03-01

Bacteriophage infection is a large factor in dairy industrial production failure on the basis of pure inoculation fermentation, and developing good commercial starter cultures from wild dairy products and improving the environmental vigor of starter cultures by enhancing their phage resistance are still the most effective solutions. Here we used a spontaneous isolation method to obtain bacteriophage-resistant mutants of Lactobacillus delbrueckii ssp. bulgaricus strains that are used in traditional Chinese fermented dairy products. We analyzed their phenotypes, fermentation characteristics, and resistance mechanisms. The results showed that bacteriophage-insensitive mutants (BIM) BIM8 and BIM12 had high bacteriophage resistance while exhibiting fermentation and coagulation attributes that were as satisfying as those of their respective parent strains KLDS1.1016 and KLDS1.1028. According to the attachment receptor detection, mutants BIM8 and BIM12 exhibited reduced absorption to bacteriophage phiLdb compared with their respective bacteriophage-sensitive parent strains because of changes to the polysaccharides or teichoic acids connected to their peptidoglycan layer. Additionally, genes, including HSDR, HSDM, and HSDS, encoding 3 subunits of a type I restriction-modification system were identified in their respective parent strains. We also discovered that HSDR and HSDM were highly conserved but that HSDS was variable because it is responsible for the DNA specificity of the complex. The late lysis that occurred only in strain KLDS1.1016 and not in strain KLDS1.1028 suggests that the former and its mutant BIM8 also may have an activatable restriction-modification mechanism. We conclude that the L. bulgaricus BIM8 and BIM12 mutants have great potential in the dairy industry as starter cultures, and their phage-resistance mechanism was effective mainly due to the adsorption interference and restriction-modification system. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
From Oss CAD to Bim for Cultural Heritage Digital Representation

NASA Astrophysics Data System (ADS)

Logothetis, S.; Karachaliou, E.; Stylianidis, E.

2017-02-01

The paper illustrates the use of open source Computer-aided design (CAD) environments in order to develop Building Information Modelling (BIM) tools able to manage 3D models in the field of cultural heritage. Nowadays, the development of Free and Open Source Software (FOSS) has been rapidly growing and their use tends to be consolidated. Although BIM technology is widely known and used, there is a lack of integrated open source platforms able to support all stages of Historic Building Information Modelling (HBIM) processes. The present research aims to use a FOSS CAD environment in order to develop BIM plug-ins which will be able to import and edit digital representations of cultural heritage models derived by photogrammetric methods.
Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model.

PubMed

Palus, Sandra; Schur, Robert; Akashi, Yoshihiro J; Bockmeyer, Barbara; Datta, Rakesh; Halem, Heather; Dong, Jesse; Culler, Michael D; Adams, Volker; Anker, Stefan D; Springer, Jochen

2011-01-01

Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output. Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a rat model of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics. Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p<0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9±0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76±0.07 for BIM-28131, 0.68±0.12 for BIM-28125, and 0.48±0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment. Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound.
Bleeding impacting mortality after noncardiac surgery: a protocol to establish diagnostic criteria, estimate prognostic importance, and develop and validate a prediction guide in an international prospective cohort study

PubMed Central

Roshanov, Pavel S.; Eikelboom, John W.; Crowther, Mark; Tandon, Vikas; Borges, Flavia K.; Kearon, Clive; Lamy, Andre; Whitlock, Richard; Biccard, Bruce M.; Szczeklik, Wojciech; Guyatt, Gordon H.; Panju, Mohamed; Spence, Jessica; Garg, Amit X.; McGillion, Michael; VanHelder, Tomas; Kavsak, Peter A.; de Beer, Justin; Winemaker, Mitchell; Sessler, Daniel I.; Le Manach, Yannick; Sheth, Tej; Pinthus, Jehonathan H.; Thabane, Lehana; Simunovic, Marko R.I.; Mizera, Ryszard; Ribas, Sebastian; Devereaux, P.J.

2017-01-01

Introduction: Various definitions of bleeding have been used in perioperative studies without systematic assessment of the diagnostic criteria for their independent association with outcomes important to patients. Our proposed definition of bleeding impacting mortality after noncardiac surgery (BIMS) is bleeding that is independently associated with death during or within 30 days after noncardiac surgery. We describe our analysis plan to sequentially 1) establish the diagnostic criteria for BIMS, 2) estimate the independent contribution of BIMS to 30-day mortality and 3) develop and internally validate a clinical prediction guide to estimate patient-specific risk of BIMS. Methods: In the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) study, we prospectively collected bleeding data for 16 079 patients aged 45 years or more who had noncardiac inpatient surgery between 2007 and 2011 at 12 centres in 8 countries across 5 continents. We will include bleeding features independently associated with 30-day mortality in the diagnostic criteria for BIMS. Candidate features will include the need for reoperation due to bleeding, the number of units of erythrocytes transfused, the lowest postoperative hemoglobin concentration, and the absolute and relative decrements in hemoglobin concentration from the preoperative value. We will then estimate the incidence of BIMS and its independent association with 30-day mortality. Last, we will construct and internally validate a clinical prediction guide for BIMS. Interpretation: This study will address an important gap in our knowledge about perioperative bleeding, with implications for the 200 million patients who undergo noncardiac surgery globally every year. Trial registration: ClinicalTrials.gov, no NCT00512109. PMID:28943515
Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

PubMed

Wu, Yanna; Ma, Shanshan; Xia, Yong; Lu, Yangpeng; Xiao, Shiyin; Cao, Yali; Zhuang, Sidian; Tan, Xiangpeng; Fu, Qiang; Xie, Longchang; Li, Zhiming; Yuan, Zhongmin

2017-01-26

Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.
Randomized trial of constraint-induced movement therapy and bimanual training on activity outcomes for children with congenital hemiplegia.

PubMed

Sakzewski, Leanne; Ziviani, Jenny; Abbott, David F; Macdonell, Richard A L; Jackson, Graeme D; Boyd, Roslyn N

2011-04-01

To determine if constraint-induced movement therapy (CIMT) is more effective than bimanual training (BIM) in improving upper limb activity outcomes for children with congenital hemiplegia in a matched-pairs randomized trial. Sixty-three children (mean age 10.2, SD 2.7, range 5-16 y; 33 males, 30 females), 16 in Manual Ability Classification System level I, 46 level II, and 1 level III and 16 in Gross Motor Function Classification level I, 47 level II) were randomly allocated to either CIMT or BIM group day camps (60 hours over 10 days). The Melbourne Assessment of Unilateral Upper Limb Function assessed unimanual capacity of the impaired limb and Assisting Hand Assessment evaluated bimanual coordination at baseline, 3 and 26 weeks, scored by blinded raters. After concealed random allocation, there was no baseline difference between groups. CIMT had superior outcomes compared with BIM for unimanual capacity at 26 weeks (estimated mean difference [EMD] 4.4, 95% confidence interval [CI] 2.2-6.7; p < 0.001). There was no other significant difference between groups post-intervention. Both groups demonstrated significant improvements in bimanual performance at 3 weeks, with gains maintained by BIM at 26 weeks (EMD 2.3; 95% CI 0.6-4.0; p = 0.008). Interpretation Overall, there were only small differences between the two training approaches. CIMT yielded greater changes in unimanual capacity of the impaired upper limb compared with BIM. Results generally reflect specificity of practice, with CIMT improving unimanual capacity and BIM improving bimanual performance. Considerable inter-individual variation in response to either intervention was evident. Future research should consider serial sequencing unimanual then BIM approaches to optimize upper limb outcomes for children with congenital hemiplegia. © The Authors. Journal compilation © Mac Keith Press 2011.

Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2.

PubMed

Ferrante, E; Pellegrini, C; Bondioni, S; Peverelli, E; Locatelli, M; Gelmini, P; Luciani, P; Peri, A; Mantovani, G; Bosari, S; Beck-Peccoz, P; Spada, A; Lania, A

2006-09-01

Somatostatin analogs currently used in the treatment of acromegaly and other neuroendocrine tumors inhibit hormone secretion and cell proliferation by binding to somatostatin receptor type (SST) 2 and 5. The antiproliferative pathways coupled to these receptors have been only partially characterized. The aim of this study was to evaluate the effect of octreotide and super selective SST2 (BIM23120) and SST5 (BIM23206) analogs on apoptotic activity and apoptotic gene expression in human somatotroph tumor cells. Eight somatotroph tumors expressing similar levels of SST2 and SST5 evaluated by real-time PCR and western blot analyses were included in the study. In cultured cells obtained from these tumors, octreotide induced a dose-dependent increase of caspase-3 activity (160+/-20% vs basal at 10 nM) and cleaved cytokeratin 18 levels (172+/-25% vs basal) at concentrations higher than 0.1 nM. This effect was due to SST2 activation since BIM23120 elicited comparable responses, while BIM23206 was ineffective. BIM23120-stimulated apoptosis was dependent on phosphatases, since it was abrogated by the inhibitor orthovanadate, and independent from the induction of apoptosis-related genes, such as p53, p63, p73, Bcl-2, Bax, BID, BIK, TNFSF8, and FADD. In somatotroph tumors, both BIM23120 and BIM2306 caused growth arrest as indicated by the increase in p27 and decrease in cyclin D1 expression. In conclusion, the present study showed that octreotide-induced apoptosis in human somatotroph tumor cells by activating SST2. This effect, together with the cytostatic action exerted by both SST2 and SST5 analogs, might account for the tumor shrinkage observed in acromegalic patients treated with long-acting somatostatin analogs.
Application of BIM technology in construction bidding

NASA Astrophysics Data System (ADS)

wei, Li

2017-12-01

bidding is a very important step of construction project. For the owners, bidding is the key link of selecting the best construction plan and saving the project cost to the maximum extent. For Construction Corporation, it is the key to show their construction technology which can improve the probability of winning the bid. this paper researches on the application of BIM technology in bidding process of construction project in detail, and discussesthe application of BIM technology in construction field comprehensively.
Geo-Information Technology of 8-Level Responsibility: Concept and Standard of Construction Management for Implementation of The BIM-Technology in Russia

NASA Astrophysics Data System (ADS)

Komosko, Vladimir; Serebryakov, Sergey; Strokov, Vladimir

2017-12-01

Currently, the increase in construction efficiency in the world is associated with the introduction and development of information modelling of construction objects (BIM-technology). The BIM-technology is a process of collective creation and use of information about a structure that forms the basis for all decisions throughout the life cycle of an object. The BIM-technology with the help of a number of software products provides automation of production, it does not provide a methodology for the introduction of these products. The article describes the technology of 8-level responsibility, which is guaranteed to give systematically a new quality of management in construction, related to the requirements of the Russian Government Decree No. 87 of February 16, 2008. The technology of 8-level responsibility (8LR) in the detailed specification of GD No. 87, (territory, construction stage, master plan object, section (part) of the project) extends the number of inseparable levels to 8 (part of the object, element, mark, position), where the “position” is the last indivisible detail of the object. There is reason to argue that the use of the “8LR Technology” in addition to the BIM-technology will provide a synergistic effect and will remove a number of obstacles to the BIM introduction in Russia and system control in the construction and operation of objects of any complexity in Russia.
The relationship between cost estimates reliability and BIM adoption: SEM analysis

NASA Astrophysics Data System (ADS)

Ismail, N. A. A.; Idris, N. H.; Ramli, H.; Rooshdi, R. R. Raja Muhammad; Sahamir, S. R.

2018-02-01

This paper presents the usage of Structural Equation Modelling (SEM) approach in analysing the effects of Building Information Modelling (BIM) technology adoption in improving the reliability of cost estimates. Based on the questionnaire survey results, SEM analysis using SPSS-AMOS application examined the relationships between BIM-improved information and cost estimates reliability factors, leading to BIM technology adoption. Six hypotheses were established prior to SEM analysis employing two types of SEM models, namely the Confirmatory Factor Analysis (CFA) model and full structural model. The SEM models were then validated through the assessment on their uni-dimensionality, validity, reliability, and fitness index, in line with the hypotheses tested. The final SEM model fit measures are: P-value=0.000, RMSEA=0.079<0.08, GFI=0.824, CFI=0.962>0.90, TLI=0.956>0.90, NFI=0.935>0.90 and ChiSq/df=2.259; indicating that the overall index values achieved the required level of model fitness. The model supports all the hypotheses evaluated, confirming that all relationship exists amongst the constructs are positive and significant. Ultimately, the analysis verified that most of the respondents foresee better understanding of project input information through BIM visualization, its reliable database and coordinated data, in developing more reliable cost estimates. They also perceive to accelerate their cost estimating task through BIM adoption.
Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borensztajn, Keren S.; Bijlsma, Maarten F.; Groot, Angelique P.

2007-07-15

Coagulation Factor (F)Xa is a serine protease that plays a crucial role during blood coagulation by converting prothrombin into active thrombin. Recently, however, it emerged that besides this role in coagulation, FXa induces intracellular signaling leading to different cellular effects. Here, we show that coagulation factor (F)Xa drives tumor cells of epithelial origin, but not endothelial cells or monocytes, into apoptosis, whereas it even enhances fibroblast survival. FXa signals through the protease activated receptor (PAR)-1 to activate extracellular-signal regulated kinase (ERK) 1/2 and p38. This activation is associated with phosphorylation of the transcription factor CREB, and in tumor cells withmore » up-regulation of the BH3-only pro-apoptotic protein Bim, leading to caspase-3 cleavage, the main hallmark of apoptosis. Transfection of tumor cells with dominant negative forms of CREB or siRNA for either PAR-1, Bim, ERK1 and/or p38 inhibited the pro-apoptotic effect of FXa. In fibroblasts, FXa-induced PAR-1 activation leads to down-regulation of Bim and pre-treatment with PAR-1 or Bim siRNA abolishes proliferation. We thus provide evidence that beyond its role in blood coagulation, FXa plays a key role in cellular processes in which Bim is the central player in determining cell survival.« less
Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.

PubMed

Chen, Hengyi; Wang, Yubo; Lin, Caiyu; Lu, Conghua; Han, Rui; Jiao, Lin; Li, Li; He, Yong

2017-11-07

There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin - a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.
Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

PubMed Central

Labi, Verena; Woess, Claudia; Tuzlak, Selma; Erlacher, Miriam; Bouillet, Philippe; Strasser, Andreas; Tzankov, Alexandar

2014-01-01

BH3 domain-only proteins (BH3-only) proteins are members of the Bcl-2 family that play crucial roles in embryogenesis and the maintenance of tissue homeostasis by triggering apoptotic cell death. The BH3-only protein Bim is critical for developmental apoptosis of lymphocytes, securing establishment of tolerance and for the termination of immune responses. Bim is believed to act in concert with other BH3-only proteins or members of the tumor necrosis factor receptor family in getting rid of unwanted cells. Bmf, a related BH3-only protein, was shown to play a role in B-cell homeostasis and to mediate cell death in response to certain apoptotic triggers, including glucocorticoid, histone deacetylase inhibitors, and overexpression of the c-Myc proto-oncogene. Here we show that Bim and Bmf have overlapping functions during mouse development and coregulate lymphocyte homeostasis and apoptosis in a nonredundant manner. Double deficiency of Bim and Bmf caused more B lymphadenopathy than loss of either BH3-only protein alone, and this was associated with autoimmune glomerulonephritis and a range of malignancies in aged mice. Thus, our results demonstrate that Bim and Bmf act in concert to prevent autoimmunity and malignant disease, strengthening the rational for the development of BH3-only protein mimicking therapeutics for the treatment of such disorders. PMID:24632712
Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells.

PubMed

Qin, Guiqi; Zhao, ChuBiao; Zhang, Lili; Liu, Hongyu; Quan, Yingyao; Chai, Liuying; Wu, Shengnan; Wang, Xiaoping; Chen, Tongsheng

2015-08-01

This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (ΔΨm), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced ΔΨm collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells.
Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

PubMed Central

Aguiló, N; Uranga, S; Marinova, D; Martín, C; Pardo, J

2014-01-01

Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis. PMID:25032866
Experiment for Integrating Dutch 3d Spatial Planning and Bim for Checking Building Permits

NASA Astrophysics Data System (ADS)

van Berlo, L.; Dijkmans, T.; Stoter, J.

2013-09-01

This paper presents a research project in The Netherlands in which several SMEs collaborated to create a 3D model of the National spatial planning information. This 2D information system described in the IMRO data standard holds implicit 3D information that can be used to generate an explicit 3D model. The project realized a proof of concept to generate a 3D spatial planning model. The team used the model to integrate it with several 3D Building Information Models (BIMs) described in the open data standard Industry Foundation Classes (IFC). Goal of the project was (1) to generate a 3D BIM model from spatial planning information to be used by the architect during the early design phase, and (2) allow 3D checking of building permits. The team used several technologies like CityGML, BIM clash detection and GeoBIM to explore the potential of this innovation. Within the project a showcase was created with a part of the spatial plan from the city of The Hague. Several BIM models were integrated in the 3D spatial plan of this area. A workflow has been described that demonstrates the benefits of collaboration between the spatial domain and the AEC industry in 3D. The research results in a showcase with conclusions and considerations for both national and international practice.
BIM Based Virtual Environment for Fire Emergency Evacuation

PubMed Central

Rezgui, Yacine; Ong, Hoang N.

2014-01-01

Recent building emergency management research has highlighted the need for the effective utilization of dynamically changing building information. BIM (building information modelling) can play a significant role in this process due to its comprehensive and standardized data format and integrated process. This paper introduces a BIM based virtual environment supported by virtual reality (VR) and a serious game engine to address several key issues for building emergency management, for example, timely two-way information updating and better emergency awareness training. The focus of this paper lies on how to utilize BIM as a comprehensive building information provider to work with virtual reality technologies to build an adaptable immersive serious game environment to provide real-time fire evacuation guidance. The innovation lies on the seamless integration between BIM and a serious game based virtual reality (VR) environment aiming at practical problem solving by leveraging state-of-the-art computing technologies. The system has been tested for its robustness and functionality against the development requirements, and the results showed promising potential to support more effective emergency management. PMID:25197704
BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors

PubMed Central

Faber, Anthony; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, Joao; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril; Gómez, Henry; Baselga, Jose; Arteaga, Carlos L.; Rivera, Miguel N.; Dias-Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

2011-01-01

Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. PMID:22145099
BIM and IoT: A Synopsis from GIS Perspective

NASA Astrophysics Data System (ADS)

Isikdag, U.

2015-10-01

Internet-of-Things (IoT) focuses on enabling communication between all devices, things that are existent in real life or that are virtual. Building Information Models (BIMs) and Building Information Modelling is a hype that has been the buzzword of the construction industry for last 15 years. BIMs emerged as a result of a push by the software companies, to tackle the problems of inefficient information exchange between different software and to enable true interoperability. In BIM approach most up-to-date an accurate models of a building are stored in shared central databases during the design and the construction of a project and at post-construction stages. GIS based city monitoring / city management applications require the fusion of information acquired from multiple resources, BIMs, City Models and Sensors. This paper focuses on providing a method for facilitating the GIS based fusion of information residing in digital building "Models" and information acquired from the city objects i.e. "Things". Once this information fusion is accomplished, many fields ranging from Emergency Response, Urban Surveillance, Urban Monitoring to Smart Buildings will have potential benefits.
Bim suppresses the development of SLE by limiting myeloid inflammatory responses

PubMed Central

Tsai, FuNien; Agrawal, Hemant; Abdala-Valencia, Hiam; Haines, G. Kenneth; Dominguez, Salina; Saber, Rana; Mohan, Chandra; Hutcheson, Jack; Budinger, G.R. Scott; Bouillet, Philippe; Dorfleutner, Andrea; Stehlik, Christian; Winter, Deborah R.

2017-01-01

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)–like disease that mirrors aged Bim−/− mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain–containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE. PMID:29114065
Interfacial Properties of EXXPRO(TM) and General Purpose Elastomers

NASA Astrophysics Data System (ADS)

Zhang, Y.; Rafailovich, M.; Sokolov, Jon; Qu, S.; Ge, S.; Ngyuen, D.; Li, Z.; Peiffer, D.; Song, L.; Dias, J. A.; McElrath, K. O.

1998-03-01

EXXPRO(Trademark) elastomers are used for tires and many other applications. This elastomer (denoted as BIMS) is a random copolymer of p-methylstyrene (MS) and polyisobutylene (I) with varying degrees of PMS content and bromination (B) on the p-methyl group. BIMS is impermeable to gases, and has good heat, ozone and flex resistance. Very often general purpose elastomers are blended with BIMS. The interfacial width between polybutadiene and BIMS is a sensitive function of the Br level and PMS content. By neutron reflectivity (NR), we studied the dynamics of interface formation as a function of time and temperature for BIMS with varying degrees of PMS and Br. We found that in addition to the bulk parameters, the total film thickness and the proximity of an interactive surface can affect the interfacial interaction rates. The interfacial properties can also be modified by inclusion of particles, such as carbon black (a filler component in tire rubbers). Results will be presented on the relation between the interfacial width as measured by NR and compatibilization studies via AFM and LFM.
Study of Collaborative Management for Transportation Construction Project Based on BIM Technology

NASA Astrophysics Data System (ADS)

Jianhua, Liu; Genchuan, Luo; Daiquan, Liu; Wenlei, Li; Bowen, Feng

2018-03-01

Abstract. Building Information Modeling(BIM) is a building modeling technology based on the relevant information data of the construction project. It is an advanced technology and management concept, which is widely used in the whole life cycle process of planning, design, construction and operation. Based on BIM technology, transportation construction project collaborative management can have better communication through authenticity simulation and architectural visualization and can obtain the basic and real-time information such as project schedule, engineering quality, cost and environmental impact etc. The main services of highway construction management are integrated on the unified BIM platform for collaborative management to realize information intercommunication and exchange, to change the isolated situation of information in the past, and improve the level of information management. The final BIM model is integrated not only for the information management of project and the integration of preliminary documents and design drawings, but also for the automatic generation of completion data and final accounts, which covers the whole life cycle of traffic construction projects and lays a good foundation for smart highway construction.
Efficacy and tolerability of fixed-combination bimatoprost/timolol versus fixed-combination dorzolamide/brimonidine/timolol in patients with primary open-angle glaucoma or ocular hypertension: a multicenter, prospective, crossover study.

PubMed

García-López, Alfonso; Paczka, José A; Jiménez-Román, Jesús; Hartleben, Curt

2014-12-19

Fixed-combination ocular hypotensives have multiple advantages, but triple-therapy dorzolamide/brimonidine/timolol (dorz/brim/tim) is only available in Latin and South America, and information on its relative efficacy is limited. This study compares the efficacy and tolerability of fixed-combination bimatoprost/timolol (bim/tim) and dorz/brim/tim in Mexican patients with primary open-angle glaucoma or ocular hypertension. In this investigator-masked, crossover study, patients with unmet target intraocular pressure (IOP) on once-daily bim/tim or twice-daily dorz/brim/tim received the opposite medication for 3 months before returning to their pre-baseline medication for 3 months. IOP was evaluated before and after morning instillation at months 2, 3, 5 and 6. Primary endpoints were mean IOP change and Ocular Surface Disease Index© (OSDI) score at each visit. The intent-to-treat population was the a priori analysis population, but due to the number of discontinuations, the per-protocol and intent-to-treat populations were used for the primary efficacy and sensitivity analyses, respectively. Seventy-eight and 56 patients were included in the intent-to-treat and per-protocol populations, respectively. At month 3, statistically significant IOP reductions from baseline were observed in the bim/tim (P < 0.01) and dorz/brim/tim (P < 0.0001) groups, regardless of assessment time. At month 6, patients returned to bim/tim exhibited no significant IOP increase (regardless of assessment time), but patients returned to dorz/brim/tim exhibited a statistically significant IOP increase (P < 0.001) when assessed before instillation of study treatment. Results were similar in both intent-to-treat and per-protocol analysis populations. In the per-protocol analysis, 70% of patients on bim/tim at month 3 had an IOP <14 mm Hg, which declined to 58% (P = 0.0061) at month 6 (ie, after 3 months of dorz/brim/tim treatment). In patients receiving dorz/brim/tim at month 3, 38% had an IOP <14 mm Hg, which remained comparable after return to bim/tim. OSDI scores and incidence of adverse events were similar in both groups. In this first direct comparison of the efficacy of dorz/brim/tim and bim/tim, patients switched from dorz/brim/tim to bim/tim demonstrated improved/lower IOP; when returned to dorz/brim/tim, IOP increased to levels seen at study initiation, suggesting that once-daily bim/tim may have greater IOP-lowering efficacy. Both bim/tim and dorz/brim/tim were well tolerated with minimal ocular surface damage. ClinicalTrials.gov: NCT01737853 (registered October 9, 2012).
Index cost estimate based BIM method - Computational example for sports fields

NASA Astrophysics Data System (ADS)

Zima, Krzysztof

2017-07-01

The paper presents an example ofcost estimation in the early phase of the project. The fragment of relative database containing solution, descriptions, geometry of construction object and unit cost of sports facilities was shown. The Index Cost Estimate Based BIM method calculationswith use of Case Based Reasoning were presented, too. The article presentslocal and global similarity measurement and example of BIM based quantity takeoff process. The outcome of cost calculations based on CBR method was presented as a final result of calculations.
A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

PubMed Central

Habtemichael, Negusse; Bier, Carolin; Unruhe, Britta; Weisheit, Simona; Spange, Stephanie; Nonnenmacher, Frank; Fetz, Verena; Ginter, Torsten; Reichardt, Sigrid; Liebmann, Claus; Schneider, Günter; Krämer, Oliver H.

2012-01-01

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM's clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation. PMID:22289787
A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer

PubMed Central

Allen, John C.; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A.; Chin, Tan-Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lu, Shun; Isobe, Kazutoshi; Lee, Jih-Hsiang; Yang, James C.; Zhao, Mingchuan; Zhou, Caicun; Lee, June-Koo; Lee, Se-Hoon; Lee, Ji Yun; Ahn, Myung-Ju; Tan, Tira J.; Tan, Daniel S.; Tan, Eng-Huat; Ong, S. Tiong; Lim, Wan-Teck

2017-01-01

Background A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. Results In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06–2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251–2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603–4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063–1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. Materials and Methods 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. Conclusions In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised. PMID:28467813

Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bumpus, Namandje N., E-mail: nbumpus1@jhmi.edu

Chronic use of efavirenz (EFV) has been linked to incidences of hepatotoxicity in patients receiving EFV to treat HIV-1. While recent studies have demonstrated that EFV stimulates hepatic cell death a role for the metabolites of efavirenz in this process has yet to be examined. In the present study, incubation of primary human hepatocytes with synthetic 8-hydroxyEFV (8-OHEFV), which is the primary metabolite of EFV, resulted in cell death, caspase-3 activation and reactive oxygen species formation. The metabolite exerted these effects at earlier time points and using lower concentrations than were required for the parent compound. In addition, pharmacological inhibitionmore » of cytochrome P450-dependent metabolism of EFV using 1-aminobenzotriazole markedly decreased reactive oxygen species formation and cell death. Treatment of primary human hepatocytes with EFV and 8-OHEFV also stimulated phosphorylation of c-Jun N-terminal kinase (JNK) as well as phosphorylation of the JNK substrate c-Jun. Further, the mRNA and protein expression of an isoform of Bim (Bcl-2 interacting mediator of cell death) denoted as BimEL, which is proapoptotic and has been shown to be modulated by JNK, was increased. Inhibition of JNK using SP600125 prevented the EFV- and 8-OHEFV-mediated cell death. Silencing of Bim using siRNA transfected into hepatocytes also prevented cell death resulting from 8-OHEFV-treatment. These data suggest that the oxidative metabolite 8-OHEFV is a more potent inducer of hepatic cell death than the parent compound EFV. Further, activation of the JNK signaling pathway and BimEL mRNA expression appear to be required for EFV- and 8-OHEFV-mediated hepatocyte death. -- Highlights: Black-Right-Pointing-Pointer 8-Hydroxyefavirenz is a more potent stimulator of cell death than efavirenz. Black-Right-Pointing-Pointer Efavirenz and 8-hydroxyefavirenz increase JNK activity and BimEL mRNA expression. Black-Right-Pointing-Pointer JNK and Bim are required for efavirenz- and 8-hydroxyefavirenz-mediated cell death. Black-Right-Pointing-Pointer Efavirenz and 8-hydroxyefavirenz may be novel modulators of Bim.« less
Extracting the Data From the LCM vk4 Formatted Output File

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wendelberger, James G.

