Chemical shift assignments of the partially deuterated Fyn SH2-SH3 domain.

Science.gov (United States)

Kieken, Fabien; Loth, Karine; van Nuland, Nico; Tompa, Peter; Lenaerts, Tom

2018-04-01

Src Homology 2 and 3 (SH2 and SH3) are two key protein interaction modules involved in regulating the activity of many proteins such as tyrosine kinases and phosphatases by respective recognition of phosphotyrosine and proline-rich regions. In the Src family kinases, the inactive state of the protein is the direct result of the interaction of the SH2 and the SH3 domain with intra-molecular regions, leading to a closed structure incompetent with substrate modification. Here, we report the 1 H, 15 N and 13 C backbone- and side-chain chemical shift assignments of the partially deuterated Fyn SH3-