These are slides about extracting the data from the LCM vk4 formatted output file. The following is covered: vk4 file produced by Keyence VK Software, custom analysis, no off the shelf way to read the file, reading the binary data in a vk4 file, various offsets in decimal lines, finding the height image data, directly in MATLAB, binary output beginning of height image data, color image information, color image binary data, color image decimal and binary data, MATLAB code to read vk4 file (choose a file, read the file, compute offsets, read optical image, laser optical image, read and computemore » laser intensity image, read height image, timing, display height image, display laser intensity image, display RGB laser optical images, display RGB optical images, display beginning data and save images to workspace, gamma correction subroutine), reading intensity form the vk4 file, linear in the low range, linear in the high range, gamma correction for vk4 files, computing the gamma intensity correction, observations.« less
Design and application of BIM based digital sand table for construction management

NASA Astrophysics Data System (ADS)

Fuquan, JI; Jianqiang, LI; Weijia, LIU

2018-05-01

This paper explores the design and application of BIM based digital sand table for construction management. Aiming at the demands and features of construction management plan for bridge and tunnel engineering, the key functional features of digital sand table should include three-dimensional GIS, model navigation, virtual simulation, information layers, and data exchange, etc. That involving the technology of 3D visualization and 4D virtual simulation of BIM, breakdown structure of BIM model and project data, multi-dimensional information layers, and multi-source data acquisition and interaction. Totally, the digital sand table is a visual and virtual engineering information integrated terminal, under the unified data standard system. Also, the applications shall contain visual constructing scheme, virtual constructing schedule, and monitoring of construction, etc. Finally, the applicability of several basic software to the digital sand table is analyzed.
[The role of FOXO3a-Bim signaling in triptolide induced bladder cancer T24 cells apoptosis].

PubMed

Yang, L L; Wang, X Y; Zheng, L Y; Fang, S J; Xu, M; Zhao, Z W; Ji, J S

2017-04-18

Objective: To investigate the role of FOXO3a-Bim signaling in triptolide induced bladder cancer T24 cells apoptosis. Methods: T24 cells were used and divided into control group, triptolide group(50 nmol/L), MK2206 group(50 nmol/L triptolide+ 5 μmol/L MK2206), FOXO3a-siRNA group(50 nmol/L triptolide+ 100 nmol/L FOXO3a-siRNA), Bim-siRNA group (50 nmol/L triptolide+ 100 nmol/L Bim-siRNA). MTT assay was used to analyze the cells growth inhibition.Annexin V/PI staining was implemented to detect cell apoptosis rate, the expression of p-Akt, Akt, p-FOXO3a, FOXO3a, Bim, Bax.Cleaved-caspase 3 was analyzed by Western blot. Results: After treatment with triptolide 25, 50, 100, 250 nmol/L, the cell growth inhibition rates at 24 hours(17%±9%, 24%±5%, 43%±8%, 61%±8%), 48 hours (20%±7%, 34%±6%, 56%±7%, 74%±5%) and 72 hours(32%±8%, 41%±7%, 69%±7%, 84%±3%) were significantly higher than control group respectively.The IC(50) at 24, 48, 72 hours were (113±10), (91±8), (68±5) nmol/L; the cell apoptosis rates at 24 hours (10%±4%, 15%±5%, 29%±8%, 46%±8%), 48 hours (16%±5%, 24%±6%, 40%±7%, 55%±9%) and 72 hours (27%±4%, 38%±5%, 50%±9%, 65%±8%) were significantly increased ( P <0.05). Western blot showed that triptolide reduced the expression of p-Akt, p-FOXO3a and increased the expression of Bim, Bax, cleaved-caspase 3.The cell inhibition rate in Triptolide group (30%±8%) was significantly higher than that in the control group ( P <0.05) and the rates in MK2206 group (54% ±6%), FOXO3a-siRNA group (18%±7%) and Bim-siRNA group (11%±6%) were also higher than the control group.Compared with the triptolide group, the inhibition rate in MK2206 group was significantly increased, but decreased in FOXO3a-siRNA group and Bim-siRNA group( P <0.05). Conclusion: Triptolide induces T24 cells apoptosis through FOXO3a-Bim signaling pathway.
Comparative Analysis of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) of Streptococcus thermophilus St-I and its Bacteriophage-Insensitive Mutants (BIM) Derivatives.

PubMed

Li, Wan; Bian, Xin; Evivie, Smith Etareri; Huo, Gui-Cheng

2016-09-01

The CRISPR-Cas (CRISPR together with CRISPR-associated proteins) modules are the adaptive immune system, acting as an adaptive and heritable immune system in bacteria and archaea. CRISPR-based immunity acts by integrating short virus sequences in the cell's CRISPR locus, allowing the cell to remember, recognize, and clear infections. In this study, the homology of CRISPRs sequence in BIMs (bacteriophage-insensitive mutants) of Streptococcus thermophilus St-I were analyzed. Secondary structures of the repeats and the PAMs (protospacer-associated motif) of each CRISPR locus were also predicted. Results showed that CRISPR1 has 27 repeat-spacer units, 5 of them had duplicates; CRISPR2 has one repeat-spacer unit; CRISPR3 has 28 repeat-spacer units. Only BIM1 had a new spacer acquisition in CRISPR3, while BIM2 and BIM3 had no new spacers' insertion, thus indicating that while most CRISPR1 were more active than CRISPR3, new spacer acquisition occurred just in CRSPR3 in some situations. These findings will help establish the foundation for the study of CRSPR-Cas systems in lactic acid bacteria.
Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf

PubMed Central

Labi, Verena; Bertele, Daniela; Woess, Claudia; Tischner, Denise; Bock, Florian J; Schwemmers, Sven; Pahl, Heike L; Geley, Stephan; Kunze, Mirjam; Niemeyer, Charlotte M; Villunger, Andreas; Erlacher, Miriam

2013-01-01

Anti-apoptotic Bcl-2 family members are critical for the regulation of haematopoietic stem and progenitor cell (HSPC) survival. Little is known about the role of their pro-apoptotic antagonists, i.e. ‘BH3-only’ proteins, in this cell compartment. Based on the analysis of cytokine deprivation-induced changes in mRNA expression levels of Bcl-2 family proteins, we determined the consequences of BH3-only protein depletion on HSPC survival in culture and, for selected candidates, on engraftment in vivo. Thereby, we revealed a critical role for Bim and Bmf as regulators of HSPC dynamics both during early engraftment and long-term reconstitution. HSPCs derived from wild-type donors were readily displaced by Bim- or Bmf-deficient or Bcl-2-overexpressing HSPCs as early as 10 days after engraftment. Moreover, in the absence of Bim, significantly lower numbers of transplanted HSPCs were able to fully engraft radio-depleted recipients. Finally, we provide proof of principle that RNAi-based reduction of BIM or BMF, or overexpression of BCL-2 in human CD34+ cord blood cells may be an attractive therapeutic option to increase stem cell survival and transplantation efficacy. PMID:23180554
Aggregation-Induced Emission Luminogen-Based Direct Visualization of Concentration Gradient Inside an Evaporating Binary Sessile Droplet.

PubMed

Cai, Xin; Xie, Ni; Qiu, Zijie; Yang, Junxian; He, Minghao; Wong, Kam Sing; Tang, Ben Zhong; Qiu, Huihe

2017-08-30

In this study, the concentration gradient inside evaporating binary sessile droplets of 30, 50, and 60 vol % tetrahydrofuran (THF)/water mixtures was investigated. The 5 μL THF/water droplets were evaporated on a transparent hydrophobic substrate. This is the first demonstration of local concentration mapping within an evaporating binary droplet utilizing the aggregation-induced emission material. During the first two evaporation stages of the binary droplet, the local concentration can be directly visualized by the change of fluorescence emission intensity. Time-resolved average and local concentrations can be estimated by using the pre-established function of fluorescence intensity versus water volume fraction.
BIM-Based E-Procurement: An Innovative Approach to Construction E-Procurement

PubMed Central

2015-01-01

This paper presents an innovative approach to e-procurement in construction, which uses building information models (BIM) to support the construction procurement process. The result is an integrated and electronic instrument connected to a rich knowledge base capable of advanced operations and able to strengthen transaction relationships and collaboration throughout the supply chain. The BIM-based e-procurement prototype has been developed using distinct existing electronic solutions and an IFC server and was tested in a pilot case study, which supported further discussions of the results of the research. PMID:26090518
IFC BIM-Based Methodology for Semi-Automated Building Energy Performance Simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazjanac, Vladimir

2008-07-01

Building energy performance (BEP) simulation is still rarely used in building design, commissioning and operations. The process is too costly and too labor intensive, and it takes too long to deliver results. Its quantitative results are not reproducible due to arbitrary decisions and assumptions made in simulation model definition, and can be trusted only under special circumstances. A methodology to semi-automate BEP simulation preparation and execution makes this process much more effective. It incorporates principles of information science and aims to eliminate inappropriate human intervention that results in subjective and arbitrary decisions. This is achieved by automating every part ofmore » the BEP modeling and simulation process that can be automated, by relying on data from original sources, and by making any necessary data transformation rule-based and automated. This paper describes the new methodology and its relationship to IFC-based BIM and software interoperability. It identifies five steps that are critical to its implementation, and shows what part of the methodology can be applied today. The paper concludes with a discussion of application to simulation with EnergyPlus, and describes data transformation rules embedded in the new Geometry Simplification Tool (GST).« less
Increased lymphocyte apoptosis in mouse models of colitis upon ABT-737 treatment is dependent upon BIM expression.

PubMed

Lutz, C; Mozaffari, M; Tosevski, V; Caj, M; Cippà, P; McRae, B L; Graff, C L; Rogler, G; Fried, M; Hausmann, M

2015-08-01

Exaggerated activation of lymphocytes contributes to the pathogenesis of inflammatory bowel disease (IBD). Medical therapies are linked to the BCL-2 family-mediated apoptosis. Imbalance in BCL-2 family proteins may cause failure in therapeutic responses. We investigated the role of BCL-2 inhibitor ABT-737 for lymphocyte apoptosis in mice under inflammatory conditions. B.6129P2-interleukin (IL)-10(tm1Cgn) /J (IL-10(-/-) ) weighing 25-30 g with ongoing colitis were used. Fifty mg/kg/day ABT-737 was injected intraperitoneally (i.p.). Haematological analyses were performed with an ADVIA 2120 flow cytometer and mass cytometry with a CyTOF 2. Following i.p. administration, ABT-737 was detected in both spontaneous and acute colitis in peripheral blood (PBL) and colon tissue. Treatment led to lymphopenia. CD4(+) CD44(+) CD62L(+) central memory and CD8(+) , CD44(+) CD62L(-) central memory T cells were decreased in PBL upon ABT-737 compared to vehicle-receiving controls. Increased apoptosis upon ABT-737 was determined in blood lymphocytes, splenocytes and Peyer's patches and was accompanied by a decrease in TNF and IL-1B. ABT-737 positively altered the colonic mucosa and ameliorated inflammation, as shown by colonoscopy, histology and colon length. A decreased BIM/BCL-2 ratio or absence of BIM in both Bim(-) (/) (-) and Il10(-) (/) (-) × Bim(-) (/) (-) impeded the protective effect of ABT-737. The BIM/BCL-2 ratio decreased with age and during the course of treatment. Thus, long-term treatment resulted in adapted TNF levels and macroscopic mucosal damage. ABT-737 was efficacious in diminishing lymphocytes and ameliorating colitis in a BIM-dependent manner. Regulation of inappropriate survival of lymphocytes by ABT-737 may provide a therapeutic strategy in IBD. © 2015 British Society for Immunology.
Shikonin induces apoptosis of lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling antagonized by p300.

PubMed

Jeung, Yun-Ji; Kim, Han-Gyeul; Ahn, Jiwon; Lee, Ho-Joon; Lee, Sae-Bhom; Won, Misun; Jung, Cho-Rock; Im, Joo-Young; Kim, Bo-Kyung; Park, Seung-Kiel; Son, Myung Jin; Chung, Kyung-Sook

2016-11-01

Shikonin derivatives exert powerful cytotoxic effects including induction of apoptosis. Here, we demonstrate the cytotoxic efficacy of shikonin in vivo in xenograft models, which did not affect body weight as well as its reduction of cell viability in vitro using several non-small cell lung cancer (NSCLC) cell lines. We found that inhibition of AKT by shikonin activated the forkhead box (FOX)O3a/early growth response protein (EGR)1 signaling cascade and enhanced the expression of the target gene Bim, leading to apoptosis in lung cancer cells. Overexpression of wild-type or a constitutively active mutant of FOXO3a enhanced shikonin-induced Bim expression. The NAD + -dependent histone deacetylase sirtuin (SIRT)1 amplified the pro-apoptotic effect by deacetylating FOXO3a, which induced EGR1 binding to the Bim promoter and activated Bim expression. Meanwhile, PI3K/AKT activity was enhanced, whereas that of FOXO3a was reduced and p300 was upregulated by treatment with a sublethal dose of shikonin. FOXO3a acetylation was enhanced by p300 overexpression, while shikonin-induced Bim expression was suppressed by p300 overexpression, which promoted cell survival. FOXO3a acetylation was increased by p300 overexpression and treatment with SIRT1 inhibitor, improving cell survival. In addition, shikonin-induced FOXO3a nuclear localization was blocked by AKT activation and SIRT1 inhibition, which blocked Bim expression and conferred resistance to the cytotoxic effects of shikonin. The EGR1 increase induced by shikonin was restored by pretreatment with SIRT1 inhibitor. These results suggest that shikonin induces apoptosis in some lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling, and that AKT and p300 negatively regulate this process via Bim upregulation. Copyright © 2016. Published by Elsevier B.V.
Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion*

PubMed Central

Catalán, Elena; Jaime-Sánchez, Paula; Aguiló, Nacho; Simon, Markus M.; Froelich, Christopher J.; Pardo, Julián

2015-01-01

Cytotoxic T cells (Tc) use perforin and granzyme B (gzmB) to kill virus-infected cells and cancer cells. Recent evidence suggests that human gzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active caspase-3. In contrast, mouse gzmB is thought to predominantly induce apoptosis by directly processing pro-caspase-3. However, in certain mouse cell types gzmB-mediated apoptosis mainly occurs via the mitochondrial pathway. To investigate whether Bim is involved under the latter conditions, we have now employed ex vivo virus-immune mouse Tc that selectively kill by using perforin and gzmB (gzmB+Tc) as effector cells and wild type as well as Bim- or Bak/Bax-deficient spontaneously (3T9) or virus-(SV40) transformed mouse embryonic fibroblast cells as targets. We show that gzmB+Tc-mediated apoptosis (phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) was severely reduced in 3T9 cells lacking either Bim or both Bak and Bax. This outcome was related to the ability of Tc cells to induce the degradation of Mcl-1 and Bcl-XL, the anti-apoptotic counterparts of Bim. In contrast, gzmB+Tc-mediated apoptosis was not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax. The data provide evidence that Bim participates in mouse gzmB+Tc-mediated apoptosis of certain targets by activating the mitochondrial pathway and suggest that the mode of cell death depends on the target cell. Our results suggest that the various molecular events leading to transformation and/or immortalization of cells have an impact on their relative resistance to the multiple gzmB+Tc-induced death pathways. PMID:25605735
Functional cooperation of the proapoptotic Bcl2 family proteins Bmf and Bim in vivo.

PubMed

Hübner, Anette; Cavanagh-Kyros, Julie; Rincon, Mercedes; Flavell, Richard A; Davis, Roger J

2010-01-01

Bcl2-modifying factor (Bmf) is a member of the BH3-only group of proapoptotic proteins. To test the role of Bmf in vivo, we constructed mice with a series of mutated Bmf alleles that disrupt Bmf expression, prevent Bmf phosphorylation by the c-Jun NH(2)-terminal kinase (JNK) on Ser(74), or mimic Bmf phosphorylation on Ser(74). We report that the loss of Bmf causes defects in uterovaginal development, including an imperforate vagina and hydrometrocolpos. We also show that the phosphorylation of Bmf on Ser(74) can contribute to a moderate increase in levels of Bmf activity. Studies of compound mutants with the related gene Bim demonstrated that Bim and Bmf exhibit partially redundant functions in vivo. Thus, developmental ablation of interdigital webbing on mouse paws and normal lymphocyte homeostasis require the cooperative activity of Bim and Bmf.
Increased Neurotropic Threat from Burkholderia pseudomallei Strains with a B. mallei–like Variation in the bimA Motility Gene, Australia

PubMed Central

Fane, Anne; Sarovich, Derek S.; Price, Erin P.; Rush, Catherine M.; Govan, Brenda L.; Parker, Elizabeth; Mayo, Mark; Currie, Bart J.; Ketheesan, Natkunam

2017-01-01

Neurologic melioidosis is a serious, potentially fatal form of Burkholderia pseudomallei infection. Recently, we reported that a subset of clinical isolates of B. pseudomallei from Australia have heightened virulence and potential for dissemination to the central nervous system. In this study, we demonstrate that this subset has a B. mallei–like sequence variation of the actin-based motility gene, bimA. Compared with B. pseudomallei isolates having typical bimA alleles, isolates that contain the B. mallei–like variation demonstrate increased persistence in phagocytic cells and increased virulence with rapid systemic dissemination and replication within multiple tissues, including the brain and spinal cord, in an experimental model. These findings highlight the implications of bimA variation on disease progression of B. pseudomallei infection and have considerable clinical and public health implications with respect to the degree of neurotropic threat posed to human health. PMID:28418830
Increased Neurotropic Threat from Burkholderia pseudomallei Strains with a B. mallei-like Variation in the bimA Motility Gene, Australia.

PubMed

Morris, Jodie L; Fane, Anne; Sarovich, Derek S; Price, Erin P; Rush, Catherine M; Govan, Brenda L; Parker, Elizabeth; Mayo, Mark; Currie, Bart J; Ketheesan, Natkunam

2017-05-01

Neurologic melioidosis is a serious, potentially fatal form of Burkholderia pseudomallei infection. Recently, we reported that a subset of clinical isolates of B. pseudomallei from Australia have heightened virulence and potential for dissemination to the central nervous system. In this study, we demonstrate that this subset has a B. mallei-like sequence variation of the actin-based motility gene, bimA. Compared with B. pseudomallei isolates having typical bimA alleles, isolates that contain the B. mallei-like variation demonstrate increased persistence in phagocytic cells and increased virulence with rapid systemic dissemination and replication within multiple tissues, including the brain and spinal cord, in an experimental model. These findings highlight the implications of bimA variation on disease progression of B. pseudomallei infection and have considerable clinical and public health implications with respect to the degree of neurotropic threat posed to human health.
Stat5 Signaling Specifies Basal versus Stress Erythropoietic Responses through Distinct Binary and Graded Dynamic Modalities

PubMed Central

Porpiglia, Ermelinda; Hidalgo, Daniel; Koulnis, Miroslav; Tzafriri, Abraham R.; Socolovsky, Merav

2012-01-01

Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a “knocked-in” EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and graded modalities combine to generate high-fidelity Stat5 signaling over the entire basal and stress Epo range. They suggest that dynamic behavior may encode information during STAT signal transduction. PMID:22969412
A major role for Bim in regulatory T cell homeostasis1

PubMed Central

Chougnet, Claire A.; Tripathi, Pulak; Lages, Celine S.; Raynor, Jana; Sholl, Allyson; Fink, Pamela; Plas, David R.; Hildeman, David A.

2011-01-01

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanism(s) underlying the age-dependent accrual of Treg remain unclear. Here, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, nor from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R-signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the pro-apoptotic molecule Bim compared to Treg from young mice. Further, in the absence of Bim, Treg accumulate rapidly, accounting for more than 25% of the CD4+ T cell compartment by 6 months of age. In addition, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bimlo Treg. Combined, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts. PMID:21098226
A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

PubMed Central

LaBelle, James L.; Katz, Samuel G.; Bird, Gregory H.; Gavathiotis, Evripidis; Stewart, Michelle L.; Lawrence, Chelsea; Fisher, Jill K.; Godes, Marina; Pitter, Kenneth; Kung, Andrew L.; Walensky, Loren D.

2012-01-01

Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death. PMID:22622039
T cell Bim levels reflect responses to anti–PD-1 cancer therapy

PubMed Central

Dronca, Roxana S.; Liu, Xin; Harrington, Susan M.; Chen, Lingling; Cao, Siyu; Kottschade, Lisa A.; McWilliams, Robert R.; Block, Matthew S.; Nevala, Wendy K.; Thompson, Michael A.; Mansfield, Aaron S.; Park, Sean S.; Markovic, Svetomir N.

2016-01-01

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility. PMID:27182556
Self-assembled 1D infinite inorganic [2]catenane and 2D sheet framework with calix[8]phenylazoimidazole and [4+4]metallomacrocyclic motifs based on silver and ditopic bis(imidazolyl)methane ligands

NASA Astrophysics Data System (ADS)

Jin, Tianqi; Zhou, Junqiang; Pan, Yangyang; Huang, Yu; Jin, Chuanming

2018-05-01

Three novel supramolecular complexes, [Ag4(2-mBIM)4](ClO4)4(H2O) (1), [Ag2(2-mBIM)2](PF6)2 (2) and [Ag2(PA-BIM)2](ClO4)2(CH2Cl2) (3) (2-mBIM = bis(2-methyl- imidazol-1-yl)methane; PA-BIM = 1,1-bis[(2-phenylazo)imidazol-1-yl]methane), have been prepared and structurally characterized. The reported complexes bear [4+4]metallomacrocyclic motifs comprising four silver atoms and four ditopic bis(imidazolyl)methane ligands. Complex 1 exhibits a rare 1D infinite inorganic [2]catenane structure, which was self-assembled by the interlocking action of [4+4]metallomacrocyclic units. Complex 2 is a 2D layered supramolecular motif containing [4+4]macrometallacycle units with π-π interaction between imidazole rings. Complex 3 has a 2D sheet supramolecular framework through Ag-Ag interactions in [4+4]macrometallacyclic calix [8]phenylazoimidazole with a nanocavity. The results suggest that the bisimidazolium ligands and anions play crucial roles in the formation of the different host structures. The thermal stability and photoluminescence spectra of the synthesized complexes have also been discussed.

BIM (BCL-2 interacting mediator of cell death) SAHB (stabilized α helix of BCL2) not always convinces BAX (BCL-2-associated X protein) for apoptosis.

PubMed

Verma, Sharad; Goyal, Sukriti; Tyagi, Chetna; Jamal, Salma; Singh, Aditi; Grover, Abhinav

2016-06-01

The interaction of BAX (BCL-2-associated X protein) with BIM (BCL-2 interacting mediator of cell death) SAHB (stabilized α helix of BCL2) directly initiates BAX-mediated mitochondrial apoptosis. This molecular dynamics study reveals that BIM SAHB forms a stable complex with BAX but it remains in a non-functional conformation. N terminal of BAX folds towards the core which has been reported exposed in the functional monomer. The α1-α2 loop, which has been reported in open conformation in functional BAX, acquires a closed conformation during the simulation. BH3/α2 remains less exposed as compared to initial structure. The hydrophobic residues of BIM accommodates in the rear pocket of BAX during the simulation. A steep decrease in radius of gyration and solvent accessible surface area (SASA) indicates the complex folding to acquire a more stable but inactive conformation. Further the covariance matrix reveals that the backbone atoms' motions favour the inactive conformation of the complex. This is the first report on the non-functional BAX-BIM SAHB complex by molecular dynamics simulation in the best of our knowledge. Copyright © 2016 Elsevier Inc. All rights reserved.
Bcl-2-interacting mediator of cell death influences autoantigen-driven deletion and TCR revision

PubMed Central

Hale, J. Scott; Nelson, Lisa T.; Simmons, Kalynn B.; Fink, Pamela J.

2010-01-01

Peripheral CD4+Vβ5+ T cells are tolerized to an endogenous mouse mammary tumor virus superantigen either by deletion or TCR revision. Through TCR revision, RAG reexpression mediates extrathymic TCRβ rearrangement and results in a population of post-revision CD4+Vβ5− T cells expressing revised TCRβ chains. We have hypothesized that cell death pathways regulate the selection of cells undergoing TCR revision to ensure the safety and utility of the post-revision population. Here, we investigate the role of Bim-mediated cell death in autoantigen-driven deletion and TCR revision. Bim deficiency and Bcl-2 overexpression in Vβ5 transgenic (Tg) mice both impair peripheral deletion. Vβ5 Tg Bim deficient and Bcl-2 Tg mice exhibit an elevated frequency of CD4+ T cells expressing both the transgene-encoded Vβ5 chain and a revised TCRβ chain. We now show that these dual-TCR expressing cells are TCR revision intermediates, and that the population of RAG-expressing, revising CD4+ T cells is increased in Bim deficient Vβ5 Tg mice. These findings support a role for Bim and Bcl-2 in regulating the balance of survival versus apoptosis in peripheral T cells undergoing RAG-dependent TCR rearrangements during TCR revision, thereby ensuring the utility of the post-revision repertoire. PMID:21148799
FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis.

PubMed

Wang, Jiao; Liu, Shu; Yin, Yancun; Li, Mingjin; Wang, Bo; Yang, Li; Jiang, Yangfu

2015-03-01

The anthraquinone compound rhein is a natural agent in the traditional Chinese medicine rhubarb. Preclinical studies demonstrate that rhein has anticancer activity. Treatment of a variety of cancer cells with rhein may induce apoptosis. Here, we report that rhein induces atypical unfolded protein response in breast cancer MCF-7 cells and hepatoma HepG2 cells. Rhein induces CHOP expression, eIF2α phosphorylation and caspase cleavage, while it does not induce glucose-regulated protein 78 (GRP78) expression in both MCF-7 and HepG2 cells. Meanwhile, rhein inhibits thapsigargin-induced GRP78 expression and X box-binding protein 1 splicing. In addition, rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity. Rhein induces Bim expression in MCF-7 and HepG2 cells, which can be abrogated by FOXO3a knockdown. Knockdown of FOXO3a or Bim abrogates rhein-induced caspase cleavage and apoptosis. The chemical chaperone 4-phenylbutyrate acid antagonizes the induction of FOXO activation, Bim expression and caspase cleavage by rhein, indicating that protein misfolding may be involved in triggering these deleterious effects. We conclude that FOXO3a-mediated up-regulation of Bim is a key mechanism underlying rhein-induced cancer cells apoptosis.
Development of Multi-slice Analytical Tool to Support BIM-based Design Process

NASA Astrophysics Data System (ADS)

Atmodiwirjo, P.; Johanes, M.; Yatmo, Y. A.

2017-03-01

This paper describes the on-going development of computational tool to analyse architecture and interior space based on multi-slice representation approach that is integrated with Building Information Modelling (BIM). Architecture and interior space is experienced as a dynamic entity, which have the spatial properties that might be variable from one part of space to another, therefore the representation of space through standard architectural drawings is sometimes not sufficient. The representation of space as a series of slices with certain properties in each slice becomes important, so that the different characteristics in each part of space could inform the design process. The analytical tool is developed for use as a stand-alone application that utilises the data exported from generic BIM modelling tool. The tool would be useful to assist design development process that applies BIM, particularly for the design of architecture and interior spaces that are experienced as continuous spaces. The tool allows the identification of how the spatial properties change dynamically throughout the space and allows the prediction of the potential design problems. Integrating the multi-slice analytical tool in BIM-based design process thereby could assist the architects to generate better design and to avoid unnecessary costs that are often caused by failure to identify problems during design development stages.
Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells

PubMed Central

Niu, Xiaojia; Zhao, Jianyun; Ma, Jun; Xie, Chengzhi; Edwards, Holly; Wang, Guan; Caldwell, J. Timothy; Xiang, Shengyan; Zhang, Xiaohong; Chu, Roland; Wang, Zhihong; Lin, Hai; Taub, Jeffrey W.; Ge, Yubin

2016-01-01

Purpose To investigate the molecular mechanism underlying intrinsic resistance to ABT-199. Experimental Design Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral shRNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis. Results Immunoprecipitation of Bim from ABT-199 treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared to ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. Conclusions Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. PMID:27103402
Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X).

PubMed

Thomas, Dierk; Hammerling, Bettina C; Wimmer, Anna-Britt; Wu, Kezhong; Ficker, Eckhard; Kuryshev, Yuri A; Scherer, Daniel; Kiehn, Johann; Katus, Hugo A; Schoels, Wolfgang; Karle, Christoph A

2004-12-01

The human ether-a-go-go-related gene (hERG) encodes the rapid component of the cardiac repolarizing delayed rectifier potassium current, I(Kr). The direct interaction of the commonly used protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM I) with hERG, KvLQT1/minK, and I(Kr) currents was investigated in this study. hERG and KvLQT1/minK channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. In addition, hERG currents in stably transfected human embryonic kidney (HEK 293) cells, native I(Kr) currents and action potentials in isolated guinea pig ventricular cardiomyocytes were recorded using whole-cell patch clamp electrophysiology. Bisindolylmaleimide I blocked hERG currents in HEK 293 cells and Xenopus oocytes in a concentration-dependent manner with IC(50) values of 1.0 and 13.2 muM, respectively. hERG channels were primarily blocked in the open state in a frequency-independent manner. Analysis of the voltage-dependence of block revealed a reduction of inhibition at positive membrane potentials. BIM I caused a shift of -20.3 mV in the voltage-dependence of inactivation. The point mutations tyrosine 652 alanine (Y652A) and phenylalanine 656 alanine (F656A) attenuated hERG current blockade, indicating that BIM I binds to a common drug receptor within the pore region. KvLQT1/minK currents were not significantly altered by BIM I. Finally, 1 muM BIM I reduced native I(Kr) currents by 69.2% and lead to action potential prolongation. In summary, PKC-independent effects have to be carefully considered when using BIM I as PKC inhibitor in experimental models involving hERG channels and I(Kr) currents.
Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway

PubMed Central

Chi, Hsiang-Cheng; Chen, Shen-Liang; Cheng, Yi-Hung; Lin, Tzu-Kang; Tsai, Chung-Ying; Tsai, Ming-Ming; Lin, Yang-Hsiang; Huang, Ya-Hui; Lin, Kwang-Huei

2016-01-01

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells. PMID:27490929
Sevoflurane post-conditioning protects primary rat cortical neurons against oxygen-glucose deprivation/resuscitation via down-regulation in mitochondrial apoptosis axis of Bid, Bim, Puma-Bax and Bak mediated by Erk1/2.

PubMed

Zhang, Li-Min; Zhao, Xiao-Chun; Sun, Wen-Bo; Li, Rui; Jiang, Xiao-Jing

2015-10-15

Temporal post-conditioning helps provide neuroprotection against brain injury secondary to ischemia-reperfusion and is considered an effective intervention, but the exact mechanism of sevoflurane post-conditioning is unclear. The essential axis involves activator Bid, Bim, Puma (BH3s), Bax, and Bak; activates the mitochondrial death program; and might be involved in a cell death signal. Extracellular signal-related kinases 1/2 (Erk1/2) play a pivotal role in cell growth and proliferation. We hypothesized that sevoflurane post-conditioning might inhibit Bid, Bim, Puma, Bax, and Bak expression and is activated by phosphor-Erk1/2 to decrease neuronal death. To test this hypothesis, we exposed primary cortical neuron cultures to oxygen-glucose deprivation for 1h, along with resuscitation for 24h (OGD/R). MTT assays, propidium iodide uptake (PI), JC-1 fluorescence, and Western blot indicated the following: decreased cell viability (P<0.05); increased cell death (P<0.05); decreased mitochondrial membrane potential (P<0.05); and decreased Bid, Bim, Puma, Bax, and Bak expression with OGD/R exposure. Inhibition of Erk1/2 phosphorylation could attenuate sevoflurane post-conditioning that mediated an increase in neuronal viability and mitochondrial membrane potential, as well as a decrease in cell death and Bid, Bim, Puma, Bax, and Bak expression after OGD/R treatment. The results demonstrated that sevoflurane post-conditioning caused a marked decrease in cortical neuronal death secondary to OGD/R exposure through the downregulation of the mitochondrial apoptosis axis involving Bid, Bim, Puma, Bax, and Bak that was mediated by the phosphorylation/activation of Erk1/2. Copyright © 2015 Elsevier B.V. All rights reserved.
Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells.

PubMed

Niu, Xiaojia; Zhao, Jianyun; Ma, Jun; Xie, Chengzhi; Edwards, Holly; Wang, Guan; Caldwell, J Timothy; Xiang, Shengyan; Zhang, Xiaohong; Chu, Roland; Wang, Zhihong J; Lin, Hai; Taub, Jeffrey W; Ge, Yubin

2016-09-01

To investigate the molecular mechanism underlying intrinsic resistance to ABT-199. Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis. Immunoprecipitation of Bim from ABT-199-treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. Clin Cancer Res; 22(17); 4440-51. ©2016 AACR. ©2016 American Association for Cancer Research.
Research of Ancient Architectures in Jin-Fen Area Based on GIS&BIM Technology

NASA Astrophysics Data System (ADS)

Jia, Jing; Zheng, Qiuhong; Gao, Huiying; Sun, Hai

2017-05-01

The number of well-preserved ancient buildings located in Shanxi Province, enjoying the absolute maximum proportion of ancient architectures in China, is about 18418, among which, 9053 buildings have the structural style of wood frame. The value of the application of BIM (Building Information Modeling) and GIS (Geographic Information System) is gradually probed and testified in the corresponding fields of ancient architecture’s spatial distribution information management, routine maintenance and special conservation & restoration, the evaluation and simulation of related disasters, such as earthquake. The research objects are ancient architectures in JIN-FEN area, which were first investigated by Sicheng LIANG and recorded in his work of “Chinese ancient architectures survey report”. The research objects, i.e. the ancient architectures in Jin-Fen area include those in Sicheng LIANG’s investigation, and further adjustments were made through authors’ on-site investigation and literature searching & collection. During this research process, the spatial distributing Geodatabase of research objects is established utilizing GIS. The BIM components library for ancient buildings is formed combining on-site investigation data and precedent classic works, such as “Yingzao Fashi”, a treatise on architectural methods in Song Dynasty, “Yongle Encyclopedia” and “Gongcheng Zuofa Zeli”, case collections of engineering practice, by the Ministry of Construction of Qing Dynasty. A building of Guangsheng temple in Hongtong county is selected as an example to elaborate the BIM model construction process based on the BIM components library for ancient buildings. Based on the foregoing work results of spatial distribution data, attribute data of features, 3D graphic information and parametric building information model, the information management system for ancient architectures in Jin-Fen Area, utilizing GIS&BIM technology, could be constructed to support the further research of seismic disaster analysis and seismic performance simulation.
Establishing an Appropriate Level of Detail (LoD) for a Building Information Model (BIM) - West Block, Parliament Hill, Ottawa, Canada

NASA Astrophysics Data System (ADS)

Fai, S.; Rafeiro, J.

2014-05-01

In 2011, Public Works and Government Services Canada (PWGSC) embarked on a comprehensive rehabilitation of the historically significant West Block of Canada's Parliament Hill. With over 17 thousand square meters of floor space, the West Block is one of the largest projects of its kind in the world. As part of the rehabilitation, PWGSC is working with the Carleton Immersive Media Studio (CIMS) to develop a building information model (BIM) that can serve as maintenance and life-cycle management tool once construction is completed. The scale and complexity of the model have presented many challenges. One of these challenges is determining appropriate levels of detail (LoD). While still a matter of debate in the development of international BIM standards, LoD is further complicated in the context of heritage buildings because we must reconcile the LoD of the BIM with that used in the documentation process (terrestrial laser scan and photogrammetric survey data). In this paper, we will discuss our work to date on establishing appropriate LoD within the West Block BIM that will best serve the end use. To facilitate this, we have developed a single parametric model for gothic pointed arches that can be used for over seventy-five unique window types present in the West Block. Using the AEC (CAN) BIM as a reference, we have developed a workflow to test each of these window types at three distinct levels of detail. We have found that the parametric Gothic arch significantly reduces the amount of time necessary to develop scenarios to test appropriate LoD.
Near-Infrared Polarimetry of the GG Tauri A Binary System

NASA Technical Reports Server (NTRS)

Itoh, Yoichi; Oasa, Yumiko; Kudo, Tomoyuki; Kusakabe, Nobuhiko; Hashimoto, Jun; Abe, Lyu; Brandner, Wolfgang; Brandt, Timothy D.; Carson, Joseph C.; Egner, Sebastian;

2014-01-01

A high angular resolution near-infrared image that shows the intensity of polarization for the GG Tau A binary system was obtained with the Subaru Telescope. The image shows a circumbinary disk scattering the light from the central binary. The azimuthal profile of the intensity of polarization for the circumbinary disk is roughly reproduced by a simple disk model with the Henyey-Greenstein phase function and the Rayleigh function, indicating there are small dust grains at the surface of the disk. Combined with a previous observation of the circumbinary disk, our image indicates that the gap structure in the circumbinary disk orbits counterclockwise, but material in the disk orbits clockwise. We propose that there is a shadow caused by material located between the central binary and the circumbinary disk. The separations and position angles of the stellar components of the binary in the past 20 yr are consistent with the binary orbit with a = 33.4 AU and e = 0.34.

Integrating and Managing Bim in GIS, Software Review

NASA Astrophysics Data System (ADS)

El Meouche, R.; Rezoug, M.; Hijazi, I.

2013-08-01

Since the advent of Computer-Aided Design (CAD) and Geographical Information System (GIS) tools, project participants have been increasingly leveraging these tools throughout the different phases of a civil infrastructure project. In recent years the number of GIS software that provides tools to enable the integration of Building information in geo context has risen sharply. More and more GIS software are added tools for this purposes and other software projects are regularly extending these tools. However, each software has its different strength and weakness and its purpose of use. This paper provides a thorough review to investigate the software capabilities and clarify its purpose. For this study, Autodesk Revit 2012 i.e. BIM editor software was used to create BIMs. In the first step, three building models were created, the resulted models were converted to BIM format and then the software was used to integrate it. For the evaluation of the software, general characteristics was studied such as the user interface, what formats are supported (import/export), and the way building information are imported.
Automatic building information model query generation

DOE PAGES

Jiang, Yufei; Yu, Nan; Ming, Jiang; ...

2015-12-01

Energy efficient building design and construction calls for extensive collaboration between different subfields of the Architecture, Engineering and Construction (AEC) community. Performing building design and construction engineering raises challenges on data integration and software interoperability. Using Building Information Modeling (BIM) data hub to host and integrate building models is a promising solution to address those challenges, which can ease building design information management. However, the partial model query mechanism of current BIM data hub collaboration model has several limitations, which prevents designers and engineers to take advantage of BIM. To address this problem, we propose a general and effective approachmore » to generate query code based on a Model View Definition (MVD). This approach is demonstrated through a software prototype called QueryGenerator. In conclusion, by demonstrating a case study using multi-zone air flow analysis, we show how our approach and tool can help domain experts to use BIM to drive building design with less labour and lower overhead cost.« less
Bisindoylmaleimide I suppresses adipocyte differentiation through stabilization of intracellular {beta}-catenin protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Munju; Park, Seoyoung; Gwak, Jungsug

2008-02-29

The Wnt/{beta}-catenin signaling pathway plays important roles in cell differentiation. Activation of this pathway, likely by Wnt-10b, has been shown to inhibit adipogenesis in cultured 3T3-L1 preadipocytes and mice. Here we revealed that bisindoylmaleimide I (BIM), which is widely used as a specific inhibitor of protein kinase C (PKC), inhibits adipocyte differentiation through activation of the Wnt/{beta}-catenin signaling pathway. BIM increased {beta}-catenin responsive transcription (CRT) and up-regulated intracellular {beta}-catenin levels in HEK293 cells and 3T3-L1 preadipocytes. BIM significantly decreased intracellular lipid accumulation and reduced expression of important adipocyte marker genes including peroxisome-proliferator-activated receptor {gamma} (PPAR{gamma}) and CAATT enhancer-binding protein {alpha}more » (C/EBP{alpha}) in 3T3-L1 preadipocytes. Taken together, our findings indicate that BIM inhibits adipogenesis by increasing the stability of {beta}-catenin protein in 3T3-L1 preadipocyte cells.« less
Report on the bilateral comparison between BIM (Bulgaria) and VSL (The Netherlands)

NASA Astrophysics Data System (ADS)

Dekker, Paul; Kunova, Angela; Dierikx, Erik

2017-01-01

A bilateral comparison has been organized between VSL, The Netherlands and BIM, Bulgaria in the field of spectral regular transmittance measurements. This comparison is registered as EURAMET project nr. 1073 and EURAMET.PR-K6.2 in the BIPM key comparison database. The aim of the comparison is to demonstrate the improvement of calibration measurement capabilities of BIM in this working field. If this comparison is successful, i.e. the results support the claimed improvement in uncertainties, the improved CMC's for BIM will be included in Appendix C of the CIPM mutual recognition arrangement (MRA). The results of this comparison are linked to key comparison CCPR K6. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCPR, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

PubMed Central

Lee, Y Y; Moujalled, D; Doerflinger, M; Gangoda, L; Weston, R; Rahimi, A; de Alboran, I; Herold, M; Bouillet, P; Xu, Q; Gao, X; Du, X-J; Puthalakath, H

2013-01-01

Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. PMID:23579242
Automatic building information model query generation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Yufei; Yu, Nan; Ming, Jiang

Energy efficient building design and construction calls for extensive collaboration between different subfields of the Architecture, Engineering and Construction (AEC) community. Performing building design and construction engineering raises challenges on data integration and software interoperability. Using Building Information Modeling (BIM) data hub to host and integrate building models is a promising solution to address those challenges, which can ease building design information management. However, the partial model query mechanism of current BIM data hub collaboration model has several limitations, which prevents designers and engineers to take advantage of BIM. To address this problem, we propose a general and effective approachmore » to generate query code based on a Model View Definition (MVD). This approach is demonstrated through a software prototype called QueryGenerator. In conclusion, by demonstrating a case study using multi-zone air flow analysis, we show how our approach and tool can help domain experts to use BIM to drive building design with less labour and lower overhead cost.« less
The combined use of Building Information Modelling (BIM) and Unmanned Aerial Vehicle (UAV) technologies for the 3D illustration of the progress of works in infrastructure construction projects

NASA Astrophysics Data System (ADS)

Vacanas, Yiannis; Themistocleous, Kyriacos; Agapiou, Athos; Hadjimitsis, Diofantos

2016-08-01

Building Information Modelling (BIM) technology is already part of the construction industry and is considered by professionals as a very useful tool for all phases of a construction project. BIM technology, with the particularly useful 3D illustrations which it provides, can be used to illustrate and monitor the progress of works effectively through the entire lifetime of the project. Unmanned Aerial Vehicles (UAVs) have undergone significant advances in equipment capabilities and now have the capacity to acquire high resolution imagery from different angles in a cost effective and efficient manner. By using photogrammetry, characteristics such as distances, areas, volumes, elevations, object sizes, and object shape can be determined within overlapping areas. This paper explores the combined use of BIM and UAV technologies in order to achieve efficient and accurate as-built data collection and 3D illustrations of the works progress during an infrastructure construction project.
Applying Bim to Built Heritage with Complex Shapes: the Ice House of Filarete's Ospedale Maggiore in Milan, Italy

NASA Astrophysics Data System (ADS)

Oreni, D.; Karimi, G.; Barazzetti, L.

2017-08-01

This paper presents the development of a BIM model for a stratified historic structure characterized by a complex geometry: Filarete's Ospedale Maggiore ice house, one of the few remaining historic ice houses in Milan (Fig. 1). Filarete, a well-known Renaissance architect and theorist, planned the hospital in the 15th century, but the ice house was built two centuries later with a double-storey irregular octagonal brick structure, half under and half above ground, that enclosed another circular structure called the ice room. The purpose of the double-walled structure was to store ice in the middle and store and preserve perishable food and medicine at the outer side of the ice room. During World War II, major portions of the hospital and the above-ground section of the ice house was bombed and heavily damaged. Later, in 1962, the hospital was restored and rehabilitated into a university, with the plan to conceal the ice house's remaining structure in the courtyard, which ultimately was excavated and incorporated into a new library for the university. A team of engineers, architects, and students from Politecnico di Milano and Carleton University conducted two heritage recording surveys in 2015 and 2016 to fully document the existing condition of the ice house, resulting in an inclusive laser scanner and photogrammetric point cloud dataset. The point cloud data was consolidated and imported into two leading parametric modelling software, Autodesk Revitand Graphisoft ArchiCAD©, with the goal to develop two BIMs in parallel in order to study and compare the software BIM workflow, parametric capabilities, attributes to capture the complex geometry with high accuracy, and the duration for parametric modelling. The comparison study of the two software revealed their workflow limitations, leading to integration of the BIM generative process with other pure modelling software such as Rhinoceros©. The integrative BIM process led to the production of a comprehensive BIM model that documented related historic data and the existing physical state of the ice house, to be used as a baseline for preventive maintenance, monitoring, and future conservation projects.

EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys27 acetylation in the BIM gene promoter and enhancers.

PubMed

Huang, Julia P; Ling, Kun

2017-11-01

Enhancer of zeste homolog 2 (EZH2), a subunit of polycomb repressive complex 2, is a histone methyl-transferase and is considered to work cooperatively with histone deacetylases (HDACs) in the same protein complex to mediate gene transcription repression by increasing histone H3 Lys 27 trimethylation (H3K27me3), in particular in the nucleosome (s). EZH2 is overexpressed in numerous types of cancer, including triple negative breast cancer (TNBC), a subtype of breast cancer, which there are no effective treatment options for. Thus, inhibition of EZH2 may be harnessed for targeted therapy of this disease. The present study demonstrated that co-treatment with an EZH2 inhibitor and a HDAC inhibitor additively induced apoptosis in two TNBC cell lines, namely MDA-MB-231 and MDA-MB-436. The increased rate of cell death was associated with an elevation of B cell lymphoma-2 like 11 (BIM) expression level, a pro-apoptotic protein at the protein and mRNA expression levels in these two cell lines. The expression of forkhead box O1 (FOXO1), a known upstream transcriptional activator of BIM , was upregulated in both cell lines by the HDAC inhibitor, and the effect was more pronounced in MDA-MB-436 cells with higher phosphorylation levels of protein kinase B, a negative regulator of FOXO1, compared with MDA-MB-231 cells. Conversely, FOXO1 expression was inhibited following treatment with the EZH2 inhibitor, suggesting that EZH2 and HDAC inhibitors induced BIM expression via a FOXO1-independent mechanism. The present study further revealed that the EZH2 inhibitor, but not the HDAC inhibitor, induced high levels of H3K27 acetylation (H3K27ac) in the BIM promoter. By contrast, compared with the effect of the EZH2 inhibitor, HDAC inhibitor treatment resulted in an increase in H3K27ac at two BIM enhancers. Collectively, the results of the present study indicated that EZH2 and HDACs act differentially on H3K27ac levels in the nucleosome at the promoter and enhancer regions of the BIM gene. Through the upregulation of BIM, co-treatment with EZH2 and HDAC inhibitors had a pronounced therapeutic effect on TNBC cells, suggesting that co-targeting EZH2 and HDAC proteins represents a viable therapeutic option for the treatment of TNBC.
Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim.

PubMed

Wang, Wei; Zhou, Pang-Hu; Hu, Wei

2016-03-01

Forkhead box O4 (FOXO4) has been reported to be a novel tumor suppressor gene in gastrointestinal cancers; however, its role in clear‑cell renal carcinoma cells (ccRCC) has remained largely elusive. The present study assessed the expression levels of FOXO4 in RCC tissues and cells. Furthermore, the effects of vector‑mediated overexpression of FOXO4 on the apoptotic rate of the 786‑0 and Caki‑1 cell lines and the role of Bim in this process were investigated. The results demonstrated that the protein and mRNA expression levels of FOXO4 were decreased in renal cancer tissues and cell lines compared with those in normal tissues and cell lines. FOXO4 overexpression significantly increased the apoptotic rate of ccRCC cells in vitro, along with increased protein expression levels of Bim, cleaved‑caspase 3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and cytochrome c, as well as a decrease in Bcl‑2 expression. Of note, the apoptotic effects of FOXO4 overexpression in 786‑0 cells were inhibited by small interfering RNA‑mediated knockdown of Bim. The results of the present study indicated that FOXO4 has an inhibitory effect in ccRCC, at least in part through inducing apoptosis via upregulation of Bim in the mitochondria-dependent pathway.
Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells.

PubMed

Fujiwara, Daichiro; Tsubaki, Masanobu; Takeda, Tomoya; Tomonari, Yoshika; Koumoto, Yu-Ichi; Sakaguchi, Katsuhiko; Nishida, Shozo

2017-10-01

Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
BIM determines the number of merocytic dendritic cells, a cell type that breaks immune tolerance.

PubMed

Audiger, Cindy; Lesage, Sylvie

2018-05-13

In contrast to conventional dendritic cells (cDC), when merocytic dendritic cells (mcDC) present antigens derived from apoptotic bodies, T-cell anergy is reversed rather than induced, a process that promotes autoimmunity. Interestingly, mcDC are present in higher proportion in type 1 diabetes-prone NOD mice than in autoimmune-resistant B6 and BALB/c mice, and the Insulin-dependent diabetes (Idd)13 locus is linked to mcDC proportion. Therefore, mcDC are notably associated with susceptibility to autoimmune diabetes. To identify which gene determines the proportion and absolute number of mcDC, we undertook a candidate gene approach by selecting relevant candidates within the Idd13 locus. We find that neither β2m nor Sirpa appear to influence the proportion of mcDC. Instead, we show that Bim effectively modulates mcDC number in a hematopoietic-intrinsic manner. We also demonstrate that Bim-deficiency does not impact other cDC subsets and appears to play a specific role in determining the proportion and absolute number of mcDC by promoting their survival. Together, these data demonstrate that Bim specifically modulates the number of mcDC. Identifying factors that facilitate apoptosis of mcDC by increasing BIM activity in a cell type-specific manner may help prevent autoimmunity. © 2018 Australasian Society for Immunology Inc.
Bcl-2-interacting mediator of cell death influences autoantigen-driven deletion and TCR revision.

PubMed

Hale, J Scott; Nelson, Lisa T; Simmons, Kalynn B; Fink, Pamela J

2011-01-15

Peripheral CD4(+)Vβ5(+) T cells are tolerized to an endogenous mouse mammary tumor virus superantigen either by deletion or TCR revision. Through TCR revision, RAG reexpression mediates extrathymic TCRβ rearrangement and results in a population of postrevision CD4(+)Vβ5(-) T cells expressing revised TCRβ chains. We have hypothesized that cell death pathways regulate the selection of cells undergoing TCR revision to ensure the safety and utility of the postrevision population. In this study, we investigate the role of Bcl-2-interacting mediator of cell death (Bim)-mediated cell death in autoantigen-driven deletion and TCR revision. Bim deficiency and Bcl-2 overexpression in Vβ5 transgenic (Tg) mice both impair peripheral deletion. Vβ5 Tg Bim-deficient and Bcl-2 Tg mice exhibit an elevated frequency of CD4(+) T cells expressing both the transgene-encoded Vβ5 chain and a revised TCRβ chain. We now show that these dual-TCR-expressing cells are TCR revision intermediates and that the population of RAG-expressing, revising CD4(+) T cells is increased in Bim-deficient Vβ5 Tg mice. These findings support a role for Bim and Bcl-2 in regulating the balance of survival versus apoptosis in peripheral T cells undergoing RAG-dependent TCR rearrangements during TCR revision, thereby ensuring the utility of the postrevision repertoire.
High order solution of Poisson problems with piecewise constant coefficients and interface jumps

NASA Astrophysics Data System (ADS)

Marques, Alexandre Noll; Nave, Jean-Christophe; Rosales, Rodolfo Ruben

2017-04-01

We present a fast and accurate algorithm to solve Poisson problems in complex geometries, using regular Cartesian grids. We consider a variety of configurations, including Poisson problems with interfaces across which the solution is discontinuous (of the type arising in multi-fluid flows). The algorithm is based on a combination of the Correction Function Method (CFM) and Boundary Integral Methods (BIM). Interface and boundary conditions can be treated in a fast and accurate manner using boundary integral equations, and the associated BIM. Unfortunately, BIM can be costly when the solution is needed everywhere in a grid, e.g. fluid flow problems. We use the CFM to circumvent this issue. The solution from the BIM is used to rewrite the problem as a series of Poisson problems in rectangular domains-which requires the BIM solution at interfaces/boundaries only. These Poisson problems involve discontinuities at interfaces, of the type that the CFM can handle. Hence we use the CFM to solve them (to high order of accuracy) with finite differences and a Fast Fourier Transform based fast Poisson solver. We present 2-D examples of the algorithm applied to Poisson problems involving complex geometries, including cases in which the solution is discontinuous. We show that the algorithm produces solutions that converge with either 3rd or 4th order of accuracy, depending on the type of boundary condition and solution discontinuity.
Targeting Redox Homeostasis in LKB1-deficient NSCLC

DTIC Science & Technology

2014-09-01

induction of BH3-only BIM protein or activation of caspase 3 (19, 20). In these studies, erlotinib treatment was associated with loss of mitochondrial...Cai D, Shapiro GI, et al. Proapoptotic BH3- Only BCL-2 Family Protein BIM Connects Death Signaling from Epidermal Growth Factor Receptor Inhibition
Evaluating The Impact Of Building Information Modeling (BIM) On Construction

DTIC Science & Technology

2009-01-01

and interrelated processes. The flowchart in Figure 4-26 shows a visual interpretation of the Project Delivery Process Map. Figure 4-26. PMBP...they participated in training that was not effective at the beginning of LRL’s BIM initiative. The beginner courses provided by Bentley proved to be
AN EXPLORATORY STUDY OF PREDICTORS OF PHYSICIAN PERFORMANCE.

ERIC Educational Resources Information Center

JACOBSEN, TONY L.; AND OTHERS

AN ATTEMPT WAS MADE TO DETERMINE THE PREDICTIVE ACCURACY OF THREE MEDICAL SCHOOL SELECTION DEVICES--PREMEDICAL GRADES, THE MEDICAL COLLEGE ADMISSION TEST (MCAT), AND THE BIOGRAPHICAL INVENTORY FOR MEDICINE (BIM). THE BIM REPRESENTS A NEWLY DEVISED SELECTION INSTRUMENT FOR THE MEDICAL SCHOOL. IN THE STUDY, EACH INSTRUMENT WAS VALIDATED AGAINST…
BIM in the Facility Manager's Toolkit

ERIC Educational Resources Information Center

Peglow, Timothy M.

2010-01-01

There has been a tremendous increase in use of Building Information Modeling (BIM) in the design and construction industry. There have been numerous case studies that have documented the improvements. The majority of these improvements have focused on better coordination of design resulting in fewer Requests for Information and/or change orders.…
Fabrication and Testing of Binary-Phase Fourier Gratings for Nonuniform Array Generation

NASA Technical Reports Server (NTRS)

Keys, Andrew S.; Crow, Robert W.; Ashley, Paul R.; Nelson, Tom R., Jr.; Parker, Jack H.; Beecher, Elizabeth A.

2004-01-01

This effort describes the fabrication and testing of binary-phase Fourier gratings designed to generate an incoherent array of output source points with nonuniform user-defined intensities, symmetric about the zeroth order. Like Dammann fanout gratings, these binary-phase Fourier gratings employ only two phase levels to generate a defined output array. Unlike Dammann fanout gratings, these gratings generate an array of nonuniform, user-defined intensities when projected into the far-field regime. The paper describes the process of design, fabrication, and testing for two different version of the binary-phase grating; one designed for a 12 micron wavelength, referred to as the Long-Wavelength Infrared (LWIR) grating, and one designed for a 5 micron wavelength, referred to as the Mid-Wavelength Infrared Grating (MWIR).
Coordination between Understanding Historic Buildings and BIM Modelling: A 3D-Output Oriented and typological Data Capture Method

NASA Astrophysics Data System (ADS)

Li, K.; Li, S. J.; Liu, Y.; Wang, W.; Wu, C.

2015-08-01

At the present, in trend of shifting the old 2D-output oriented survey to a new 3D-output oriented survey based on BIM technology, the corresponding working methods and workflow for data capture, process, representation, etc. have to be changed.Based on case study of two buildings in the Summer Palace of Beijing, and Jiayuguan Pass at the west end of the Great Wall (both World Heritage sites), this paper puts forward a "structure-and-type method" by means of typological method used in archaeology, Revit family system, and the tectonic logic of building to realize a good coordination between understanding of historic buildings and BIM modelling.
BIM Methodology Approach to Infrastructure Design: Case Study of Paniga Tunnel

NASA Astrophysics Data System (ADS)

Osello, Anna; Rapetti, Niccolò; Semeraro, Francesco

2017-10-01

Nowadays, the implementation of Building Information Modelling (BIM) in civil design represent a new challenge for the AECO (Architecture, Engineering, Construction, Owner and Operator) world, which will involve the interest of many researchers in the next years. It is due to the incentives of Public Administration and European Directives that aim to improve the efficiency and to enhance a better management of the complexity of infrastructure projects. For these reasons, the goal of this research is to propose a methodology for the use of BIM in a tunnel project, analysing the definition of a correct level of detail (LOD) and the possibility to share information via interoperability for FEM analysis.
Mode-locking in advection-reaction-diffusion systems: An invariant manifold perspective

NASA Astrophysics Data System (ADS)

Locke, Rory A.; Mahoney, John R.; Mitchell, Kevin A.

2018-01-01

Fronts propagating in two-dimensional advection-reaction-diffusion systems exhibit a rich topological structure. When the underlying fluid flow is periodic in space and time, the reaction front can lock to the driving frequency. We explain this mode-locking phenomenon using the so-called burning invariant manifolds (BIMs). In fact, the mode-locked profile is delineated by a BIM attached to a relative periodic orbit (RPO) of the front element dynamics. Changes in the type (and loss) of mode-locking can be understood in terms of local and global bifurcations of the RPOs and their BIMs. We illustrate these concepts numerically using a chain of alternating vortices in a channel geometry.
The Barriers and Causes of Building Information Modelling Usage for Interior Design Industry

NASA Astrophysics Data System (ADS)

Hamid, A. B. Abd; Taib, M. Z. Mohd; Razak, A. H. N. Abdul; Embi, M. R.

2017-12-01

Building Information Modeling (BIM) has since developed alongside the improvement in the construction industry, purposely to simulate the design, management, construction and documentation. It facilitates and monitors the construction through visualization and emphasizes on various inputs to virtually design and construct a building using specific software. This study aims to identify and elaborate barriers of BIM usage in interior design industry in Malaysia. This study is initiated with a pilot survey utilising sixteen respondents that has been randomly chosen. Respondents are attached with interior design firms that are registered by Lembaga Arkitek Malaysia (LAM). The research findings are expected to provide significant information to encourage BIM adoption among interior design firms.
Integration of Bim, Web Maps and Iot for Supporting Comfort Analysis

NASA Astrophysics Data System (ADS)

Gunduz, M.; Isikdag, U.; Basaraner, M.

2017-11-01

The use of the Internet is expanding and the technological capabilities of electronic devices are evolving. Today, Internet of Things (IoT) solutions can be developed that were never even imaginable before. In this paper, a case study is presented on the joint use of Building Information Model (BIM), Geographical Information Systems (GIS) and Internet of Things (IoT) technologies. It is a part of an ongoing study that intends to overcome some problems about the management of complex facilities. In the study, a BIM has been converted and displayed in 2D on Google Maps, and information on various sensors have been represented on the web with geographic coordinates in real-time.
REACH: study protocol of a randomised trial of rehabilitation very early in congenital hemiplegia

PubMed Central

Boyd, Roslyn N; Ziviani, Jenny; Sakzewski, Leanne; Novak, Iona; Badawi, Nadia; Pannek, Kerstin; Elliott, Catherine; Greaves, Susan; Guzzetta, Andrea; Whittingham, Koa; Valentine, Jane; Morgan, Cathy; Wallen, Margaret; Eliasson, Ann-Christin; Findlay, Lisa; Ware, Robert; Fiori, Simona; Rose, Stephen

2017-01-01

Objectives Congenital hemiplegia is the most common form of cerebral palsy (CP). Children with unilateral CP show signs of upper limb asymmetry by 8 months corrected age (ca) but are frequently not referred to therapy until after 12 months ca. This study compares the efficacy of infant-friendly modified constraint-induced movement therapy (Baby mCIMT) to infant friendly bimanual therapy (Baby BIM) on upper limb, cognitive and neuroplasticity outcomes in a multisite randomised comparison trial. Methods and analysis 150 infants (75 in each group), aged between 3 and 6 months ca, with asymmetric brain injury and clinical signs of upper extremity asymmetry will be recruited. Children will be randomised centrally to receive equal doses of either Baby mCIMT or Baby BIM. Baby mCIMT comprises restraint of the unimpaired hand using a simple restraint (eg, glove, sock), combined with intensive parent implemented practice focusing on active use of the impaired hand in a play-based context. In contrast, Baby BIM promotes active play requiring both hands in a play-based context. Both interventions will be delivered by parents at home with monthly home visits and interim telecommunication support by study therapists. Assessments will be conducted at study entry; at 6, 12 months ca immediately postintervention (primary outcome) and 24 months ca (retention). The primary outcome will be the Mini-Assisting Hand Assessment. Secondary outcomes include the Bayley Scale for Infant and Toddler Development (cognitive and motor domains) and the Hand Assessment of Infants. A subset of children will undertake MRI scans at 24 months ca to evaluate brain lesion severity and brain (re)organisation after intervention. Ethics and dissemination Full ethical approvals for this study have been obtained from the relevant sites. The findings will be disseminated in peer-reviewed publications. Trial registration number Australian and New Zealand Clinical Trials Registry: ACTRN12615000180516, Pre results. PMID:28928195
Low-temperature vibrational dynamics of fused silica and binary silicate glasses

NASA Astrophysics Data System (ADS)

Cai, Ling; Shi, Ying; Hrdina, Ken; Moore, Lisa; Wu, Jingshi; Daemen, Luke L.; Cheng, Yongqiang

2018-02-01

Inelastic neutron scattering was used to study the vibrational dynamics of fused silica and its mixed binary glasses that were doped with either TiO2 or K2O . The energy transfer was measured from zero to 180 meV where the so-called Boson peaks (BP) at low energy and molecular vibrations at high energy are included. Although most of the vibrational spectra at the high energy resemble those reported in earlier literature, a defect-mode-like peak is observed for the doped binary systems near 120 meV . At very low temperature, the BP intensity increases rapidly with temperature and then, at higher temperature, the peak intensity decreases. As a result, a maximum is observed in the temperature dependence of the BP intensity. This maximum was shown in all four samples, but the pure SiO2 sample shows the highest intensity peak and the lowest temperature for peak position. Broadband energy spectra reveal a shift of intensity from BP to the more localized modes at higher energy. Temperature evolution of BP and its relationship with heat conduction and thermal expansion are discussed.
Interactive BIM-Enabled Safety Training Piloted in Construction Education

ERIC Educational Resources Information Center

Clevenger, Caroline; Lopez del Puerto, Carla; Glick, Scott

2015-01-01

This paper documents and assesses the development of a construction safety training module featuring interactive, BIM-enabled, 3D visualizations to test if such a tool can enhance safety training related to scaffolds. This research documents the technical challenges and the lessons learned through the development and administration of a prototype…
Students' Perceptions of BIM Education in the Higher Education Sector: A UK and US Perspective

ERIC Educational Resources Information Center

Shelbourn, M.; Macdonald, J.; McCuen, T.; Lee, S.

2017-01-01

The use of building information modelling (BIM) has increased in the global architecture, engineering, construction and owner-operated (AECO) industries. This increased use has contributed to a recognition by project stakeholders of its importance across the building life cycle, leading higher education institutions to rethink their AECO…

Archive of digital chirp subbottom profile data collected during USGS cruises 13BIM02 and 13BIM07 offshore of the Chandeleur Islands, Louisiana, 2013

USGS Publications Warehouse

Forde, Arnell S.; Miselis, Jennifer L.; Flocks, James G.; Bernier, Julie C.; Wiese, Dana S.

2014-01-01

On July 5–19 (cruise 13BIM02) and August 22–September 1 (cruise 13BIM07), 2013, the U.S. Geological Survey (USGS) conducted geophysical surveys to investigate the geologic controls on barrier island evolution and medium-term and interannual sediment transport along the oil spill mitigation sand berm constructed at the north end and offshore of the Chandeleur Islands, Louisiana. This investigation is part of a broader USGS study, which seeks to understand barrier island evolution better over medium time scales (months to years). This report serves as an archive of unprocessed digital chirp subbottom data, trackline maps, navigation files, Geographic Information System (GIS) files, Field Activity Collection System (FACS) logs, and formal Federal Geographic Data Committee (FGDC) metadata. Gained–showing a relative increase in signal amplitude–digital images of the seismic profiles are provided. Refer to the Abbreviations page for explanations of acronyms and abbreviations used in this report.
APCCdc20 Suppresses Apoptosis through Targeting Bim for Ubiquitination and Destruction

PubMed Central

Wan, Lixin; Tan, Mingjia; Yang, Jie; Inuzuka, Hiroyuki; Dai, Xiangpeng; Wu, Tao; Liu, Jia; Shaik, Shavali; Chen, Guoan; Deng, Jing; Malumbres, Marcos; Letai, Anthony; Kirschner, Marc W.; Sun, Yi; Wei, Wenyi

2014-01-01

SUMMARY APCCdc20 plays pivotal roles in governing mitotic progression. By suppressing APCCdc20, anti-mitotic agents activate the spindle-assembly-checkpoint (SAC), and induce apoptosis after prolonged-treatment, while depletion of endogenous Cdc20 suppresses in vivo tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here we report that the BH3-only pro-apoptotic protein Bim is an APCCdc20 target, as such depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in an siRNA screen that upon knockdown sensitizes otherwise resistant cancer cells to chemo-radiation therapies in a Bim-dependent manner. Consistently, human Adult-T-cell-Leukemia (ATL) cells that acquire elevated APCCdc20 activity via expressing the Tax-viral-oncoprotein, exhibit reduced Bim levels and resistance to anti-cancer agents. These results reveal an important role for APCCdc20 in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anti-cancer agents. PMID:24871945
Parametric Modelling of As-Built Beam Framed Structure in Bim Environment

NASA Astrophysics Data System (ADS)

Yang, X.; Koehl, M.; Grussenmeyer, P.

2017-02-01

A complete documentation and conservation of a historic timber roof requires the integration of geometry modelling, attributional and dynamic information management and results of structural analysis. Recently developed as-built Building Information Modelling (BIM) technique has the potential to provide a uniform platform, which provides possibility to integrate the traditional geometry modelling, parametric elements management and structural analysis together. The main objective of the project presented in this paper is to develop a parametric modelling tool for a timber roof structure whose elements are leaning and crossing beam frame. Since Autodesk Revit, as the typical BIM software, provides the platform for parametric modelling and information management, an API plugin, able to automatically create the parametric beam elements and link them together with strict relationship, was developed. The plugin under development is introduced in the paper, which can obtain the parametric beam model via Autodesk Revit API from total station points and terrestrial laser scanning data. The results show the potential of automatizing the parametric modelling by interactive API development in BIM environment. It also integrates the separate data processing and different platforms into the uniform Revit software.
Milk β-casein as a vehicle for delivery of bis(indolyl)methane: Spectroscopy and molecular docking studies

NASA Astrophysics Data System (ADS)

Dezhampanah, Hamid; Esmaili, Masoomeh; Khorshidi, Alireza

2017-05-01

The interaction of bis(indolyl)methane with bovine milk β-casein was investigated using spectroscopy and molecular docking studies at different temperatures (25-37 °C). The circular dichroism and Fourier transform infrared spectroscopic data demonstrated that β-casein interacts with BIM molecule mainly via both the hydrophobic and hydrophilic interactions with a minor change in the secondary structure of β-casein. The fluorescence quenching measurements revealed that the presence of a single binding site on β-casein for BIM with the binding constant value of ∼104 M-1. The negative values of entropy and enthalpy changes confirm the predominate role of hydrogen binding and van der Waals interactions in the binding process. Fӧrster energy transfer measurement suggested that the distance between bound BIM and Trp residue is higher than the respective critical distance. Hence, the static quenching is more likely responsible for the fluorescence quenching rather than the mechanism of non-radiative. Docking study showed that BIM molecule forms three hydrogen bonds and several van der Waals contacts with β-casein.
BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues.

PubMed

Muthalagu, Nathiya; Junttila, Melissa R; Wiese, Katrin E; Wolf, Elmar; Morton, Jennifer; Bauer, Barbara; Evan, Gerard I; Eilers, Martin; Murphy, Daniel J

2014-09-11

MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC's oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Utilization of BIM for automation of quantity takeoffs and cost estimation in transport infrastructure construction projects in the Czech Republic

NASA Astrophysics Data System (ADS)

Vitásek, Stanislav; Matějka, Petr

2017-09-01

The article deals with problematic parts of automated processing of quantity takeoff (QTO) from data generated in BIM model. It focuses on models of road constructions, and uses volumes and dimensions of excavation work to create an estimate of construction costs. The article uses a case study and explorative methods to discuss possibilities and problems of data transfer from a model to a price system of construction production when such transfer is used for price estimates of construction works. Current QTOs and price tenders are made with 2D documents. This process is becoming obsolete because more modern tools can be used. The BIM phenomenon enables partial automation in processing volumes and dimensions of construction units and matching the data to units in a given price scheme. Therefore price of construction can be estimated and structured without lengthy and often imprecise manual calculations. The use of BIM for QTO is highly dependent on local market budgeting systems, therefore proper push/pull strategy is required. It also requires proper requirements specification, compatible pricing database and software.
From structure from motion to historical building information modeling: populating a semantic-aware library of architectural elements

NASA Astrophysics Data System (ADS)

Santagati, Cettina; Lo Turco, Massimiliano

2017-01-01

In recent years, we have witnessed a huge diffusion of building information modeling (BIM) approaches in the field of architectural design, although very little research has been undertaken to explore the value, criticalities, and advantages attributable to the application of these methodologies in the cultural heritage domain. Furthermore, the last developments in digital photogrammetry lead to the easy generation of reliable low-cost three-dimensional textured models that could be used in BIM platforms to create semantic-aware objects that could compose a specific library of historical architectural elements. In this case, the transfer between the point cloud and its corresponding parametric model is not so trivial and the level of geometrical abstraction could not be suitable with the scope of the BIM. The aim of this paper is to explore and retrace the milestone works on this crucial topic in order to identify the unsolved issues and to propose and test a unique and simple workflow practitioner centered and based on the use of the latest available solutions for point cloud managing into commercial BIM platforms.
Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy.

PubMed

Miyamura, Koichi; Miyamoto, Toshihiro; Tanimoto, Mitsune; Yamamoto, Kazuhito; Kimura, Shinya; Kawaguchi, Tatsuya; Matsumura, Itaru; Hata, Tomoko; Tsurumi, Hisashi; Saito, Shigeki; Hino, Masayuki; Tadokoro, Seiji; Meguro, Kuniaki; Hyodo, Hideo; Yamamoto, Masahide; Kubo, Kohmei; Tsukada, Junichi; Kondo, Midori; Aoki, Makoto; Okada, Hikaru; Yanada, Masamitsu; Ohyashiki, Kazuma; Taniwaki, Masafumi

2016-12-01

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition

PubMed Central

Bate-Eya, Laurel T.; den Hartog, Ilona J.M.; van der Ploeg, Ida; Schild, Linda; Koster, Jan; Santo, Evan E.; Westerhout, Ellen M.; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.; Dolman, M. Emmy M.

2016-01-01

The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression. PMID:27056887
Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events.

PubMed

Han, Jie; Goldstein, Leslie A; Gastman, Brian R; Froelich, Christopher J; Yin, Xiao-Ming; Rabinowich, Hannah

2004-05-21

Recent studies have suggested that in the absence of Bid, granzyme B (GrB) can utilize an unknown alternative pathway to mediate mitochondrial apoptotic events. The current study has elucidated just such a pathway for GrB-mediated mitochondrial apoptotic alterations. Two Bcl-2 family members have been identified as interactive players in this newly discovered mitochondrial response to GrB: the pro-survival protein Mcl-1L and the pro-apoptotic protein, Bim. Expression of Mcl-1L, which localizes mainly to the outer mitochondrial membrane, decreases significantly in cells subjected to CTL-free cytotoxicity mediated by a combination of GrB and replication-deficient adenovirus. The data suggest that Mcl-1L is a substrate for GrB and for caspase-3, but the two enzymes appear to target different cleavage sites. The cleavage pattern of endogenous Mcl-1L resembles that of in vitro translated Mcl-1L subjected to similar proteolytic activity. Co-immunoprecipitation experiments performed with endogenous as well as with in vitro translated proteins suggest that Mcl-1L is a high affinity binding partner of the three isoforms of Bim (extra-long, long, and short). Bim, a BH3-only protein, is capable of mediating the release of mitochondrial cytochrome c, and this activity is inhibited by the presence of exogenous Mcl-1L. The findings presented herein imply that Mcl-1L degradation by either GrB or caspase-3 interferes with Bim sequestration by Mcl-1L.
Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells.

PubMed

Luedtke, Daniel A; Niu, Xiaojia; Pan, Yihang; Zhao, Jianyun; Liu, Shuang; Edwards, Holly; Chen, Kang; Lin, Hai; Taub, Jeffrey W; Ge, Yubin

2017-01-01

Acute myeloid leukemia (AML) is a serious disease. The 5-year survival rates remain frustratingly low (65% for children and 26% for adults). Resistance to frontline chemotherapy (usually cytarabine) often develops; therefore a new treatment modality is needed. Bcl-2 family proteins play an important role in balancing cell survival and apoptosis. The antiapoptotic Bcl-2 family proteins have been found to be dysregulated in AML. ABT-199, a BH3 mimetic, was developed to target antiapoptotic protein Bcl-2. Although ABT-199 has demonstrated promising results, resistance occurs. Previous studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2, but this is compensated by increased association of Bim with prosurvival protein Mcl-1, stabilizing Mcl-1, resulting in resistance to ABT-199. In this study, we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML cells. We found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient samples. The synergistic induction of apoptosis was decreased upon Bak, Bax and Bim knockdown. While A-1210477 treatment alone also increased Mcl-1 protein levels, combination with ABT-199 reduced binding of Bim to Mcl-1. Our results demonstrate that sequestration of Bim by Mcl-1, a mechanism of ABT-199 resistance, can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477.
Metric Survey and Bim Technologies to Record Decay Conditions

NASA Astrophysics Data System (ADS)

Lo Turco, M.; Mattone, M.; Rinaudo, F.

2017-05-01

The paper proposes a method able to describe, classify and organize information assets concerned with Architectural Heritage, through the use of integrated survey procedures, mainly based on Terrestrial Laser Scanner (TLS). The point clouds are then imported into the Building Information Modeling (BIM) software to start with the modeling phase. With regard to this issue, in the last period Building Information Modeling is emerging as the most reliable method to manage architectural design and building processes. Literature supplies both theoretical approaches and several practical applications. However, very little researches are devoted to BIM applied to historical architecture, even if some initial results indicate the actual HBIM (Historic/Heritage BIM) as a possible instrument for the design of an intervention aimed at the conservation of the Cultural Heritage. The focus of the research is the creation of parametric objects representing the preservation status of materials and building components: 3D modeling of decays in the BIM platform ensures to enrich the related database with graphic, geometric and alphanumeric data that can be effectively used to design and manage future interventions. The added value consists in its capability to associate new parameters that describe both the state of conservation of the materials and the detailed description of interventions needed to restore the building. The analyzed case study belongs to Ferrovie dello Stato (the main Italian Railways company) and it is part of the maintenance area, which was originally constituted by a roundhouse containing 51 sheltered railroad tracks and two big sheds.
The Adapted Italian Version of the Baller Identity Measurement Scale to Evaluate the Student-Athletes' Identity in Relation to Gender, Age, Type of Sport, and Competition Level.

PubMed

Lupo, Corrado; Mosso, Cristina Onesta; Guidotti, Flavia; Cugliari, Giovanni; Pizzigalli, Luisa; Rainoldi, Alberto

2017-01-01

The purpose of this paper is twofold: to validate the properties of the Italian version of the Baller Identity Measurement Scale (i.e., BIMS-IT), a self-report questionnaire based on the athletic and academic identities; and to investigate differences in psychosocial factors such as gender, age, type of sport, and competition level. The dimensionality of the BIMS-IT was explored by means of the exploratory factor analysis, considering the scale's internal consistency too (Confirmatory Factor Analysis). Results related to exploratory and confirmatory factor analysis supported a model of measurement composed of two correlated factors: the athletic and academic identities and affectivity related to identities. For both factors, differences emerged between age, and competition level sub groups. In particular, higher identity scores emerged for ≤ 24 years old student-athletes with respect to their age counterparts. National sub-elite student-athletes reported lower identity values than those of national elite and international levels. Results suggest that the Italian version of the BIMS-IT is psychometrically robust and could be adopted for empirical uses. The higher identity scores reported by younger and higher competition level participants suggest a correspondent higher involvement into the student-athlete role. However, BIMS-IT represents a distinct model with respect to the original American BIMS, determining the need of further research on the student-athletes' identity to better clarify any socio-cultural contest effects.
The Adapted Italian Version of the Baller Identity Measurement Scale to Evaluate the Student-Athletes’ Identity in Relation to Gender, Age, Type of Sport, and Competition Level

PubMed Central

Cugliari, Giovanni; Pizzigalli, Luisa

2017-01-01

The purpose of this paper is twofold: to validate the properties of the Italian version of the Baller Identity Measurement Scale (i.e., BIMS-IT), a self-report questionnaire based on the athletic and academic identities; and to investigate differences in psychosocial factors such as gender, age, type of sport, and competition level. The dimensionality of the BIMS-IT was explored by means of the exploratory factor analysis, considering the scale’s internal consistency too (Confirmatory Factor Analysis). Results related to exploratory and confirmatory factor analysis supported a model of measurement composed of two correlated factors: the athletic and academic identities and affectivity related to identities. For both factors, differences emerged between age, and competition level sub groups. In particular, higher identity scores emerged for ≤ 24 years old student-athletes with respect to their age counterparts. National sub-elite student-athletes reported lower identity values than those of national elite and international levels. Results suggest that the Italian version of the BIMS-IT is psychometrically robust and could be adopted for empirical uses. The higher identity scores reported by younger and higher competition level participants suggest a correspondent higher involvement into the student-athlete role. However, BIMS-IT represents a distinct model with respect to the original American BIMS, determining the need of further research on the student-athletes’ identity to better clarify any socio-cultural contest effects. PMID:28056046
An estimation framework for building information modeling (BIM)-based demolition waste by type.

PubMed

Kim, Young-Chan; Hong, Won-Hwa; Park, Jae-Woo; Cha, Gi-Wook

2017-12-01

Most existing studies on demolition waste (DW) quantification do not have an official standard to estimate the amount and type of DW. Therefore, there are limitations in the existing literature for estimating DW with a consistent classification system. Building information modeling (BIM) is a technology that can generate and manage all the information required during the life cycle of a building, from design to demolition. Nevertheless, there has been a lack of research regarding its application to the demolition stage of a building. For an effective waste management plan, the estimation of the type and volume of DW should begin from the building design stage. However, the lack of tools hinders an early estimation. This study proposes a BIM-based framework that estimates DW in the early design stages, to achieve an effective and streamlined planning, processing, and management. Specifically, the input of construction materials in the Korean construction classification system and those in the BIM library were matched. Based on this matching integration, the estimates of DW by type were calculated by applying the weight/unit volume factors and the rates of DW volume change. To verify the framework, its operation was demonstrated by means of an actual BIM modeling and by comparing its results with those available in the literature. This study is expected to contribute not only to the estimation of DW at the building level, but also to the automated estimation of DW at the district level.
a Tool for Crowdsourced Building Information Modeling Through Low-Cost Range Camera: Preliminary Demonstration and Potential

NASA Astrophysics Data System (ADS)

Capocchiano, F.; Ravanelli, R.; Crespi, M.

2017-11-01

Within the construction sector, Building Information Models (BIMs) are more and more used thanks to the several benefits that they offer in the design of new buildings and the management of the existing ones. Frequently, however, BIMs are not available for already built constructions, but, at the same time, the range camera technology provides nowadays a cheap, intuitive and effective tool for automatically collecting the 3D geometry of indoor environments. It is thus essential to find new strategies, able to perform the first step of the scan to BIM process, by extracting the geometrical information contained in the 3D models that are so easily collected through the range cameras. In this work, a new algorithm to extract planimetries from the 3D models of rooms acquired by means of a range camera is therefore presented. The algorithm was tested on two rooms, characterized by different shapes and dimensions, whose 3D models were captured with the Occipital Structure SensorTM. The preliminary results are promising: the developed algorithm is able to model effectively the 2D shape of the investigated rooms, with an accuracy level comprised in the range of 5 - 10 cm. It can be potentially used by non-expert users in the first step of the BIM generation, when the building geometry is reconstructed, for collecting crowdsourced indoor information in the frame of BIMs Volunteered Geographic Information (VGI) generation.
Betulinic acid derivative B10 inhibits glioma cell proliferation through suppression of SIRT1, acetylation of FOXO3a and upregulation of Bim/PUMA.

PubMed

Huo, Longwei; Bai, Xiaobin; Wang, Yafei; Wang, Maode

2017-08-01

Glioma is the most common primary malignant tumor of the central nervous system. B10 is a new glycosylated derivative of betulinic acid with enhanced cytotoxic activity. The present study was designed to explore the molecular mechanism underlying the anticancer effect of B10 in glioma cells. 25-50μM B10 resulted in a significant decrease of cell viability and BrdU incorporation. 25-50mg/kg B10 significantly reduced the implanted tumor weight and volume in nude mice. Activation of apoptosis was found in glioma cells when the cells were exposed to B10, as evidenced by increased number of TUNEL-stained cells, increased caspase 3 and 9 activities, and Bax and cleaved PARP expression. B10 caused a significant decrease in mitochondrial oxygen consumption rate, mitochondrial complex I, II, III, IV, and V activities, and ATP level, and increase of mitochondrial ROS production, indicating the induction of mitochondrial dysfunction. B10 reduced the expression of sirtuin (SIRT) 1 and resulted in an increase in forkhead box O (FOXO) 3a expression and acetylation. Activation of SIRT1 by SRT-1720 and downregualtion of FOXO3a using shRNA significantly inhibited B10-induced cytotoxicity. B10 markedly increased the expression of Bim and PUMA. Downregualtion of FOXO3a or activation of SIRT1 significantly inhibited B10-induced increase of Bim and PUMA expression. Downregualtion of Bim or PUMA could suppress B10-induced increase of Bax expression. Moreover, B10-induced cytotoxicity was significantly suppressed by downregulation of Bim or PUMA. In summary, we identified B10 as a potent therapeutic candidate for glioma treatment and SIRT1-FOXO3a-Bim/PUMA axis as a novel therapeutic target. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation.

PubMed

Shi, Puyu; Oh, You-Take; Deng, Liang; Zhang, Guojing; Qian, Guoqing; Zhang, Shuo; Ren, Hui; Wu, Grant; Legendre, Benjamin; Anderson, Emily; Ramalingam, Suresh S; Owonikoko, Taofeek K; Chen, Mingwei; Sun, Shi-Yong

2017-11-01

Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567-79. ©2017 AACR . ©2017 American Association for Cancer Research.
Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice.

PubMed

Barbieri, Federica; Pattarozzi, Alessandra; Gatti, Monica; Aiello, Cinzia; Quintero, Ana; Lunardi, Gianluigi; Bajetto, Adriana; Ferrari, Angelo; Culler, Michael D; Florio, Tullio

2009-11-01

Somatostatin receptors (SSTR1-5) mediate antiproliferative effects. In C6 rat glioma cells, somatostatin is cytostatic in vitro via phosphotyrosine phosphatase-dependent inhibition of ERK1/2 activity mediated by SSTR1, -2, and -5. Here we analyzed the effects of SSTR activation on C6 glioma growth in vivo and the intracellular mechanisms involved, comparing somatostatin effects with selective agonists for SSTR1, -2, and -5 (BIM-23745, BIM-23120, BIM-23206) or receptor biselective compounds (SSTR1 and -2, BIM-23704; and SSTR2 and -5, BIM-23190). Nude mice subcutaneously xenografted with C6 cells were treated with somatostatin, SSTR agonists (50 μg, twice/day), or vehicle. Tumor growth was evaluated every 3 days for 19 days. The intracellular pathways responsible of SSTR effects in vivo were evaluated measuring Ki-67, phospho-ERK1/2, and p27(kip1) expression by immunohistochemistry in sections from explanted tumors. Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27(Kip1), whereas only a modest activation of caspase-3 was observed. Somatostatin (acting on SSTR1, -2, and -5) displayed the highest efficacy; SSTR5 selective agonist showed a stronger effect than SSTR1 agonist, and SSTR2 agonist was less effective. On the other hand, SSTR1 and -2 agonists maximally reduced tumor neovascularization. The combined activation of SSTR1 and -2 showed a synergistic activity, reaching a higher efficacy than BIM-23206, whereas the simultaneous activation of SSTR2 and -5 resulted in a response resembling SSTR5 effects. Thus the simultaneous activation of different SSTRs inhibits glioma cell proliferation in vivo through both direct cytotostatic and antiangiogenic effects.
Effects of miR-155 on proliferation and apoptosis by regulating FoxO3a/BIM in liver cancer cell line HCCLM3.

PubMed

Liao, W-W; Zhang, C; Liu, F-R; Wang, W-J

2018-03-01

MiR-155 has been shown to be up-regulated in hepatocellular carcinoma (HCC) patients. B-cell lymphoma-2 (Bcl-2) interacting mediator of cell death (BIM) regulates cell proliferation and apoptosis, as its down-regulation is involved in HCC onset. Transcriptional factor FoxO3a mediates BIM expression and is related to HCC pathogenesis. Bioinformatics analysis showed targeted regulation of FoxO3a by miR-155. This study aims to investigate whether miR-155 plays a role in mediating FoxO3a/BIM signal pathway and HCC occurrence. HCC patients were collected for tumor and adjacent tissues, in which microRNA-155 (miR-155) and FoxO3a expressions were examined. In vitro cultured HCCLM3, HepG2 and L-02 cells were tested for basal apoptotic rate by flow cytometry and were compared for miR-155 and FoxO3a expression. Dual-luciferase reporter gene assay demonstrated the targeted relationship between miR-155 and FoxO3a. HCCLM3 cells were treated with miR-155 inhibitor and/or FoxO3a-pMD18-T. Cell apoptosis and proliferation were examined by using flow cytometry and MTT assays, respectively. Western blot and spectrometry assay were employed to quantify the FoxO3a, BIM expressions, and caspase activity. Compared to adjacent tissues, HCC tissues had significantly higher miR-155 and significantly lower FoxO3a expression (p<0.05). HCCLM3 and HepG2 cells had significantly lower FoxO3a expression and basal apoptotic rate compared to L02 cells, whilst miR-155 level was significantly higher (p<0.05). MiR-155 targeted and inhibited 3'-UTR of FoxO3a, increasing BIM expression, caspase-3, and caspase-9 activities, and enhancing cell apoptosis and weakening proliferation. HCC tissues elevated the miR-155 and suppressed the FoxO3a expressions. MiR-155 targeted and inhibited FoxO3a expression to suppress the BIM, depress caspase-3 and caspase-9 activities, therefore inhibiting the HCC cell apoptosis and facilitating proliferation.

Sustainable Design Approach: A case study of BIM use

NASA Astrophysics Data System (ADS)

Abdelhameed, Wael

2017-11-01

Achieving sustainable design in areas such as energy-efficient design depends largely on the accuracy of the analysis performed after the design is completed with all its components and material details. There are different analysis approaches and methods that predict relevant values and metrics such as U value, energy use and energy savings. Although certain differences in the accuracy of these approaches and methods have been recorded, this research paper does not focus on such matter, where determining the reason for discrepancies between those approaches and methods is difficult, because all error sources act simultaneously. The research paper rather introduces an approach through which BIM, building information modelling, can be utilised during the initial phases of the designing process, by analysing the values and metrics of sustainable design before going into the design details of a building. Managing all of the project drawings in a single file, BIM -building information modelling- is well known as one digital platform that offers a multidisciplinary detailed design -AEC model (Barison and Santos, 2010, Welle et.al., 2011). The paper presents in general BIM use in the early phases of the design process, in order to achieve certain required areas of sustainable design. The paper proceeds to introduce BIM use in specific areas such as site selection, wind velocity and building orientation, in terms of reaching the farther possible sustainable solution. In the initial phases of designing, material details and building components are not fully specified or selected yet. The designer usually focuses on zoning, topology, circulations, and other design requirements. The proposed approach employs the strategies and analysis of BIM use during those initial design phases in order to have the analysis and results of each solution or alternative design. The stakeholders and designers would have a better effective decision making process with a full clarity of each alternative's consequences. The architect would settle down and proceed in the alternative design of the best sustainable analysis. In later design stages, using the sustainable types of materials such as insulation, cladding, etc., and applying sustainable building components such as doors, windows, etc. would add more improvements and enhancements in reaching better values and metrics. The paper describes the methodology of this design approach through BIM strategies adopted in design creation. Case studies of architectural designs are used to highlight the details and benefits of this proposed approach.
Exploring LIS Students' Beliefs in Importance and Self-Efficacy of Core Information Literacy Competencies

ERIC Educational Resources Information Center

Pinto, Maria; Pascual, Rosaura Fernandez

2016-01-01

Understanding perceptions of Library and Information Science (LIS) students on two dimensions--belief in the importance (BIM) of a set of core information competencies, and Self-Efficacy (SE)--is pursued. Factor analysis implementation raises a clear distinction between BIM and SE results. This analysis points to two sets of competencies:…
A Model Based Framework for Semantic Interpretation of Architectural Construction Drawings

ERIC Educational Resources Information Center

Babalola, Olubi Oluyomi

2011-01-01

The study addresses the automated translation of architectural drawings from 2D Computer Aided Drafting (CAD) data into a Building Information Model (BIM), with emphasis on the nature, possible role, and limitations of a drafting language Knowledge Representation (KR) on the problem and process. The central idea is that CAD to BIM translation is a…
Integrating Building Information Modeling and Green Building Certification: The BIM-LEED Application Model Development

ERIC Educational Resources Information Center

Wu, Wei

2010-01-01

Building information modeling (BIM) and green building are currently two major trends in the architecture, engineering and construction (AEC) industry. This research recognizes the market demand for better solutions to achieve green building certification such as LEED in the United States. It proposes a new strategy based on the integration of BIM…
Risks Associated with Federal Construction Projects

DTIC Science & Technology

2011-06-01

awarding contracts for construction projects (USACE, 2010). BIM offers a method to effectively design a facility while maximizing work performance during...includes Requirements, Programming, Funding, Solicitation, AEC Evaluation, Award , Project Validation, Design and Construction, and Project Management...includes the Solicitation, AEC Evaluation, and Award Steps. In this Phase, BIM is only used in the Solicitation and the AEC Evaluation steps
Scalable Deployment of Advanced Building Energy Management Systems

DTIC Science & Technology

2013-06-01

Building Automation and Control Network BDAS Building Data Acquisition System BEM building energy model BIM building information modeling BMS...A prototype toolkit to seamlessly and automatically transfer a Building Information Model ( BIM ) to a Building Energy Model (BEM) has been...circumvent the need to manually construct and maintain a detailed building energy simulation model . This detailed
BH3-only protein Bim inhibits activity of antiapoptotic members of Bcl-2 family when expressed in yeast.

PubMed

Juhásová, Barbora; Mentel, Marek; Bhatia-Kiššová, Ingrid; Zeman, Igor; Kolarov, Jordan; Forte, Michael; Polčic, Peter

2011-09-02

Proteins of the Bcl-2 family regulate programmed cell death in mammals by promoting the release of cytochrome c from mitochondria in response to various proapoptotic stimuli. The mechanism by which BH3-only members of the family activate multidomain proapoptotic proteins Bax and Bak to form a pore in mitochondrial membranes remains under dispute. We report that cell death promoting activity of BH3-only protein Bim can be reconstituted in yeast when both Bax and antiapoptotic protein Bcl-X(L) are present, suggesting that Bim likely activates Bax indirectly by inhibiting antiapoptotic proteins. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire

PubMed Central

Li, Kun-Po; Fahnrich, Anke; Roy, Eron; Cuda, Carla M.; Grimes, H. Leighton; Perlman, Harris R.; Kalies, Kathrin; Hildeman, David A.

2017-01-01

CD8αα TCRαβ+ intestinal intraepithelial lymphocytes play a critical role in promoting intestinal homeostasis, although mechanisms controlling their development and peripheral homeostasis remain unclear. In this study, we examined the spatiotemporal role of Bim in the thymic selection of CD8αα precursors and the fate of these cells in the periphery. We found that T cell–specific expression of Bim during early/cortical, but not late/medullary, thymic development controls the agonist selection of CD8αα precursors and limits their private TCRβ repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCRαβhi thymocytes. Although these DN thymocytes fail to re-express coreceptors after OP9-DL1 culture, they eventually mature and accumulate in the spleen where TCR and IL-15/STAT5 signaling promotes their conversion to CD8αα cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8αα cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15–driven maturation of CD8αα cells that is critical for intestinal homeostasis. Thus, we found a temporal and tissue-specific role for Bim in limiting thymic agonist selection of CD8αα precursors and their TCRβ repertoire, but not in the maintenance of CD8αα intraepithelial lymphocytes in the intestine. PMID:27852740
The pro-apoptotic protein Bmf co-operates with Bim and Puma in neuron death induced by β-amyloid or NGF deprivation.

PubMed

Akhter, Rumana; Saleem, Suraiya; Saha, Akash; Biswas, Subhas Chandra

2018-04-01

The pro-apoptotic Bcl-2 homology 3 domain only (BH3-only) proteins are central regulators of cell death in various physiological and pathological conditions, including Alzheimer's disease (AD). Bcl-2 modifying factor (Bmf) is one such BH3-only protein that is implicated in various death paradigms such as anoikis, seizures, cancer and autoimmunity. It also co-operates with other BH3-only proteins such as Bim in various death paradigms. However, its role in neurodegeneration is under-investigated. Here, we report for the first time the essential role of Bmf and its co-operativity with direct activator BH3-only proteins Bim and Puma in neuron death induced by beta-amyloid (Aβ) toxicity or NGF deprivation. Oligomeric Aβ is main pathologic species in AD and NGF deprivation is relevant for both developmental as well as pathologic neuron death. We find that Bmf over-expression causes cell death and Bmf knockdown protects neurons against death evoked by Aβ or NGF deprivation. We also find that Bmf co-operates with other important BH3-only proteins such as Bim and Puma in neuron death induced by Aβ or NGF deprivation. Simultaneous knocking down of these molecules by their respective shRNAs provide enhanced protection against Aβ. Taken together, our results elucidate the essential role of Bmf and its co-operative effects with already known neuron death inducers, Bim and Puma, in neuron death evoked by Aβ treatment or NGF deprivation. Copyright © 2018 Elsevier Inc. All rights reserved.
DMFC (3,5-dimethyl-7H-furo[3,2-g]chromen-7-one) regulates Bim to trigger Bax and Bak activation to suppress drug-resistant human hepatoma.

PubMed

Xiang, Jun; Wang, Zhe; Liu, Qianqian; Li, Xia; Sun, Jianguo; Fung, Kwok-Pui; Liu, Feiyan

2017-03-01

3,5-Dimethyl- 7 H-furo[3,2-g]chromen-7-one (DMFC) is a coumarin derivative with anti-cancer activity against human hepatoma cells, but the mechanisms underlying DMFC function in cancer suppression is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying DMFC anti-cancer activity and determining whether DMFC is effective in suppression of drug-resistant human hepatocellular carcinoma. We show here that DMFC effectively suppresses both the parent and the multidrug-resistant hepatoma cell growth in vitro and DMFC suppresses hepatoma cell growth at least in part through inducing tumor cell apoptosis. In the molecular level, we observed that DMFC treatment decreases Bcl-2 level by a post-transcriptional mechanism and activates Bim transcription to increase Bim mRNA and protein level in hepatoma cells. Furthermore, co-immunoprecipitation studies revealed that DMFC-induced Bim interrupts interactions between Bcl-2 and Bax and between Mcl-1 and Bak, resulting in dissociation of Bax from Bcl-2 and Bak from Mcl-1 and subsequent activation of both Bax and Bak. Activation of Bax and Bak leads to mitochondrial outer membrane permeabilization and cytochrome c release. Consistent with its potent apoptosis-inducing activity, DMFC exhibited potent activity against the multidrug-resistant hepatoma xenograft growth in vivo. Therefore, we determine that DMFC suppresses hepatoma growth through decreasing Bcl-2 and increasing Bim to induce tumor cell apoptosis and hold great promise for further development as a therapeutic agent to treat chemoresistant hepatoma.
Synthesis, characterization, and antimicrobial activity of silver(I) and copper(II) complexes of phosphate derivatives of pyridine and benzimidazole.

PubMed

Kalinowska-Lis, Urszula; Szewczyk, Eligia M; Chęcińska, Lilianna; Wojciechowski, Jakub M; Wolf, Wojciech M; Ochocki, Justyn

2014-01-01

Two silver(I) complexes--[Ag(4-pmOpe)]NO₃}(n) and [Ag(2-bimOpe)₂]NO₃--and three copper(II) complexes--[Cu₄Cl₆O(2-bimOpe)₄], [CuCl₂(4-pmOpe)₂], and [CuCl₂(2-bis(pm)Ope]--were synthesized by reaction of silver(I) nitrate or copper(II) chloride with phosphate derivatives of pyridine and benzimidazole, namely diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe), 1H-benzimidazol-2-ylmethyl diethyl phosphate (2-bimOpe), and ethyl bis(pyridin-2-ylmethyl)phosphate (2-bis(pm)Ope). These compounds were characterized by ¹H, ¹³C, and ³¹P NMR as well as IR spectroscopy, elemental analysis, and ESIMS spectrometry. Additionally, molecular and crystal structures of {[Ag(4-pmOpe)]NO₃}n and [Cu₄Cl₆O(2-bimOpe)₄] were determined by single-crystal X-ray diffraction analysis. The antimicrobial profiles of synthesized complexes and free ligands against test organisms from the ATCC and clinical sources were determined. Silver(I) complexes showed good antimicrobial activities against Candida albicans strains (MIC values of ∼19 μM). [Ag(2-bimOpe)₂]NO₃ was particularly active against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus epidermidis, with MIC values of ∼5 and ∼10 μM, respectively. Neither copper(II) complexes nor the free ligands inhibited the growth of test organisms at concentrations below 500 μg mL⁻¹. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Development of a 3D Underground Cadastral System with Indoor Mapping for As-Built BIM: The Case Study of Gangnam Subway Station in Korea.

PubMed

Kim, Sangmin; Kim, Jeonghyun; Jung, Jaehoon; Heo, Joon

2015-12-09

The cadastral system provides land ownership information by registering and representing land boundaries on a map. The current cadastral system in Korea, however, focuses mainly on the management of 2D land-surface boundaries. It is not yet possible to provide efficient or reliable land administration, as this 2D system cannot support or manage land information on 3D properties (including architectures and civil infrastructures) for both above-ground and underground facilities. A geometrical model of the 3D parcel, therefore, is required for registration of 3D properties. This paper, considering the role of the cadastral system, proposes a framework for a 3D underground cadastral system that can register various types of 3D underground properties using indoor mapping for as-built Building Information Modeling (BIM). The implementation consists of four phases: (1) geometric modeling of a real underground infrastructure using terrestrial laser scanning data; (2) implementation of as-built BIM based on geometric modeling results; (3) accuracy assessment for created as-built BIM using reference points acquired by total station; and (4) creation of three types of 3D underground cadastral map to represent underground properties. The experimental results, based on indoor mapping for as-built BIM, show that the proposed framework for a 3D underground cadastral system is able to register the rights, responsibilities, and restrictions corresponding to the 3D underground properties. In this way, clearly identifying the underground physical situation enables more reliable and effective decision-making in all aspects of the national land administration system.
Building information modeling (BIM) approach to the GMT Project

NASA Astrophysics Data System (ADS)

Teran, Jose; Sheehan, Michael; Neff, Daniel H.; Adriaanse, David; Grigel, Eric; Farahani, Arash

2014-07-01

The Giant Magellan Telescope (GMT), one of several next generation Extremely Large Telescopes (ELTs), is a 25.4 meter diameter altitude over azimuth design set to be built at the summit of Cerro Campánas at the Las Campánas Observatory in Chile. The paper describes the use of Building Information Modeling (BIM) for the GMT project.
Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa.

PubMed

Kirschnek, S; Vier, J; Gautam, S; Frankenberg, T; Rangelova, S; Eitz-Ferrer, P; Grespi, F; Ottina, E; Villunger, A; Häcker, H; Häcker, G

2011-11-01

Neutrophils enter the peripheral blood from the bone marrow and die after a short time. Molecular analysis of spontaneous neutrophil apoptosis is difficult as these cells die rapidly and cannot be easily manipulated. We use conditional Hoxb8 expression to generate mouse neutrophils and test the regulation of apoptosis by extensive manipulation of B-cell lymphoma protein 2 (Bcl-2)-family proteins. Spontaneous apoptosis was preceded by downregulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic Bcl-2 homology domain (BH3)-only protein Bcl-2-interacting mediator of cell death (Bim) gave some protection, but only neutrophils deficient in both BH3-only proteins, Bim and Noxa, were strongly protected against apoptosis. Function of Noxa was at least in part neutralization of induced myeloid leukemia cell differentiation protein (Mcl-1) in neutrophils and progenitors. Loss of Bim and Noxa preserved neutrophil function in culture, and apoptosis-resistant cells remained in circulation in mice. Apoptosis regulated by Bim- and Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation, required for the termination of neutrophil function and neutrophil-dependent inflammation.
Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule*

PubMed Central

Zhao, Lixia; He, Feng; Liu, Haiyang; Zhu, Yushan; Tian, Weili; Gao, Ping; He, Hongping; Yue, Wen; Lei, Xiaobo; Ni, Biyun; Wang, Xiaohui; Jin, Haijing; Hao, Xiaojiang; Lin, Jialing; Chen, Quan

2012-01-01

Overwhelming evidence indicates that Bax and Bak are indispensable for mediating cytochrome c release from mitochondria during apoptosis. Here we report a Bax/Bak-independent mechanism of cytochrome c release and apoptosis. We identified a natural diterpenoid compound that induced apoptosis in bax/bak double knock-out murine embryonic fibroblasts and substantially reduced the tumor growth from these cells implanted in mice. Treatment with the compound significantly increased expression of Bim, which migrated to mitochondria, altering the conformation of and forming oligomers with resident Bcl-2 to induce cytochrome c release and caspase activation. Importantly, purified Bim and Bcl-2 proteins cooperated to permeabilize a model mitochondrial outer membrane; this was accompanied by oligomerization of these proteins and deep embedding of Bcl-2 in the membrane. Therefore, the diterpenoid compound induces a structural and functional conversion of Bcl-2 through Bim to permeabilize the mitochondrial outer membrane, thereby inducing apoptosis independently of Bax and Bak. Because Bcl-2 family proteins play important roles in cancer development and relapse, this novel cell death mechanism can be explored for developing more effective anticancer therapeutics. PMID:22065578
Conservation Process Model (cpm): a Twofold Scientific Research Scope in the Information Modelling for Cultural Heritage

NASA Astrophysics Data System (ADS)

Fiorani, D.; Acierno, M.

2017-05-01

The aim of the present research is to develop an instrument able to adequately support the conservation process by means of a twofold approach, based on both BIM environment and ontology formalisation. Although BIM has been successfully experimented within AEC (Architecture Engineering Construction) field, it has showed many drawbacks for architectural heritage. To cope with unicity and more generally complexity of ancient buildings, applications so far developed have shown to poorly adapt BIM to conservation design with unsatisfactory results (Dore, Murphy 2013; Carrara 2014). In order to combine achievements reached within AEC through BIM environment (design control and management) with an appropriate, semantically enriched and flexible The presented model has at its core a knowledge base developed through information ontologies and oriented around the formalization and computability of all the knowledge necessary for the full comprehension of the object of architectural heritage an its conservation. Such a knowledge representation is worked out upon conceptual categories defined above all within architectural criticism and conservation scope. The present paper aims at further extending the scope of conceptual modelling within cultural heritage conservation already formalized by the model. A special focus is directed on decay analysis and surfaces conservation project.
Building Information Management as a Tool for Managing Knowledge throughout whole Building Life Cycle

NASA Astrophysics Data System (ADS)

Nývlt, Vladimír; Prušková, Kristýna

2017-10-01

BIM today is much more than drafting in 3D only, and project participants are further challenging, what is the topic of both this paper, and further research. Knowledge of objects, their behaviour, and other characteristics has high impact on whole building life cycle. Other structured and unstructured knowledge is rightfully added (e.g. historically based experience, needs and requirements of users, investors, needs for project and objects revisions) Grasping of all attributes into system for collection, managing and time control of knowledge. Further important findings lie in the necessity of understanding how to manage knowledge needs with diverse and variable ways, when BIM maturity levels are advanced, as defined by Bew and Richards (2008). All decisions made would always rely on good, timely, and correct data. Usage of BIM models in terms of Building Information Management can support all decisions through data gathering, sharing, and using across all disciplines and all Life Cycle steps. It particularly significantly improves possibilities and level of life cycle costing. Experience and knowledge stored in data models of BIM, describing user requirements, best practices derived from other projects and/or research outputs will help to understand sustainability in its complexity and wholeness.
Review and Prospect of BIM Policy in China

NASA Astrophysics Data System (ADS)

Liu, Bingsheng; Wang, Min; Zhang, Yutao; Liu, Rui; Wang, Anmin

2017-10-01

In the process of architectural design, construction, operation and maintenance, the problem of inefficiency and inaccuracy in information application and exchange has caused substantial waste of resources and risk in construction industry. Building Information Management provides an opportunity to address the issue. Building information modelling (BIM) has been increasingly applied in design, construction and other information management in China as its important role in reducing engineering changes, improving engineering quality, shortening project duration, saving project cost, enhancing information sharing among the participants many others. As an integration of process and product, its development and implementation need government regulation to enhance its applications effect and standardize its adoption and implementation. Especially, the government guidance affects the application and development of new technology to a great extent in China. However, relevant policy development falls behind the rapid development of its application in practice in China, which has led to many problems in construction practice. In order to develop effective BIM policy for China, this paper conducted a comprehensive review about existing BIM policy in China by analysing its status and problems, comparing it with the corresponding policy in developed countries such as the USA and UK. The expected policy development direction is also discussed and proposed.
Point clouds in BIM

NASA Astrophysics Data System (ADS)

Antova, Gergana; Kunchev, Ivan; Mickrenska-Cherneva, Christina

2016-10-01

The representation of physical buildings in Building Information Models (BIM) has been a subject of research since four decades in the fields of Construction Informatics and GeoInformatics. The early digital representations of buildings mainly appeared as 3D drawings constructed by CAD software, and the 3D representation of the buildings was only geometric, while semantics and topology were out of modelling focus. On the other hand, less detailed building representations, with often focus on ‘outside’ representations were also found in form of 2D /2,5D GeoInformation models. Point clouds from 3D laser scanning data give a full and exact representation of the building geometry. The article presents different aspects and the benefits of using point clouds in BIM in the different stages of a lifecycle of a building.
Tetrakis(1-imidazolyl) borate (BIM4) based zwitterionic and related molecules used as electron injection layers

DOEpatents

Li, Huaping; Xu, Yunhua; Bazan, Guillermo C

2013-02-05

Tetrakis(1-imidazolyl)borate (BIm4) based zwitterionic and/or related molecules for the fabrication of PLEDs is provided. Device performances with these materials approaches that of devices with Ba/Al cathodes for which the cathode contact is ohmic. Methods of producing such materials, and electron injection layers and devices containing these materials are also provided.

Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose–response phenomenon

PubMed Central

Shen, Jie; Bejanian, Marina

2016-01-01

Purpose Many patients with glaucoma require combination therapies to achieve target intraocular pressure (IOP) and preserve visual function. Ocular hypotensives often contain a preservative (eg, benzalkonium chloride [BAK]), but preservative-free (PF) formulations have been developed for patients with sensitivity. A Phase III study found the efficacy of bimatoprost 0.03%/timolol 0.5% (bim/tim, Ganfort®) PF to be equivalent to that of preserved bim/tim, although a trend favoring bim/tim PF was observed. As BAK is a corneal penetration enhancer, this literature review aims to explain these findings by exploring the relationship between timolol concentration and its IOP-lowering effect. Methods Systematic searches were performed in Scopus and PubMed for clinical trials published in English between 1960 and July 2014 using the keywords “timolol”, “intraocular pressure”, and the concentrations “1%, 0.5%, OR 0.25%”. Articles that directly compared IOP-lowering effects of ≥2 concentrations of timolol were identified by manual screening, and cross-checked for duplication. Results Seventeen studies that included 10–371 patients were evaluated; the majority were randomized (16/17), double-masked (14/17), and enrolled patients with open-angle glaucoma or ocular hypertension (12/17). All studies investigated timolol in preserved formulations. Timolol concentrations tested ranged from 0.008% to 1.5%. Of 13 studies comparing timolol 0.25% versus 0.5%, two found the 0.25% dose to have greater IOP-lowering effects, and three reported the opposite; eight reported similar IOP lowering. Results also indicate that timolol 0.5% may be more effective than higher concentrations. Conclusion The evidence suggests that timolol may have an inverted U-shaped dose–response curve, and that its optimal IOP-lowering concentration is between 0.25% and 0.5%. Compared with bim/tim, removal of the permeability enhancer BAK in bim/tim PF could have resulted in a lower timolol concentration at the target site, bringing the effective concentration within the 0.25%–0.5% range and enhancing the efficacy of bim/tim PF. PMID:27041984
Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes.

PubMed

Diao, Xingxing; Scheidweiler, Karl B; Wohlfarth, Ariane; Zhu, Mingshe; Pang, Shaokun; Huestis, Marilyn A

Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. It is much more challenging to confirm a specific isomer's intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 μM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5'-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5'-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.
Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax.

PubMed

Bajpai, R; Matulis, S M; Wei, C; Nooka, A K; Von Hollen, H E; Lonial, S; Boise, L H; Shanmugam, M

2016-07-28

Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM.
Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax

PubMed Central

Bajpai, R; Matulis, SM; Wei, C; Nooka, AK; Von Hollen, HE; Lonial, S; Boise, LH; Shanmugam, M

2016-01-01

Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM. PMID:26640142
ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure

PubMed Central

Marum, Justine E.; Yeung, David T.; Purins, Leanne; Reynolds, John; Parker, Wendy T.; Stangl, Doris; Wang, Paul P. S.; Price, David J.; Tuke, Jonathan; Schreiber, Andreas W.; Scott, Hamish S.; Hughes, Timothy P.

2017-01-01

Scoring systems used at diagnosis of chronic myeloid leukemia (CML), such as Sokal risk, provide important response prediction for patients treated with imatinib. However, the sensitivity and specificity of scoring systems could be enhanced for improved identification of patients with the highest risk. We aimed to identify genomic predictive biomarkers of imatinib response at diagnosis to aid selection of first-line therapy. Targeted amplicon sequencing was performed to determine the germ line variant profile in 517 and 79 patients treated with first-line imatinib and nilotinib, respectively. The Sokal score and ASXL1 rs4911231 and BIM rs686952 variants were independent predictors of early molecular response (MR), major MR, deep MRs (MR4 and MR4.5), and failure-free survival (FFS) with imatinib treatment. In contrast, the ASXL1 and BIM variants did not consistently predict MR or FFS with nilotinib treatment. In the imatinib-treated cohort, neither Sokal or the ASXL1 and BIM variants predicted overall survival (OS) or progression to accelerated phase or blast crisis (AP/BC). The Sokal risk score was combined with the ASXL1 and BIM variants in a classification tree model to predict imatinib response. The model distinguished an ultra-high-risk group, representing 10% of patients, that predicted inferior OS (88% vs 97%; P = .041), progression to AP/BC (12% vs 1%; P = .034), FFS (P < .001), and MRs (P < .001). The ultra-high-risk patients may be candidates for more potent or combination first-line therapy. These data suggest that germ line genetic variation contributes to the heterogeneity of response to imatinib and may contribute to a prognostic risk score that allows early optimization of therapy. PMID:29296778
Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death.

PubMed

Kim, Jin Hee; Kang, Tae Heung; Noh, Kyung Hee; Bae, Hyun Cheol; Kim, Seok-Ho; Yoo, Young Do; Seong, Seung-Yong; Kim, Tae Woo

2009-01-29

Dendritic cells (DCs) have become an important measure for the treatment of malignancies. Current DC preparations, however, generate short-lived DCs because they are subject to cell death from various apoptotic pressures. Antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) is one of the main obstacles to limit the DC-mediated immune priming since CTLs can recognize the target antigen expressing DCs as target cells and kill the DCs. CTLs secret perforin and serine protease granzymes during CTL killing. Perforin and serine protease granzymes induce the release of a number of mitochondrial pro-apoptotic factors, which are controlled by members of the BCL-2 family, such as BAK, BAX and BIM. FasL linking to Fas on DCs triggers the activation of caspase-8, which eventually leads to mitochondria-mediated apoptosis via truncation of BID. In this study, we tried to enhance the DC priming capacity by prolonging DC survival using anti-apoptotic siRNA targeting these key pro-apoptotic molecules in CTL killing. Human papillomavirus (HPV)-16 E7 antigen presenting DCs that were transfected with these anti-apoptotic siRNAs showed increased resistance to T cell-mediated death, leading to enhanced E7-specific CD8(+) T cell activation in vitro and in vivo. Among them, siRNA targeting BIM (siBIM) generated strongest E7-specific E7-specific CD8(+) T cell immunity. More importantly, vaccination with E7 presenting DCs transfected with siBIM was capable of generating a marked therapeutic effect in vaccinated mice. Our data indicate that ex vivo manipulation of DCs with siBIM may represent a plausible strategy for enhancing dendritic cell-based vaccine potency.
EGFR-TKIs plus chemotherapy demonstrated superior efficacy than EGFR-TKIs alone as first-line setting in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism.

PubMed

Liu, Sangtian; He, Yayi; Jiang, Tao; Ren, Shengxiang; Zhou, Fei; Zhao, Chao; Li, Xuefei; Zhang, Jie; Su, Chunxia; Chen, Xiaoxia; Cai, Weijing; Gao, Guanghui; Li, Wei; Wu, Fengying; Li, Jiayu; Zhao, Jing; Hu, Qiong; Zhao, Mingchuan; Zhou, Caicun; Hirsch, Fred R

2018-06-01

Non-small-cell lung cancer (NSCLC) patients with both epidermal growth factor receptor (EGFR) positive mutation and B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism had a poor clinical response to EGFR-tyrosine kinase inhibitors (TKIs). The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus chemotherapy versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism. A retrospective, non-randomized analysis was conducted. BIM deletion polymorphism was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from peripheral blood cells. Clinical characteristics, overall survival (OS), progress-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared between EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy group. 65 patients were enrolled. 36 of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% vs. 38.9%, P = 0.046). Median PFS was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 vs 4.7 m; P = 0.008). Median OS was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 vs 14.2 m; P = 0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone. EGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged PFS and numerically longer OS in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings. Copyright © 2018 Elsevier B.V. All rights reserved.
Bim regulates the survival and suppressive capability of CD8+ FOXP3+ regulatory T cells during murine GVHD.

PubMed

Agle, Kimberle; Vincent, Benjamin G; Piper, Clint; Belle, Ludovic; Zhou, Vivian; Shlomchik, Warren; Serody, Jonathan S; Drobyski, William R

2018-05-16

CD8 + Foxp3 + T cells (Tregs) are a potent regulatory population whose functional and ontological similarities to CD4 + Fox3 + T cells have not been well delineated. Using an experimental model of graft versus host disease (GVHD), we observed that CD8 + Tregs were significantly less potent than CD4 + Tregs for the suppression of GVHD. To define the mechanistic basis for this observation, we examined the T cell repertoire and the transcriptional profile of in vivo-derived CD4 + and CD8 + Tregs that emerged early during this disease. Polyclonal and alloantigen-induced CD8 + Tregs had repertoire diversity that was similar to that of conventional CD8 + T cells, indicating that a restricted repertoire was not the proximate cause of decreased suppression. Transcriptional profiling revealed that CD8 + Tregs possessed a canonical Treg transcriptional signature that was similar to that observed in CD4 + Tregs, yet distinct from conventional CD8 + T cells. Pathway analysis, however, demonstrated that CD8 + Tregs had differential gene expression in pathways involved in cell death and survival. This was further confirmed by detailed mRNA sequence analysis and protein expression studies which demonstrated that CD8 + Tregs had increased expression of Bim and reduced expression of Mcl-1. Transplantation with CD8 + Foxp3 + Bim -/- Tregs resulted in prolonged Treg survival and reduced GVHD lethality compared to wild type CD8 + Tregs, providing functional confirmation that increased expression of Bim was responsible for reduced in vivo efficacy. Thus, Bim regulates the survival and suppressive capability of CD8 + Tregs which may have implications for their use in regulatory T cell therapy. Copyright © 2018 American Society of Hematology.
B7-H1 limits the entry of effector CD8(+) T cells to the memory pool by upregulating Bim.

PubMed

Gibbons, Rachel M; Liu, Xin; Pulko, Vesna; Harrington, Susan M; Krco, Christopher J; Kwon, Eugene D; Dong, Haidong

2012-10-01

Protective T‑cell immunity against cancer and infections is dependent on the generation of a durable effector and memory T‑cell pool. Studies from cancer and chronic infections reveal that B7-H1 (PD-L1) engagement with its receptor PD-1 promotes apoptosis of effector T cells. It is not clear how B7-H1 regulates T‑cell apoptosis and the subsequent impact of B7-H1 on the generation of memory T cells. In immunized B7-H1-deficient mice, we detected an increased expansion of effector CD8(+) T cells and a delayed T‑cell contraction followed by the emergence of a protective CD8(+) T‑cell memory capable of completely rejecting tumor metastases in the lung. Intracellular staining revealed that antigen-primed CD8(+) T cells in B7-H1-deficient mice express lower levels of the pro-apoptotic molecule Bim. The engagement of activated CD8(+) T cells by a plate-bound B7-H1 fusion protein led to the upregulation of Bim and increased cell death. Assays based on blocking antibodies determined that both PD-1 and CD80 are involved in the B7-H1-mediated regulation of Bim in activated CD8(+) T cells. Our results suggest that B7-H1 may negatively regulate CD8(+) T‑cell memory by enhancing the depletion of effector CD8(+) T cells through the upregulation of Bim. Our findings may provide a new strategy for targeting B7-H1 signaling in effector CD8(+) T cells to achieve protective antitumor memory responses.
Development of a 3D Underground Cadastral System with Indoor Mapping for As-Built BIM: The Case Study of Gangnam Subway Station in Korea

PubMed Central

Kim, Sangmin; Kim, Jeonghyun; Jung, Jaehoon; Heo, Joon

2015-01-01

The cadastral system provides land ownership information by registering and representing land boundaries on a map. The current cadastral system in Korea, however, focuses mainly on the management of 2D land-surface boundaries. It is not yet possible to provide efficient or reliable land administration, as this 2D system cannot support or manage land information on 3D properties (including architectures and civil infrastructures) for both above-ground and underground facilities. A geometrical model of the 3D parcel, therefore, is required for registration of 3D properties. This paper, considering the role of the cadastral system, proposes a framework for a 3D underground cadastral system that can register various types of 3D underground properties using indoor mapping for as-built Building Information Modeling (BIM). The implementation consists of four phases: (1) geometric modeling of a real underground infrastructure using terrestrial laser scanning data; (2) implementation of as-built BIM based on geometric modeling results; (3) accuracy assessment for created as-built BIM using reference points acquired by total station; and (4) creation of three types of 3D underground cadastral map to represent underground properties. The experimental results, based on indoor mapping for as-built BIM, show that the proposed framework for a 3D underground cadastral system is able to register the rights, responsibilities, and restrictions corresponding to the 3D underground properties. In this way, clearly identifying the underground physical situation enables more reliable and effective decision-making in all aspects of the national land administration system. PMID:26690174
Human Reliability Prediction System User’s Manual

DTIC Science & Technology

1977-12-01

L Oh.~Nt C.A ICIA I I OMIII ots ?if# IVte AEA AL #4001Im.4,4 up I.-. tte )’fhawA ta *(.qOtte bim.s -vtait hP lSoulp * V1CALS ChET TING 0 IKIVA ofI...on human fectorsin under- sea warfare. Washington, D.C.: Committee on Undersea Warfare, 1949. 8. Blanchard, R.E. Survey of Navy user needs for human
Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.

PubMed

Matulis, S M; Gupta, V A; Nooka, A K; Hollen, H V; Kaufman, J L; Lonial, S; Boise, L H

2016-05-01

Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. The results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in four of the five cell lines tested. The most striking results were seen with dexamethasone (Dex). Co-treatment of human myeloma cell lines and primary patient samples, with Dex and venetoclax, significantly increased cell death over venetoclax alone in four of the five cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of Dex. This results in alterations in Bim binding to anti-apoptotic proteins. Dex shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity.
Dexamethasone treatment promotes Bcl-2-dependence in multiple myeloma resulting in sensitivity to Venetoclax

PubMed Central

Matulis, Shannon M.; Gupta, Vikas A.; Nooka, Ajay K.; Von Hollen, Hayley; Kaufman, Jonathan L.; Lonial, Sagar; Boise, Lawrence H.

2015-01-01

Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. Results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in 4 of the 5 cell lines tested. The most striking results were seen with dexamethasone. Co-treatment of human myeloma cell lines and primary patient samples, with dexamethasone and venetoclax significantly increased cell death over venetoclax alone in 4 of the 5 cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of dexamethasone. This results in alterations in Bim binding to anti-apoptotic proteins. Dexamethasone shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with dexamethasone could be an effective therapy for a broader range of patients than would be predicted by single agent activity. PMID:26707935
Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

PubMed Central

Buchheit, C L; Angarola, B L; Steiner, A; Weigel, K J; Schafer, Z T

2015-01-01

Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells. PMID:25526094
Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration.

PubMed

Buchheit, C L; Angarola, B L; Steiner, A; Weigel, K J; Schafer, Z T

2015-08-01

Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.
Eupafolin enhances TRAIL-mediated apoptosis through cathepsin S-induced down-regulation of Mcl-1 expression and AMPK-mediated Bim up-regulation in renal carcinoma Caki cells.

PubMed

Han, Min Ae; Min, Kyoung-Jin; Woo, Seon Min; Seo, Bo Ram; Kwon, Taeg Kyu

2016-10-04

Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells.
Eupafolin enhances TRAIL-mediated apoptosis through cathepsin S-induced down-regulation of Mcl-1 expression and AMPK-mediated Bim up-regulation in renal carcinoma Caki cells

PubMed Central

Woo, Seon Min; Seo, Bo Ram; Kwon, Taeg Kyu

2016-01-01

Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells. PMID:27582546
Control system of mobile radiographic complex to study equations of state of substances

NASA Astrophysics Data System (ADS)

Belov, O. V.; Valekzhanin, R. V.; Kustov, D. V.; Shamro, O. A.; Sharov, T. V.

2017-05-01

A source of x-ray radiation is one of the tools to study equations of state of substances in dynamics. The mobile radiographic bench based on BIM-1500 [1] was developed in RFNC-VNIIEF to increase output parameters of the x-ray radiation source. From automated control system side, BIM-1500 is a set of six high-voltage generators based on the capacitive energy storage, technological equipment, and elements of a blocking system. This paper considers automated control system of the mobile radiographic bench MCA BIM 1500. It consists of six high-voltage generator control circuits, synchronization subsystem, and block subsystem. The object of control has some peculiarities: high level of electromagnetic noise, remoteness of the control panel from the object of control. In connection with this, the coupling devices are arranged closer to the object of control and performed in the form of a set of galvanically insulated control units, which are combined into a net. The operator runs MCA BIM using the operator’s screens on PC or by means of manual control on the equipment in the mode of debugging. The control software provides performance of the experiment in automatic regime in accordance with preset settings. The operator can stop the experiment at the stage of charging the capacitive storage.
Exploring Bim for Operational Integrated Asset Management - a Preliminary Study Utilising Real-World Infrastructure Data

NASA Astrophysics Data System (ADS)

Boyes, G. A.; Ellul, C.; Irwin, D.

2017-10-01

The use of 3D information models within collaborative working environments and the practice of Building Information Modelling (BIM) are becoming more commonplace within infrastructure projects. Currently used predominantly during the design and construction phase, the use of BIM is capable in theory of providing the information at handover that will satisfy the Asset Information Requirements (AIRs) of the future Infrastructure Manager (IM). One particular challenge is establishing a link between existing construction-centric information and the asset-centric information needed for future operations. Crossrail, a project to build a new high-frequency railway underneath London, is handling many such challenges as they prepare to handover their digital information to the future operator, in particular the need to provide a two-way link between a federated 3D CAD model and an object-relational Asset Information Management System (AIMS). This paper focusses on the potential for improved Asset Management (AM) by integrating BIM and GIS systems and practices, and makes a preliminary report on how 3D spatial queries can be used to establish a two-way relational link between two information systems (3D geometry and asset lists), as well as the challenges being overcome to transform the data to be suitable for AM.
An odor interaction model of binary odorant mixtures by a partial differential equation method.

PubMed

Yan, Luchun; Liu, Jiemin; Wang, Guihua; Wu, Chuandong

2014-07-09

A novel odor interaction model was proposed for binary mixtures of benzene and substituted benzenes by a partial differential equation (PDE) method. Based on the measurement method (tangent-intercept method) of partial molar volume, original parameters of corresponding formulas were reasonably displaced by perceptual measures. By these substitutions, it was possible to relate a mixture's odor intensity to the individual odorant's relative odor activity value (OAV). Several binary mixtures of benzene and substituted benzenes were respectively tested to establish the PDE models. The obtained results showed that the PDE model provided an easily interpretable method relating individual components to their joint odor intensity. Besides, both predictive performance and feasibility of the PDE model were proved well through a series of odor intensity matching tests. If combining the PDE model with portable gas detectors or on-line monitoring systems, olfactory evaluation of odor intensity will be achieved by instruments instead of odor assessors. Many disadvantages (e.g., expense on a fixed number of odor assessors) also will be successfully avoided. Thus, the PDE model is predicted to be helpful to the monitoring and management of odor pollutions.

Binary-Phase Fourier Gratings for Nonuniform Array Generation

NASA Technical Reports Server (NTRS)

Keys, Andrew S.; Crow, Robert W.; Ashley, Paul R.

2003-01-01

We describe a design method for a binary-phase Fourier grating that generates an array of spots with nonuniform, user-defined intensities symmetric about the zeroth order. Like the Dammann fanout grating approach, the binary-phase Fourier grating uses only two phase levels in its grating surface profile to generate the final spot array. Unlike the Dammann fanout grating approach, this method allows for the generation of nonuniform, user-defined intensities within the final fanout pattern. Restrictions governing the specification and realization of the array's individual spot intensities are discussed. Design methods used to realize the grating employ both simulated annealing and nonlinear optimization approaches to locate optimal solutions to the grating design problem. The end-use application driving this development operates in the near- to mid-infrared spectrum - allowing for higher resolution in grating specification and fabrication with respect to wavelength than may be available in visible spectrum applications. Fabrication of a grating generating a user-defined nine spot pattern is accomplished in GaAs for the near-infrared. Characterization of the grating is provided through the measurement of individual spot intensities, array uniformity, and overall efficiency. Final measurements are compared to calculated values with a discussion of the results.
BIM cost analysis of transport infrastructure projects

NASA Astrophysics Data System (ADS)

Volkov, Andrey; Chelyshkov, Pavel; Grossman, Y.; Khromenkova, A.

2017-10-01

The article describes the method of analysis of the energy costs of transport infrastructure objects using BIM software. The paper consideres several options of orientation of a building using SketchUp and IES VE software programs. These options allow to choose the best direction of the building facades. Particular attention is given to a distribution of a temperature field in a cross-section of the wall according to the calculation made in the ELCUT software. The issues related to calculation of solar radiation penetration into a building and selection of translucent structures are considered in the paper. The article presents data on building codes relating to the transport sector, on the basis of which the calculations were made. The author emphasizes that BIM-programs should be implemented and used in order to optimize a thermal behavior of a building and increase its energy efficiency using climatic data.
BIM authoring for an image-based bridge maintenance system of existing cable-supported bridges

NASA Astrophysics Data System (ADS)

Dang, N. S.; Shim, C. S.

2018-04-01

Infrastructure nowadays is increasingly become the main backbone for the metropolitan development in general. Along with the rise of new facilities, the demand in term of maintenance for the existing bridges is indispensable. Recently, the terminology of “preventive maintenance” is not unfamiliar with the engineer, literally is the use of a bridge maintenance system (BMS) based on a BIM-oriented model. In this paper, the process of generating a BMS based on BIM model is introduced in detail. Data management for this BMS is separated into two modules: site inspection system and information management system. The noteworthy aspect of this model lays on the closed and automatic process of “capture image, generate the technical damage report, and upload/feedback to the BMS” in real-time. A pilot BMS system for a cable-supported bridge is presented which showed a good performance and potential to further development of preventive maintenance.
Synthesis, characterization, photoluminescence, and electrochemical studies of novel mononuclear Cu(II) and Zn(II) complexes with the 1-benzylimidazolium ligand

NASA Astrophysics Data System (ADS)

Bibi, Sherino; Mohammad, Sharifah; Manan, Ninie Suhana Abdul; Ahmad, Jimmy; Kamboh, Muhammad Afzal; Khor, Sook Mei; Yamin, Bohari M.; Abdul Halim, Siti Nadiah

2017-08-01

Two new mononuclear coordination complexes [Cu(bim)4Cl2]ṡ2H2O (1) and [Zn(bim)2Cl2] (2) containing the 1-benzylimidazole (bim) ligand were successfully synthesized. Both complexes were characterized by IR, UV-vis, and fluorescence spectroscopies, single crystal and powder X-ray diffraction measurements, and thermogravimetric analysis. Self-assembly during the recrystallization process resulted in the formation of octahedral and tetrahedral Cu(II) and Zn(II) complexes, respectively. The single crystals obtained are representative of the bulk material, as shown by the powder X-ray diffraction patterns. Cyclic voltammetry measurements showed that complex 1 undergoes a quasi-reversible redox reaction, while complex 2 undergoes reduction alone, and no oxidation peak was observed; this is due to the stability of the reduced form of complex 2.
The COBAIN (COntact Binary Atmospheres with INterpolation) Code for Radiative Transfer

NASA Astrophysics Data System (ADS)

Kochoska, Angela; Prša, Andrej; Horvat, Martin

2018-01-01

Standard binary star modeling codes make use of pre-existing solutions of the radiative transfer equation in stellar atmospheres. The various model atmospheres available today are consistently computed for single stars, under different assumptions - plane-parallel or spherical atmosphere approximation, local thermodynamical equilibrium (LTE) or non-LTE (NLTE), etc. However, they are nonetheless being applied to contact binary atmospheres by populating the surface corresponding to each component separately and neglecting any mixing that would typically occur at the contact boundary. In addition, single stellar atmosphere models do not take into account irradiance from a companion star, which can pose a serious problem when modeling close binaries. 1D atmosphere models are also solved under the assumption of an atmosphere in hydrodynamical equilibrium, which is not necessarily the case for contact atmospheres, as the potentially different densities and temperatures can give rise to flows that play a key role in the heat and radiation transfer.To resolve the issue of erroneous modeling of contact binary atmospheres using single star atmosphere tables, we have developed a generalized radiative transfer code for computation of the normal emergent intensity of a stellar surface, given its geometry and internal structure. The code uses a regular mesh of equipotential surfaces in a discrete set of spherical coordinates, which are then used to interpolate the values of the structural quantites (density, temperature, opacity) in any given point inside the mesh. The radiaitive transfer equation is numerically integrated in a set of directions spanning the unit sphere around each point and iterated until the intensity values for all directions and all mesh points converge within a given tolerance. We have found that this approach, albeit computationally expensive, is the only one that can reproduce the intensity distribution of the non-symmetric contact binary atmosphere and can be used with any existing or new model of the structure of contact binaries. We present results on several test objects and future prospects of the implementation in state-of-the-art binary star modeling software.
Far-field phase contrast from orbiting objects: Characterizing progenitors of binary mergers

NASA Astrophysics Data System (ADS)

Matthias, P.; Hofmann, R.

2018-05-01

We propose an idea to determine the size of a binary, composed of two compact stars or black holes, its diffractive power, the distance between components, and the distance to an observer, in exploiting the emergence of intensity contrast by free-space propagation when the phase of coherent light from a very distant background source is affected by diffraction. We assume that this effect can be characterized by the projected real part of an effective refractive index n . Here we model the according two-dimensional exit phase-map by a superposition of two Gaussians. In the extreme far field, phase information is captured by scaling functions which are analyzed here. Both spatial and temporal scanning of the intensity contrast are discussed. While the former mode can be used, e.g., to determine the distance to the observer, the latter allows, e.g., one to measure the overall diffractive power of the binary in terms of the particular dependence of a scaling curve on the projected spatial separation between the binary's components. Both modes of observation may be of relevance in monitoring the progenitor dynamics of binary collapse using radio telescopes.
Role of aerosols in enhancing SVOC flux between air and indoor surfaces and its influence on exposure

NASA Astrophysics Data System (ADS)

Liu, Cong; Morrison, Glenn C.; Zhang, Yinping

2012-08-01

Indoor surfaces play an important role in the transport of, and exposure to, semi-volatile organic compounds (SVOCs) in buildings. In this study, we develop a model that accounts for SVOC transport mediated by particles and find that, due to large gas-particle partition coefficients along with large differences in Brownian and gas diffusivities, SVOC transport across concentration boundary layers is significantly enhanced in the presence of particles. Two important dimensionless parameters, Bim,g and Bim,g/Bim,p, were identified: Bim,g is the ratio of 1) the characteristic time for the SVOC to transport across the concentration boundary layer to 2) the characteristic time for boundary layer to either be "swept" of SVOCs by particles or "saturated" by release of SVOCs from particles. This parameter can be regarded as a dimensionless mass transfer coefficient. Bim,g/Bim,p characterizes the SVOC mass associated with particles, relative to SVOCs in the gas-phase. Analysis on monodisperse particles shows that flux can be enhanced by as much as a factor of 5 over transport in the absence of particles, for a large particle/gas partition coefficient (log Kpart = 13), small particles (dp ˜ 0.1 μm) and a small free stream velocity (U∞ = 0.01 m s-1). As particle diameter decreases, flux enhancement tends to increase. However, as particles become very small (e.g., dp < 0.05 μm), flux enhancement for SVOCs with log Kpart = 13 decreases slightly. Particles larger than 2 μm do not significantly influence the flux. An exponential correlation is found to fit the results for polydisperse particles associated with typical indoor environments, cooking and smoking. Two illustrative examples are used to show that, 1) the timescale for di(2-ethylhexyl) phthalate (DEHP) to approach equilibrium between the gas and a surface is shortened from 3.0 years to 0.45 years; and 2) in the presence of particles, the gas-phase DEHP concentration and emission rate are predicted to be as much as 4 times higher by our model than that by prior model estimates. Particle mediated gas-phase transport of SVOCs can result an increase in occupant exposure by a factor of 4-10.
Choice of threshold line angle for binary phase-only filters

NASA Astrophysics Data System (ADS)

Vijaya Kumar, Bhagavatula; Hendrix, Charles D.

1993-10-01

The choice of threshold line angle (TLA) is an important issue in designing Binary Phase-Only Filters (BPOFs). In this paper, we derive expressions that explicitly relate the TLA to correlation peak intensity. We also show some examples that illustrate the effect of choosing the wrong TLA.
Assessment of Life Cycle Information Exchanges (LCie): Understanding the Value-Added Benefit of a COBie Process

DTIC Science & Technology

2013-10-01

exchange (COBie), Building Information Modeling ( BIM ), value-added analysis, business processes, project management 16. SECURITY CLASSIFICATION OF: 17...equipment. The innovative aspect of Building In- formation Modeling ( BIM ) is that it creates a computable building descrip- tion. The ability to use a...interoperability. In order for the building information to be interoperable, it must also con- form to a common data model , or schema, that defines the class
Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs.

PubMed

Matrone, C; Pivonello, R; Colao, A; Cappabianca, P; Cavallo, L M; Del Basso De Caro, M L; Taylor, J E; Culler, M D; Lombardi, G; Di Renzo, G F; Annunziato, L

2004-03-01

The role of somatostatin (SS) receptor subtype 1 (SSTR(1)) in mediating the inhibitory effect of SS on growth hormone (GH) secreting pituitary tumors has been recently demonstrated. In the present study, we evaluated the effect of the selective SSTR(1) agonist BIM-23745 on in vitro GH secretion in GH-secreting pituitary tumor cells, deriving from patients resistant or partially responsive to octreotide long-acting release (octreotide-LAR) or lanreotide therapy in vivo and expressing SSTR(1) mRNA. In addition, the inhibiting effect of BIM-23745 on the GH secretion was compared with that of octreotide. Our data demonstrate that (1) SSTR(1) receptor was present in 56.25% (9/16) of the GH-secreting adenomas examined; (2) in all GH-secreting pituitary tumors that expressed SSTR(1), BIM-23745 significantly inhibited GH secretion in vitro, and (3) when SSTR(1) subtype was present in tumors from patients resistant to octreotide-LAR or lanreotide therapy, BIM-23745 was able to inhibit the in vitro GH secretion. In conclusion, the results of the current study suggest that SS analogs selective for the SSTR(1) may represent a further useful approach for the treatment of acromegaly in patients resistant or partially responsive to octreotide-LAR or lanreotide treatment in vivo. Copyright 2004 S. Karger AG, Basel
MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib

PubMed Central

Wirth, Matthias; Stojanovic, Natasa; Christian, Jan; Paul, Mariel C.; Stauber, Roland H.; Schmid, Roland M.; Häcker, Georg; Krämer, Oliver H.; Saur, Dieter; Schneider, Günter

2014-01-01

The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri-methylated lysine 4 of histone H3, marking active chromatin. We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC. PMID:25147211
RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice

PubMed Central

Herold, Marco J.

2016-01-01

Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53−/− mice. Thus, potentially oncogenic DNA lesions are likely to also trigger apoptosis through additional, p53-independent processes. We found that loss of the BH3-only protein BIM accelerated lymphoma development in p53-deficient mice. This process was negated by concomitant loss of RAG1/2-mediated antigen receptor gene rearrangement. This demonstrates that BIM is critical for the induction of apoptosis caused by potentially oncogenic DNA lesions elicited by RAG1/2-induced gene rearrangement. Furthermore, this highlights the role of a BIM-mediated tumor suppressor pathway that acts in parallel to the p53 pathway and remains active even in the absence of wild-type p53 function, suggesting this may be exploited in the treatment of p53-deficient cancers. PMID:27621418
Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.

PubMed

Dong, Hongli; Carlton, Michael E; Lerner, Adam; Epstein, Paul M

2015-01-01

Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad.
Bilateral comparison of 100 pF capacitance standards (ongoing BIPM key comparison BIPM.EM-K14.b) between the BIM, Bulgaria, and the BIPM, April 2012 to September 2012

NASA Astrophysics Data System (ADS)

Sapunova, I.; Fletcher, N.; Goebel, R.; Stock, M.

2015-01-01

This report gives the result of a bilateral comparison of capacitance between the BIM (Bulgaria) and the BIPM carried out in 2012. Two 100 pF travelling standards belonging to the BIPM were used. The comparison was carried out with an 'A-B-A' pattern of measurements; the standards were measured first at the BIPM for a period of about one month, then for a similar period at the BIM, and finally again at the BIPM. The measurand was the two terminal-pair capacitance at a frequency of 1000 Hz and for a measuring voltage of 15 V. The BIPM was the pilot laboratory, and the comparison forms part of the ongoing BIPM key comparison BIPM.EM-K14.a. The results from the BIM and the BIPM were found to be in good agreement, with a difference smaller than the relative expanded uncertainty (95% confidence, k = 2) of 1.1 × 10-6. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Bilateral comparison of 10 pF capacitance standards (ongoing BIPM key comparison BIPM.EM-K14.a) between the BIM, Bulgaria, and the BIPM, April 2012 to September 2012

NASA Astrophysics Data System (ADS)

Sapunova, I.; Fletcher, N.; Goebel, R.; Stock, M.

2015-01-01

This report gives the result of a bilateral comparison of capacitance between the BIM (Bulgaria) and the BIPM carried out in 2012. Two 10 pF travelling standards belonging to the BIPM were used. The comparison was carried out with an 'A-B-A' pattern of measurements; the standards were measured first at the BIPM for a period of about one month, then for a similar period at the BIM, and finally again at the BIPM. The measurand was the two terminal-pair capacitance at a frequency of 1000 Hz and for a measuring voltage of 15 V. The BIPM was the pilot laboratory, and the comparison forms part of the ongoing BIPM key comparison BIPM.EM-K14.a. The results from the BIM and the BIPM were found to be in good agreement, with a difference smaller than the relative expanded uncertainty (95% confidence, k = 2) of 1.1 × 10-6. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Fabrication, vascularization and osteogenic properties of a novel synthetic biomimetic induced membrane for the treatment of large bone defects

PubMed Central

Browne, Christopher; Bishop, Julius; Yang, Yunzhi

2014-01-01

The induced membrane has been widely used in the treatment of large bone defects but continues to be limited by a relatively lengthy healing process and a requisite two stage surgical procedure. Here we report the development and characterization of a synthetic biomimetic induced membrane (BIM) consisting of an inner highly pre-vascularized cell sheet and an outer osteogenic layer using cell sheet engineering. The pre-vascularized inner layer was formed by seeding human umbilical vein endothelial cells (HUVECs) on a cell sheet comprised of a layer of undifferentiated human bone marrow-derived mesenchymal stem cells (hMSCs). The outer osteogenic layer was formed by inducing osteogenic differentiation of hMSCs. In vitro results indicated the undifferentiated hMSCs cell sheet facilitated the alignment of HUVECs and significantly promoted the formation of vascular-like networks. Furthermore, seeded HUVECs rearranged the extracellular matrix produced by hMSCs sheet. After subcutaneously implantation, the composite constructs showed rapid vascularization and anastomosis with the host vascular system, forming functional blood vessels in vivo. Osteogenic potential of the BIM was evidenced by immunohistochemistry staining of osteocalcin, tartrate-resistant acid phosphatase (TRAP) staining, and alizarin red staining. In summary, the synthetic BIM showed rapid vascularization, significant anastomoses, and osteogenic potential in vivo. This synthetic BIM has the potential for treatment of large bone defects in the absence of infection. PMID:24747351
Modelling and Accuracy in a Bim Environment for Planned Conservation: the Apartment of Troia of Giulio Romano

NASA Astrophysics Data System (ADS)

Adami, A.; Scala, B.; Spezzoni, A.

2017-02-01

Modeling of Cultural Heritage in a BIM environment, and in general of existing buildings, requires special attention because there are two diametrically opposed possibilities. On the one hand the attempt is to realize a very complex and accurate model, in order to provide the most comprehensive representation of the architecture as possible. The opposite position leads to build a very schematic and symbolic model of as-built architecture. It is not easy to determine which is the right balance between these two attitudes because each architecture requires a personalized approach and not standards. It's, however, necessary to find rules to figure out which items are represented, what is the minimum level of detail to consider adequate and how to deal with alterations from simple and linear geometries. These two facing possibilities deal with different goals and tools. In the field of restoration or planned conservation, that is the most common approach for existing buildings, the attention focuses on the exceptions and particularities of each architecture: the important aspect is to understand and describe exactly each part as a singularity (as it is). In this context it is very difficult to find a standard or a common solution. The first possibility of modelling seems to be very close to this approach, but it clashes with two important aspects. A first problem concerns the modelling software. Usually commercial BIM modelling software doesn't allow to realize very complex and high detailed solutions. They prefer working with predefined families and try to categorize each element in standard solution. The possibility to build new families is expected, but it often requires a lot of time. The second difficulty is the real efficiency of such an accurate model. In fact, it could be very difficult to link external elements to the model or use it in many traditional BIM applications. In this paper, we suggest another possible approach that represents the first result of a research about the modelling of Cultural Heritage for BIM application. The proposed solution aims to give as much information as possible about the architecture, and, at the same time, to guarantee a higher efficiency. In this case we considered commercial BIM software like Revit or Archicad. They are the most widespread and well-known software BIM oriented and they also allow the use of their embedded database structure. The core of our solution is to describe the architecture not only by a 3D model but also by the representation of the reliability of the accuracy of the model itself. In this way we try to combine the necessity of working with commercial software, in which it is difficult to be very accurate, and the information about the real object. In historical complex architecture, for example, it is very difficult to find a straight and planar wall. It is quite difficult, or at least time consuming, to model that kind of wall with high accuracy. But it is possible to represent the real wall by a schematic wall with a false color map which describes where the 3D model is well fitting and where there are some differences. In this way we don't lose any information but, at the same time, we have a very usable BIM model.
Reciprocal sensitivity of diffuse large B-cell lymphoma cells to Bcl-2 inhibitors BIRD-2 versus venetoclax

PubMed Central

Vervloessem, Tamara; Akl, Haidar; Tousseyn, Thomas; De Smedt, Humbert; Parys, Jan B.; Bultynck, Geert

2017-01-01

Bcl-2 is often upregulated in cancers to neutralize the BH3-only protein Bim at the mitochondria. BH3 mimetics (e.g. ABT-199 (venetoclax)) kill cancer cells by targeting Bcl-2’s hydrophobic cleft and disrupting Bcl-2/Bim complexes. Some cancers with elevated Bcl-2 display poor responses towards BH3 mimetics, suggesting an additional function for anti-apoptotic Bcl-2 in these cancers. Indeed, Bcl-2 via its BH4 domain prevents cytotoxic Ca2+ release from the endoplasmic reticulum (ER) by directly inhibiting the inositol 1,4,5-trisphosphate receptor (IP3R). The cell-permeable Bcl-2/IP3R disruptor-2 (BIRD-2) peptide can kill these Bcl-2-dependent cancers by targeting Bcl-2’s BH4 domain, unleashing pro-apoptotic Ca2+-release events. We compared eight “primed to death” diffuse large B-cell lymphoma cell lines (DLBCL) for their apoptotic sensitivity towards BIRD-2 and venetoclax. By determining their IC50 using cytometric cell-death analysis, we discovered a reciprocal sensitivity towards venetoclax versus BIRD-2. Using immunoblotting, we quantified the expression levels of IP3R2 and Bim in DLBCL cell lysates, revealing that BIRD-2 sensitivity correlated with IP3R2 levels but not with Bim levels. Moreover, the requirement of intracellular Ca2+ for BIRD-2- versus venetoclax-induced cell death was different. Indeed, BAPTA-AM suppressed BIRD-2-induced cell death, but promoted venetoclax-induced cell death in DLBCL cells. Finally, compared to single-agent treatments, combining BIRD-2 with venetoclax synergistically enhanced cell-death induction, correlating with a Ca2+-dependent upregulation of Bim after BIRD-2 treatment. Our findings suggest that some cancer cells require Bcl-2 proteins at the mitochondria, preventing Bax activation via its hydrophobic cleft, while others require Bcl-2 proteins at the ER, preventing cytotoxic Ca2+-signaling events via its BH4 domain. PMID:29340082
Reciprocal sensitivity of diffuse large B-cell lymphoma cells to Bcl-2 inhibitors BIRD-2 versus venetoclax.

PubMed

Vervloessem, Tamara; Akl, Haidar; Tousseyn, Thomas; De Smedt, Humbert; Parys, Jan B; Bultynck, Geert

2017-12-19

Bcl-2 is often upregulated in cancers to neutralize the BH3-only protein Bim at the mitochondria. BH3 mimetics (e.g. ABT-199 (venetoclax)) kill cancer cells by targeting Bcl-2's hydrophobic cleft and disrupting Bcl-2/Bim complexes. Some cancers with elevated Bcl-2 display poor responses towards BH3 mimetics, suggesting an additional function for anti-apoptotic Bcl-2 in these cancers. Indeed, Bcl-2 via its BH4 domain prevents cytotoxic Ca 2+ release from the endoplasmic reticulum (ER) by directly inhibiting the inositol 1,4,5-trisphosphate receptor (IP 3 R). The cell-permeable Bcl-2/IP 3 R disruptor-2 (BIRD-2) peptide can kill these Bcl-2-dependent cancers by targeting Bcl-2's BH4 domain, unleashing pro-apoptotic Ca 2+ -release events. We compared eight "primed to death" diffuse large B-cell lymphoma cell lines (DLBCL) for their apoptotic sensitivity towards BIRD-2 and venetoclax. By determining their IC 50 using cytometric cell-death analysis, we discovered a reciprocal sensitivity towards venetoclax versus BIRD-2. Using immunoblotting, we quantified the expression levels of IP 3 R2 and Bim in DLBCL cell lysates, revealing that BIRD-2 sensitivity correlated with IP 3 R2 levels but not with Bim levels. Moreover, the requirement of intracellular Ca 2+ for BIRD-2- versus venetoclax-induced cell death was different. Indeed, BAPTA-AM suppressed BIRD-2-induced cell death, but promoted venetoclax-induced cell death in DLBCL cells. Finally, compared to single-agent treatments, combining BIRD-2 with venetoclax synergistically enhanced cell-death induction, correlating with a Ca 2+ -dependent upregulation of Bim after BIRD-2 treatment. Our findings suggest that some cancer cells require Bcl-2 proteins at the mitochondria, preventing Bax activation via its hydrophobic cleft, while others require Bcl-2 proteins at the ER, preventing cytotoxic Ca 2+ -signaling events via its BH4 domain.
Parametric Modelling (bim) for the Documentation of Vernacular Construction Methods: a Bim Model for the Commissariat Building, Ottawa, Canada

NASA Astrophysics Data System (ADS)

Fai, S.; Filippi, M.; Paliaga, S.

2013-07-01

Whether a house of worship or a simple farmhouse, the fabrication of a building reveals both the unspoken cultural aspirations of the builder and the inevitable exigencies of the construction process. In other-words, why buildings are made is intimately and inevitably associated with how buildings are made. Nowhere is this more evident than in vernacular architecture. At the Carleton Immersive Media Studio (CIMS) we are concerned that the de-population of Canada's rural areas, paucity of specialized tradespersons, and increasing complexity of building codes threaten the sustainability of this invaluable cultural resource. For current and future generations, the quantitative and qualitative values of traditional methods of construction are essential for an inclusive cultural memory. More practically, and equally pressing, an operational knowledge of these technologies is essential for the conservation of our built heritage. To address these concerns, CIMS has launched a number of research initiatives over the past five years that explore novel protocols for the documentation and dissemination of knowledge related to traditional methods of construction. Our current project, Cultural Diversity and Material Imagination in Canadian Architecture (CDMICA), made possible through funding from Canada's Social Sciences and Humanities Research Council (SSHRC), explores the potential of building information modelling (BIM) within the context of a web-based environment. In this paper, we discuss our work-to-date on the development of a web-based library of BIM details that is referenced to ''typical'' assemblies culled from 19C and early 20C construction manuals. The parametric potential of these ''typical'' details is further refined by evidence from the documentation of ''specific'' details studied during comprehensive surveys of extant heritage buildings. Here, we consider a BIM of the roof truss assembly of one of the oldest buildings in Canada's national capital - the Commissariat Building and current home to the Bytown Museum - as a case study within the CDMICA project.

Grouper iridovirus GIV66 is a Bcl-2 protein that inhibits apoptosis by exclusively sequestering Bim.

PubMed

Banjara, Suresh; Mao, Jiahao; Ryan, Timothy M; Caria, Sofia; Kvansakul, Marc

2018-04-13

Programmed cell death or apoptosis is a critical mechanism for the controlled removal of damaged or infected cells, and proteins of the Bcl-2 family are important arbiters of this process. Viruses have been shown to encode functional and structural homologs of Bcl-2 to counter premature host-cell apoptosis and ensure viral proliferation or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the Iridoviridae family and harbors GIV66, a putative Bcl-2-like protein and mitochondrially localized apoptosis inhibitor. However, the molecular and structural basis of GIV66-mediated apoptosis inhibition is currently not understood. To gain insight into GIV66's mechanism of action, we systematically evaluated its ability to bind peptides spanning the BH3 domain of pro-apoptotic Bcl-2 family members. Our results revealed that GIV66 harbors an unusually high level of specificity for pro-apoptotic Bcl-2 and displays affinity only for Bcl-2-like 11 (Bcl2L11 or Bim). Using crystal structures of both apo-GIV66 and GIV66 bound to the BH3 domain from Bim, we unexpectedly found that GIV66 forms dimers via an interface that results in occluded access to the canonical Bcl-2 ligand-binding groove, which breaks apart upon Bim binding. This observation suggests that GIV66 dimerization may affect GIV66's ability to bind host pro-death Bcl-2 proteins and enables highly targeted virus-directed suppression of host apoptosis signaling. Our findings provide a mechanistic understanding for the potent anti-apoptotic activity of GIV66 by identifying it as the first single-specificity, pro-survival Bcl-2 protein and identifying a pivotal role of Bim in GIV-mediated inhibition of apoptosis. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
What we learn from eclipsing binaries in the ultraviolet

NASA Technical Reports Server (NTRS)

Guinan, Edward F.

1990-01-01

Recent results on stars and stellar physics from IUE (International Ultraviolet Explorer) observations of eclipsing binaries are discussed. Several case studies are presented, including V 444 Cyg, Aur stars, V 471 Tau and AR Lac. Topics include stellar winds and mass loss, stellar atmospheres, stellar dynamos, and surface activity. Studies of binary star dynamics and evolution are discussed. The progress made with IUE in understanding the complex dynamical and evolutionary processes taking place in W UMa-type binaries and Algol systems is highlighted. The initial results of intensive studies of the W UMa star VW Cep and three representative Algol-type binaries (in different stages of evolution) focused on gas flows and accretion, are included. The future prospects of eclipsing binary research are explored. Remaining problems are surveyed and the next challenges are presented. The roles that eclipsing binaries could play in studies of stellar evolution, cluster dynamics, galactic structure, mass luminosity relations for extra galactic systems, cosmology, and even possible detection of extra solar system planets using eclipsing binaries are discussed.
Periodic Emission from the Gamma-ray Binary 1FGL J1018.6-5856

NASA Technical Reports Server (NTRS)

Celic, O.; Corbet, R. H. D.; Donato, D.; Ferrara, E. C.; Gehrels, N.; Harding, A. K.; Hays, E.; McEnery, J. E.; Thompson, D. J.; Troja, E.

2012-01-01

Gamma-ray binaries are stellar systems containing a neutron star or black hole with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that IFGL JI018.6-5856 exhibits intensity and spectral modulation with a 16.6 day period. We identified a variable X-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an 06V f) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. IFGL J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.
Periodic emission from the gamma-ray binary 1FGL J1018.6-5856.

PubMed

Fermi LAT Collaboration; Ackermann, M; Ajello, M; Ballet, J; Barbiellini, G; Bastieri, D; Belfiore, A; Bellazzini, R; Berenji, B; Blandford, R D; Bloom, E D; Bonamente, E; Borgland, A W; Bregeon, J; Brigida, M; Bruel, P; Buehler, R; Buson, S; Caliandro, G A; Cameron, R A; Caraveo, P A; Cavazzuti, E; Cecchi, C; Çelik, Ö; Charles, E; Chaty, S; Chekhtman, A; Cheung, C C; Chiang, J; Ciprini, S; Claus, R; Cohen-Tanugi, J; Corbel, S; Corbet, R H D; Cutini, S; de Luca, A; den Hartog, P R; de Palma, F; Dermer, C D; Digel, S W; do Couto e Silva, E; Donato, D; Drell, P S; Drlica-Wagner, A; Dubois, R; Dubus, G; Favuzzi, C; Fegan, S J; Ferrara, E C; Focke, W B; Fortin, P; Fukazawa, Y; Funk, S; Fusco, P; Gargano, F; Gasparrini, D; Gehrels, N; Germani, S; Giglietto, N; Giordano, F; Giroletti, M; Glanzman, T; Godfrey, G; Grenier, I A; Grove, J E; Guiriec, S; Hadasch, D; Hanabata, Y; Harding, A K; Hayashida, M; Hays, E; Hill, A B; Hughes, R E; Jóhannesson, G; Johnson, A S; Johnson, T J; Kamae, T; Katagiri, H; Kataoka, J; Kerr, M; Knödlseder, J; Kuss, M; Lande, J; Longo, F; Loparco, F; Lovellette, M N; Lubrano, P; Mazziotta, M N; McEnery, J E; Michelson, P F; Mitthumsiri, W; Mizuno, T; Monte, C; Monzani, M E; Morselli, A; Moskalenko, I V; Murgia, S; Nakamori, T; Naumann-Godo, M; Norris, J P; Nuss, E; Ohno, M; Ohsugi, T; Okumura, A; Omodei, N; Orlando, E; Ozaki, M; Paneque, D; Parent, D; Pesce-Rollins, M; Pierbattista, M; Piron, F; Pivato, G; Porter, T A; Rainò, S; Rando, R; Razzano, M; Reimer, A; Reimer, O; Ritz, S; Romani, R W; Roth, M; Saz Parkinson, P M; Sgrò, C; Siskind, E J; Spandre, G; Spinelli, P; Suson, D J; Takahashi, H; Tanaka, T; Thayer, J G; Thayer, J B; Thompson, D J; Tibaldo, L; Tinivella, M; Torres, D F; Tosti, G; Troja, E; Uchiyama, Y; Usher, T L; Vandenbroucke, J; Vianello, G; Vitale, V; Waite, A P; Winer, B L; Wood, K S; Wood, M; Yang, Z; Zimmer, S; Coe, M J; Di Mille, F; Edwards, P G; Filipović, M D; Payne, J L; Stevens, J; Torres, M A P

2012-01-13

Gamma-ray binaries are stellar systems containing a neutron star or black hole, with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation with a 16.6-day period. We identified a variable x-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGL J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.
Periodic Emission from the Gamma-Ray Binary 1FGL J1018.6-5856

NASA Technical Reports Server (NTRS)

2012-01-01

Gamma-ray binaries are stellar systems containing a neutron star or black hole, with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy, A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL ]1018.6-5856 exhibits intensity and spectral modulation with a 16.6 day period. We identified a variable x-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGL ]1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.
Introduction of Building Information Modeling (BIM) Technologies in Construction

NASA Astrophysics Data System (ADS)

Milyutina, M. A.

2018-05-01

The issues of introduction of building information modeling (BIM) in construction industry are considered in this work. The advantages of this approach and perspectives of the transition to new design technologies, construction process management, and operation in the near future are stated. The importance of development of pilot projects that should identify the ways and means of verification of the regulatory and technical base, as well as economic indicators in the transition to Building Information Technologies in the construction, is noted.
A review of building information modelling

NASA Astrophysics Data System (ADS)

Wang, Wen; Han, Rui

2018-05-01

Building Information Modelling (BIM) is widely seen as a catalyst for innovation and productivity. It is becoming standard for new construction and is the most significant technology changing how we design, build, use and manage the building. It is a dominant technological trend in the software industry and although the theoretical groundwork was laid in the previous century, it is a popular topic in academic research. BIM is discussed in this study, which results can provide better and more comprehensive choices for building owners, designers, and developers in future.
1974: the discovery of the first binary pulsar

NASA Astrophysics Data System (ADS)

Damour, Thibault

2015-06-01

The 1974 discovery, by Russell A Hulse and Joseph H Taylor, of the first binary pulsar, PSR B1913+16, opened up new possibilities for the study of relativistic gravity. PSR B1913+16, as well as several other binary pulsars, provided direct observational proof that gravity propagates at the velocity of light and has a quadrupolar structure. Binary pulsars also provided accurate tests of the strong-field regime of relativistic gravity. General relativity has passed all of the binary pulsar tests with flying colors. The discovery of binary pulsars also had very important consequences for astrophysics, leading to accurate measurement of neutron star masses, improved understanding of the possible evolution scenarios for the co-evolution of binary stars, and proof of the existence of binary neutron stars emitting gravitational waves for hundreds of millions of years, before coalescing in catastrophic events radiating intense gravitational wave signals, and probably also leading to important emissions of electromagnetic radiation and neutrinos. This article reviews the history of the discovery of the first binary pulsar, and describes both its immediate impact and its longer-term effect on theoretical and experimental studies of relativistic gravity.
Substituent and ring effects on enthalpies of formation: 2-methyl- and 2-ethylbenzimidazoles versus benzene- and imidazole-derivatives

NASA Astrophysics Data System (ADS)

Jiménez, Pilar; Roux, María Victoria; Dávalos, Juan Z.; Temprado, Manuel; Ribeiro da Silva, Manuel A. V.; Ribeiro da Silva, Maria Das Dores M. C.; Amaral, Luísa M. P. F.; Cabildo, Pilar; Claramunt, Rosa M.; Mó, Otilia; Yáñez, Manuel; Elguero, José

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-methylbenzimidazole (2MeBIM) and 2-ethylbenzimidazole (2EtBIM) are reported and the results compared with those of benzimidazole itself (BIM). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311+G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of benzenes, imidazoles and benzimidazoles bearing H (unsubstituted), methyl and ethyl groups shows remarkable homogeneity. The energetic group contribution transferability is not followed, but either using it or adding an empirical interaction term, it is possible to generate an enormous collection of reasonably accurate data for different substituted heterocycles (pyrazole-derivatives, pyridine-derivatives, etc.) from the large amount of values available for substituted benzenes and those of the parent (pyrazole, pyridine) heterocycles.
a Framework for Architectural Heritage Hbim Semantization and Development

NASA Astrophysics Data System (ADS)

Brusaporci, S.; Maiezza, P.; Tata, A.

2018-05-01

Despite the recognized advantages of the use of BIM in the field of architecture and engineering, the extension of this procedure to the architectural heritage is neither immediate nor critical. The uniqueness and irregularity of historical architecture, on the one hand, and the great quantity of information necessary for the knowledge of architectural heritage, on the other, require appropriate reflections. The aim of this paper is to define a general framework for the use of BIM procedures for architectural heritage. The proposed methodology consists of three different Level of Development (LoD), depending on the characteristics of the building and the objectives of the study: a simplified model with a low geometric accuracy and a minimum quantity of information (LoD 200); a model nearer to the reality but, however, with a high deviation between virtual and real model (LoD 300); a detailed BIM model that reproduce as much as possible the geometric irregularities of the building and is enriched by the maximum quantity of information available (LoD 400).
Developing Historic Building Information Modelling Guidelines and Procedures for Architectural Heritage in Ireland

NASA Astrophysics Data System (ADS)

Murphy, M.; Corns, A.; Cahill, J.; Eliashvili, K.; Chenau, A.; Pybus, C.; Shaw, R.; Devlin, G.; Deevy, A.; Truong-Hong, L.

2017-08-01

Cultural heritage researchers have recently begun applying Building Information Modelling (BIM) to historic buildings. The model is comprised of intelligent objects with semantic attributes which represent the elements of a building structure and are organised within a 3D virtual environment. Case studies in Ireland are used to test and develop the suitable systems for (a) data capture/digital surveying/processing (b) developing library of architectural components and (c) mapping these architectural components onto the laser scan or digital survey to relate the intelligent virtual representation of a historic structure (HBIM). While BIM platforms have the potential to create a virtual and intelligent representation of a building, its full exploitation and use is restricted to narrow set of expert users with access to costly hardware, software and skills. The testing of open BIM approaches in particular IFCs and the use of game engine platforms is a fundamental component for developing much wider dissemination. The semantically enriched model can be transferred into a WEB based game engine platform.
Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery.

PubMed

Yan, Jin; He, Wangxiao; Yan, Siqi; Niu, Fan; Liu, Tianya; Ma, Bohan; Shao, Yongping; Yan, Yuwei; Yang, Guang; Lu, Wuyuan; Du, Yaping; Lei, Bo; Ma, Peter X

2018-02-27

Developing a sophisticated nanomedicine platform to deliver therapeutics effectively and safely into tumor/cancer cells remains challenging in the field of nanomedicine. In particular, reliable peptide drug delivery systems capable of overcoming biological barriers are still lacking. Here, we developed a simple, rapid, and robust strategy to manufacture nanoclusters of ∼90 nm in diameter that are self-assembled from lanthanide-doped nanoparticles (5 nm), two anticancer peptides with different targets (BIM and PMI), and one cyclic peptide iNGR targeted to cancer cells. The peptide-lanthanide nanoclusters (LDC-PMI-BIM-iNGR) enhanced the resistance of peptide drugs to proteolysis, disassembled in response to reductive conditions that are present in the tumor microenvironment and inhibited cancer cell growth in vitro and in vivo. Notably, LDC-PMI-BIM-iNGR exhibited extremely low systemic toxicity and side effects in vivo. Thus, the peptide-lanthanide nanocluster may serve as an ideal multifunctional platform for safe, targeted, and efficient peptide drug delivery in cancer therapy.
Leveraging Existing Heritage Documentation for Animations: Senate Virtual Tour

NASA Astrophysics Data System (ADS)

Dhanda, A.; Fai, S.; Graham, K.; Walczak, G.

2017-08-01

The use of digital documentation techniques has led to an increase in opportunities for using documentation data for valorization purposes, in addition to technical purposes. Likewise, building information models (BIMs) made from these data sets hold valuable information that can be as effective for public education as it is for rehabilitation. A BIM can reveal the elements of a building, as well as the different stages of a building over time. Valorizing this information increases the possibility for public engagement and interest in a heritage place. Digital data sets were leveraged by the Carleton Immersive Media Studio (CIMS) for parts of a virtual tour of the Senate of Canada. For the tour, workflows involving four different programs were explored to determine an efficient and effective way to leverage the existing documentation data to create informative and visually enticing animations for public dissemination: Autodesk Revit, Enscape, Autodesk 3ds Max, and Bentley Pointools. The explored workflows involve animations of point clouds, BIMs, and a combination of the two.
Parametric Accuracy: Building Information Modeling Process Applied to the Cultural Heritage Preservation

NASA Astrophysics Data System (ADS)

Garagnani, S.; Manferdini, A. M.

2013-02-01

Since their introduction, modeling tools aimed to architectural design evolved in today's "digital multi-purpose drawing boards" based on enhanced parametric elements able to originate whole buildings within virtual environments. Semantic splitting and elements topology are features that allow objects to be "intelligent" (i.e. self-aware of what kind of element they are and with whom they can interact), representing this way basics of Building Information Modeling (BIM), a coordinated, consistent and always up to date workflow improved in order to reach higher quality, reliability and cost reductions all over the design process. Even if BIM was originally intended for new architectures, its attitude to store semantic inter-related information can be successfully applied to existing buildings as well, especially if they deserve particular care such as Cultural Heritage sites. BIM engines can easily manage simple parametric geometries, collapsing them to standard primitives connected through hierarchical relationships: however, when components are generated by existing morphologies, for example acquiring point clouds by digital photogrammetry or laser scanning equipment, complex abstractions have to be introduced while remodeling elements by hand, since automatic feature extraction in available software is still not effective. In order to introduce a methodology destined to process point cloud data in a BIM environment with high accuracy, this paper describes some experiences on monumental sites documentation, generated through a plug-in written for Autodesk Revit and codenamed GreenSpider after its capability to layout points in space as if they were nodes of an ideal cobweb.
Modulation of glucocorticoid resistance in pediatric T-cell Acute Lymphoblastic Leukemia by increasing BIM expression with the PI3K/mTOR inhibitor BEZ235

PubMed Central

Hall, Connor P.; Reynolds, C. Patrick; Kang, Min H.

2015-01-01

Purpose The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in ALL. Experimental Design The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry and immunoprecipitation. Results Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the pro-apoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression. Conclusion Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL. PMID:26080839
Viral/Nonviral Chimeric Nanoparticles to Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing

PubMed Central

Hong, Cheol Am; Cho, Soo Kyung; Edson, Julius A.; Kim, Jane; Ingato, Dominique; Pham, Bryan; Chuang, Anthony; Fruman, David; Kwon, Young Jik

2017-01-01

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of Chronic Myelogenous Leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic anti-leukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and inter-linked pathological pathways. PMID:27472284
Mir-24 regulates hepatocyte apoptosis via BIM during acute liver failure.

PubMed

Feng, Zhiwen; Li, Zhi; Zhu, Deming; Ling, Wei; Zheng, Lei; Pu, Liyong; Kong, Lianbao

2017-01-01

Acuteliver failure (ALF) has a high mortality rate and is characterized by massive hepatocyte destruction. Although microRNAs (miRNAs) play an important role in manyliver diseases, the role of miRNAs in ALF development is unknown. In this study, the murine ALF model was induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (D-GalN/LPS). Compared with saline-treated mice, miR-24 was distinctly down-regulated post D-GalN/LPS challenge in vivo and D-galactosamine/tumor necrosis factor (D-GalN/TNF) challenge in vitro , which was confirmed by quantitative real-time polymerase chain reaction. Meanwhile, the mRNA and protein levels of the BH3-only-domain-containing protein BIM were upregulated after challenge both in vivo and in vitro . Previous studies have demonstrated that hepatocyte apoptosis is a distinguishing feature of D-GalN/LPS-associated liver failure. In this study, D-GalN/LPS-challenged mice showed higher alanine aminotransferase and aspartate aminotransferase levels, more severe liver damage, increased numbers of apoptotic hepatocytes and higher levels of caspase-3 compared with saline-treated mice. In D-GalN/TNF-treated BNLCL2 cells, miR-24 overexpression attenuated apoptosis.Furthermore, miR-24 overexpression reduced BIM mRNA and protein levels in vitro . Taken together, these findings demonstrate that miR-24 regulates hepatocyte apoptosis via BIM during ALF development, suggesting that miR-24 is a novel onco-miRNA that may provide potential therapeutic targets for ALF.
Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

PubMed

Woo, S M; Min, K-J; Seo, B R; Nam, J-O; Choi, K S; Yoo, Y H; Kwon, T K

2014-11-06

Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.
"iBIM"--internet-based interactive modules: an easy and interesting learning tool for general surgery residents.

PubMed

Azer, Nader; Shi, Xinzhe; de Gara, Chris; Karmali, Shahzeer; Birch, Daniel W

2014-04-01

The increased use of information technology supports a resident- centred educational approach that promotes autonomy, flexibility and time management and helps residents to assess their competence, promoting self-awareness. We established a web-based e-learning tool to introduce general surgery residents to bariatric surgery and evaluate them to determine the most appropriate implementation strategy for Internet-based interactive modules (iBIM) in surgical teaching. Usernames and passwords were assigned to general surgery residents at the University of Alberta. They were directed to the Obesity101 website and prompted to complete a multiple-choice precourse test. Afterwards, they were able to access the interactive modules. Residents could review the course material as often as they wanted before completing a multiple-choice postcourse test and exit survey. We used paired t tests to assess the difference between pre- and postcourse scores. Out of 34 residents who agreed to participate in the project, 12 completed the project (35.3%). For these 12 residents, the precourse mean score was 50 ± 17.3 and the postcourse mean score was 67 ± 14 (p = 0.020). Most residents who participated in this study recommended using the iBIMs as a study tool for bariatric surgery. Course evaluation scores suggest this novel approach was successful in transferring knowledge to surgical trainees. Further development of this tool and assessment of implementation strategies will determine how iBIM in bariatric surgery may be integrated into the curriculum.
Mcl-1–Bim complexes accommodate surprising point mutations via minor structural changes

PubMed Central

Fire, Emiko; Gullá, Stefano V; Grant, Robert A; Keating, Amy E

2010-01-01

Mcl-1 is an antiapoptotic Bcl-2-family protein that protects cells against death. Structures of Mcl-1, and of other anti-apoptotic Bcl-2 proteins, reveal a surface groove into which the α-helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl-2 family function. We report the crystal structure of human Mcl-1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl-1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine-to-alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix α3 accommodating an isoleucine-to-tyrosine mutation at this same position. We surveyed the variation in available Mcl-1 and Bcl-xL structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3-only proteins with Mcl-1. With the antiapoptotic Bcl-2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl-1. PMID:20066663

Bim Orientation: Grades of Generation and Information for Different Type of Analysis and Management Process

NASA Astrophysics Data System (ADS)

Banfi, F.

2017-08-01

Architecture, Engineering and Construction (AEC) industry is facing a great process re-engineering of the management procedures for new constructions, and recent studies show a significant increase of the benefits obtained through the use of Building Information Modelling (BIM) methodologies. This innovative approach needs new developments for information and communication technologies (ICT) in order to improve cooperation and interoperability among different actors and scientific disciplines. Accordingly, BIM could be described as a new tool capable of collect/analyse a great quantity of information (Big data) and improve the management of building during its life of cycle (LC). The main aim of this research is, in addition to a reduction in production times, reduce physical and financial resources (economic impact), to demonstrate how technology development can support a complex generative process with new digital tools (modelling impact). This paper reviews recent BIMs of different historical Italian buildings such as Basilica of Collemaggio in L'Aquila, Masegra Castle in Sondrio, Basilica of Saint Ambrose in Milan and Visconti Bridge in Lecco and carries out a methodological analysis to optimize output information and results combining different data and modelling techniques into a single hub (cloud service) through the use of new Grade of Generation (GoG) and Information (GoI) (management impact). Finally, this study shows the need to orient GoG and GoI for a different type of analysis, which requires a high Grade of Accuracy (GoA) and an Automatic Verification System (AVS ) at the same time.
Critical Issues and Key Points from the Survey to the Creation of the Historical Building Information Model: the Case of Santo Stefano Basilica

NASA Astrophysics Data System (ADS)

Castagnetti, C.; Dubbini, M.; Ricci, P. C.; Rivola, R.; Giannini, M.; Capra, A.

2017-05-01

The new era of designing in architecture and civil engineering applications lies in the Building Information Modeling (BIM) approach, based on a 3D geometric model including a 3D database. This is easier for new constructions whereas, when dealing with existing buildings, the creation of the BIM is based on the accurate knowledge of the as-built construction. Such a condition is allowed by a 3D survey, often carried out with laser scanning technology or modern photogrammetry, which are able to guarantee an adequate points cloud in terms of resolution and completeness by balancing both time consuming and costs with respect to the request of final accuracy. The BIM approach for existing buildings and even more for historical buildings is not yet a well known and deeply discussed process. There are still several choices to be addressed in the process from the survey to the model and critical issues to be discussed in the modeling step, particularly when dealing with unconventional elements such as deformed geometries or historical elements. The paper describes a comprehensive workflow that goes through the survey and the modeling, allowing to focus on critical issues and key points to obtain a reliable BIM of an existing monument. The case study employed to illustrate the workflow is the Basilica of St. Stefano in Bologna (Italy), a large monumental complex with great religious, historical and architectural assets.
Low intensity magnetic field influences short-term memory: A study in a group of healthy students.

PubMed

Navarro, Enrique A; Gomez-Perretta, Claudio; Montes, Francisco

2016-01-01

This study analyzes if an external magnetic stimulus (2 kHz and approximately 0.1 μT applied near frontal cortex) influences working memory, perception, binary decision, motor execution, and sustained attention in humans. A magnetic stimulus and a sham stimulus were applied to both sides of the head (frontal cortex close to temporal-parietal area) in young and healthy male test subjects (n = 65) while performing Sternberg's memory scanning task. There was a significant change in reaction time. Times recorded for perception, sustained attention, and motor execution were lower in exposed subjects (P < 0.01). However, time employed in binary decision increased for subjects exposed to magnetic fields. From results, it seems that a low intensity 2 kHz exposure modifies short-term working memory, as well as perception, binary decision, motor execution, and sustained attention. © 2015 Wiley Periodicals, Inc.
Robustness of weighted networks

NASA Astrophysics Data System (ADS)

Bellingeri, Michele; Cassi, Davide

2018-01-01

Complex network response to node loss is a central question in different fields of network science because node failure can cause the fragmentation of the network, thus compromising the system functioning. Previous studies considered binary networks where the intensity (weight) of the links is not accounted for, i.e. a link is either present or absent. However, in real-world networks the weights of connections, and thus their importance for network functioning, can be widely different. Here, we analyzed the response of real-world and model networks to node loss accounting for link intensity and the weighted structure of the network. We used both classic binary node properties and network functioning measure, introduced a weighted rank for node importance (node strength), and used a measure for network functioning that accounts for the weight of the links (weighted efficiency). We find that: (i) the efficiency of the attack strategies changed using binary or weighted network functioning measures, both for real-world or model networks; (ii) in some cases, removing nodes according to weighted rank produced the highest damage when functioning was measured by the weighted efficiency; (iii) adopting weighted measure for the network damage changed the efficacy of the attack strategy with respect the binary analyses. Our results show that if the weighted structure of complex networks is not taken into account, this may produce misleading models to forecast the system response to node failure, i.e. consider binary links may not unveil the real damage induced in the system. Last, once weighted measures are introduced, in order to discover the best attack strategy, it is important to analyze the network response to node loss using nodes rank accounting the intensity of the links to the node.
Periodic Emission from the Gamma-Ray Binary 1FGL J1018.6-5856

DOE PAGES

Ackermann, M.

2012-01-12

Gamma-ray binaries are stellar systems containing a neutron star or black hole with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation with a 16.6 day period. We identified a variable X-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGLmore » J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.« less
Testing the Merger Paradigm: X-ray Observations of Radio-Selected Sub-Galactic-Scale Binary AGNs

NASA Astrophysics Data System (ADS)

Fu, Hai

2016-09-01

Interactions play an important role in galaxy evolution. Strong gas inflows are expected in the process of gas-rich mergers, which may fuel intense black hole accretion and star formation. Sub-galactic-scale binary/dual AGNs thus offer elegant laboratories to study the merger-driven co-evolution phase. However, previous samples of kpc-scale binaries are small and heterogeneous. We have identified a flux-limited sample of kpc-scale binary AGNs uniformly from a wide-area high-resolution radio survey conducted by the VLA. Here we propose Chandra X-ray characterization of a subset of four radio-confirmed binary AGNs at z 0.1. Our goal is to compare their X-ray properties with those of matched control samples to test the merger-driven co-evolution paradigm.
Taste Mixture Interactions: Suppression, Additivity, and the Predominance of Sweetness

PubMed Central

Green, Barry G.; Lim, Juyun; Osterhoff, Floor; Blacher, Karen; Nachtigal, Danielle

2010-01-01

Most of what is known about taste interactions has come from studies of binary mixtures. The primary goal of this study was to determine whether asymmetries in suppression between stimuli in binary mixtures predict the perception of tastes in more complex mixtures (e.g., ternary, quaternary mixtures). Also of interest was the longstanding question of whether overall taste intensity derives from the sum of the tastes perceived within a mixture (perceptual additivity) or from the sum of the perceived intensities of the individual stimuli (stimulus additivity). Using the general Labeled Magnitude Scale together with a sip-and-spit procedure, we asked subjects to rate overall taste intensity and the sweetness, sourness, saltiness and bitterness of approximately equi- intense sucrose, NaCl, citric acid and QSO4 stimuli presented alone and in all possible binary, ternary and quaternary mixtures. The results showed a consistent pattern of mixture suppression in which sucrose sweetness tended to be both the least suppressed quality and the strongest suppressor of other tastes. The overall intensity of mixtures was found to be predicted best by perceptual additivity. A second experiment that was designed to rule out potentially confounding effects of the order of taste ratings and the temperature of taste solutions replicated the main findings of the first experiment. Overall, the results imply that mixture suppression favors perception of sweet carbohydrates in foods at the expense of other potentially harmful ingredients, such as high levels of sodium (saltiness) and potential poisons or spoilage (bitterness, sourness). PMID:20800076
Phasor Analysis of Binary Diffraction Gratings with Different Fill Factors

ERIC Educational Resources Information Center

Martinez, Antonio; Sanchez-Lopez, Ma del Mar; Moreno, Ignacio

2007-01-01

In this work, we present a simple analysis of binary diffraction gratings with different slit widths relative to the grating period. The analysis is based on a simple phasor technique directly derived from the Huygens principle. By introducing a slit phasor and a grating phasor, the intensity of the diffracted orders and the grating's resolving…
Recognition of binary x-ray systems utilizing the doppler effect

NASA Technical Reports Server (NTRS)

Novak, B. L.

1980-01-01

The possibility of recognizing the duality of a single class of X-ray systems utilizing the Doppler effect is studied. The procedure is based on the presence of a period which coincides with the orbital period at the intensity of the radiation in a fixed energy interval of the X-ray component of a binary system.
Excited-state proton transfer dynamics of firefly's chromophore D-luciferin in DMSO-water binary mixture.

PubMed

Kuchlyan, Jagannath; Banik, Debasis; Roy, Arpita; Kundu, Niloy; Sarkar, Nilmoni

2014-12-04

In this article we have investigated intermolecular excited-state proton transfer (ESPT) of firefly's chromophore D-luciferin in DMSO-water binary mixtures using steady-state and time-resolved fluorescence spectroscopy. The unusual behavior of DMSO-water binary mixture as reported by Bagchi et al. (J. Phys. Chem. B 2010, 114, 12875-12882) was also found using D-luciferin as intermolecular ESPT probe. The binary mixture has given evidence of its anomalous nature at low mole fractions of DMSO (below XD = 0.4) in our systematic investigation. Upon excitation of neutral D-luciferin molecule, dual fluorescence emissions (protonated and deprotonated form) are observed in DMSO-water binary mixture. A clear isoemissive point in the time-resolved area normalized emission spectra further indicates two emissive species in the excited state of D-luciferin in DMSO-water binary mixture. DMSO-water binary mixtures of different compositions are fascinating hydrogen bonding systems. Therefore, we have observed unusual changes in the fluorescence emission intensity, fluorescence quantum yield, and fluorescence lifetime of more hydrogen bonding sensitive anionic form of D-luciferin in low DMSO content of DMSO-water binary mixture.
Novel boronic acid derivatives of bis(indolyl) methane as anti-MRSA agents.

PubMed

Mandal, Santi M; Pegu, Rupa; Porto, William F; Franco, Octavio L; Pratihar, Sanjay

2017-05-15

Towards the search for a new generation of antibiotics to control methicillin-resistant Staphylococcus aureus (MRSA), the design and synthesis of various bis indolyl methane (BIM) derivatives based on their different electron donor and acceptor properties of the substituents have been made, in which boronic acid derivatives of BIM are found to be active against MRSA. The observed evidence with the lead compound reveals their strong anti-MRSA activity, which paves the way of design and further development of a new generation antibiotics. Copyright © 2017 Elsevier Ltd. All rights reserved.
Barriers to front propagation in laminar, three-dimensional fluid flows

NASA Astrophysics Data System (ADS)

Doan, Minh; Simons, J. J.; Lilienthal, Katherine; Solomon, Tom; Mitchell, Kevin A.

2018-03-01

We present experiments on one-way barriers that block reaction fronts in a fully three-dimensional (3D) fluid flow. Fluorescent Belousov-Zhabotinsky reaction fronts are imaged with laser-scanning in a laminar, overlapping vortex flow. The barriers are analyzed with a 3D extension to burning invariant manifold (BIM) theory that was previously applied to two-dimensional advection-reaction-diffusion processes. We discover tube and sheet barriers that guide the front evolution. The experimentally determined barriers are explained by BIMs calculated from a model of the flow.
Reducing Costs and Increasing Productivity in Ship Maintenance Using Product Lifecycle Management, 3D Laser Scanning and 3D Printing

DTIC Science & Technology

2014-03-01

information modeling guide series: 03—GSA BIM guide for 3D imaging (Ver. 1). Retrieved from http://www.gsa.gov/graphics/pbs/GSA_BIM_Guide_Series_03... model during a KVA knowledge audit at FRC San Diego. The information used in the creation of his KVA models was generated from the SME-provided...Kenney then used the information gathered during SME interviews to reengineer the process to include 3D printing to form his “to-be” model . The
Binary Mixtures of Particles with Different Diffusivities Demix.

PubMed

Weber, Simon N; Weber, Christoph A; Frey, Erwin

2016-02-05

The influence of size differences, shape, mass, and persistent motion on phase separation in binary mixtures has been intensively studied. Here we focus on the exclusive role of diffusivity differences in binary mixtures of equal-sized particles. We find an effective attraction between the less diffusive particles, which are essentially caged in the surrounding species with the higher diffusion constant. This effect leads to phase separation for systems above a critical size: A single close-packed cluster made up of the less diffusive species emerges. Experiments for testing our predictions are outlined.
Generation of equal-intensity coherent optical beams by binary geometrical phase on metasurface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Zheng-Han; Jiang, Shang-Chi; Xiong, Xiang

We report here the design and realization of a broadband, equal-intensity optical beam splitter with a dispersion-free binary geometric phase on a metasurface with unit cell consisting of two mirror-symmetric elements. We demonstrate experimentally that two identical beams can be efficiently generated with incidence of any polarization. The efficiency of the device reaches 80% at 1120 nm and keeps larger than 70% in the range of 1000–1400 nm. We suggest that this approach for generating identical, coherent beams have wide applications in diffraction optics and in entangled photon light source for quantum communication.
Adjustable repetition-rate multiplication of optical pulses using fractional temporal Talbot effect with preceded binary intensity modulation

NASA Astrophysics Data System (ADS)

Xie, Qijie; Zheng, Bofang; Shu, Chester

2017-05-01

We demonstrate a simple approach for adjustable multiplication of optical pulses in a fiber using the temporal Talbot effect. Binary electrical patterns are used to control the multiplication factor in our approach. The input 10 GHz picosecond pulses are pedestal-free and are shaped directly from a CW laser. The pulses are then intensity modulated by different sets of binary patterns prior to entering a fiber of fixed dispersion. Tunable repetition-rate multiplication by different factors of 2, 4, and 8 have been achieved and up to 80 GHz pulse train has been experimentally generated. We also evaluate numerically the influence of the extinction ratio of the intensity modulator on the performance of the multiplied pulse train. In addition, the impact of the modulator bias on the uniformity of the output pulses has also been analyzed through simulation and experiment and a good agreement is reached. Last, we perform numerical simulation on the RF spectral characteristics of the output pulses. The insensitivity of the signal-to-subharmonic noise ratio (SSNR) to the laser linewidth shows that our multiplication scheme is highly tolerant to the incoherence of the input optical pulses.
Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis.

PubMed

Weber, Stefan U; Schewe, Jens-Christian; Lehmann, Lutz E; Müller, Stefan; Book, Malte; Klaschik, Sven; Hoeft, Andreas; Stüber, Frank

2008-01-01

In transgenic animal models of sepsis, members of the Bcl-2 family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro-apoptotic and anti-apoptotic members of the Bcl-2 family of proteins in patients with early stage severe sepsis. In this prospective case-control study, patients were recruited from three intensive care units (ICUs) in a university hospital. Sixteen patients were enrolled when they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and 11 healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine externalisation in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed using flow cytometry. Specific mRNAs of Bcl-2 family members were quantified from whole blood by real-time PCR. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc analysis was performed. In all lymphocyte populations caspase-3 (p < 0.05) was activated, which was reflected in an increased phosphatidylserine externalisation (p < 0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p < 0.05) and B-cells (p < 0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared with critically ill patients (p < 0.001) and 51.6-fold as compared with healthy controls (p < 0.05). Bid was increased 12.9-fold compared with critically ill patients (p < 0.001). In the group of mitochondrial apoptosis inducers, Bak was upregulated 5.6-fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p < 0.001 and p < 0.05, respectively). In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl proteins was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.
Bim System for the Conservation and Preservation of the Mosaics of San Marco in Venice

NASA Astrophysics Data System (ADS)

Fassi, F.; Fregonese, L.; Adami, A.; Rechichi, F.

2017-08-01

The Basilica of San Marco in Venice is a well-known masterpiece of World Heritage. It is a real multi-faceted architecture. The management of the church and its construction site is very complicated, and requires an efficient system to collect and manage different kinds of data. The BIM approach appeared to be the most suitable to collect multi-source data, to monitor activities and guarantee the well-timed operations inside the church. The purpose of this research was to build a BIM of the Basilica, considering all aspects that characterize it and that require particular care. Many problems affected the phase of the acquisition of data, and forced the team to establish a clear working pipeline that allowed the survey simultaneously, hand in hand, with all the usual activities of the church. The fundamental principle for the organization of the whole work was the subdivision of the entire complex in smaller parts, which could be managed independently, both in the acquisition and the modelling stage. This subdivision also reflects the method used for the photogrammetric acquisition. The complexity of some elements, as capitals and statues, was acquired with different Level of Detail (LoD) using various photogrammetric acquisitions: from the most general ones to describe the space, to the most detailed one 1:1 scale renderings. In this way, different LoD point clouds correspond to different areas or details. As evident, this pipeline allows to work in a more efficient way during the survey stage, but it involves more difficulties in the modelling stage. Because of the complexity of the church and the presence of sculptural elements represented by a mesh, from the beginning the problem of the amount of data was evident: it is nonsense to manage all models in a single file. The challenging aspect of the research job was the precise requirement of the Procuratoria di San Marco: to obtain the 1:1 representation of all the mosaics of the Basilica. This requirement significantly increased the effort in the acquisition stage, because it was necessary to reach a submillimetre resolution in the photographic images sufficient to distinguish perfectly each single tessera, also in the highest domes (28 meters). Furthermore, it introduced a new problem about the management of the gigapixel - orthophotos. The BIM approach presented in this paper tries to offer a solution to all these problems. The BIM application is based not on commercial software, but on a self-implemented system, which was previously tested on the Main Spire of Milano Cathedral. The multi-scale and multi-area approach have also been maintained in the BIM construction phase. In the case of Basilica di San Marco, the most important requirement was the management of the orthophotos of each single element. It was necessary to give the user the possibility to recover, for each item, not only the geometric model, but also the raster representation -orthophoto- of its surface: in order to do it, the BIM model acts as a three-dimensional catalogue.
Coastal bathymetry data collected in 2013 from the Chandeleur Islands, Louisiana

USGS Publications Warehouse

DeWitt, Nancy T.; Miselis, Jennifer L.; Fredericks, Jake J.; Bernier, Julie C.; Reynolds, Billy J.; Kelso, Kyle W.; Thompson, David M.; Flocks, James G.; Wiese, Dana S.

2017-01-12

As part of the Barrier Island Evolution Research Project, scientists from the U.S. Geological Survey (USGS) St. Petersburg Coastal and Marine Science Center conducted nearshore geophysical surveys around the northern Chandeleur Islands, Louisiana, in July and August of 2013. The objective of the study is to better understand barrier-island geomorphic evolution, particularly storm-related depositional and erosional processes that shape the islands over annual to interannual timescales (1‒5 years). Collecting geophysical data will allow us to identify relationships between the geologic history of the island and its present day morphology and sediment distribution. This mapping effort was the third in a series of three planned surveys in this area. High resolution geophysical data collected in each of three consecutive years along this rapidly changing barrier island system will provide a unique time-series dataset that will significantly further the analyses and geomorphological interpretations of this and other coastal systems, improving our understanding of coastal response and evolution over short time scales (1‒5 years).This data series includes the geophysical data that were collected during two cruises (USGS Field Activity Numbers (FAN) 13BIM02, 13BIM03, and 13BIM04, in July 2013; and FANs 13BIM07 and 13BIM08 in August 2013) aboard the R/V Sallenger, the R/V Jabba Jaw, and the R/V Shark along the northern portion of the Chandeleur Islands, Breton National Wildlife Refuge, Louisiana. Primary data were acquired with the following equipment: (1) a Systems Engineering and Assessment, Ltd., SWATHplus interferometric sonar (468 kilohertz [kHz]), (2) an EdgeTech 424 (4‒24 kHz) chirp sub-bottom profiling system, and (3) two Odom Hydrographic Systems, Incorporated, Echotrach CV100 single beam echosounders.This data series report serves as an archive of processed interferometric swath and single-beam bathymetry data. Geographic information system data products include an interpolated digital elevation model, trackline maps, and point data files. Additional files include error analysis maps, Field Activity Collection System logs, and formal Federal Geographic Data Committee metadata.
Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study.

PubMed

Florio, Tullio; Barbieri, Federica; Spaziante, Renato; Zona, Gianluigi; Hofland, Leo J; van Koetsveld, Peter M; Feelders, Richard A; Stalla, Günter K; Theodoropoulou, Marily; Culler, Michael D; Dong, Jesse; Taylor, John E; Moreau, Jacques-Pierre; Saveanu, Alexandru; Gunz, Ginette; Dufour, Henry; Jaquet, Philippe

2008-06-01

Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

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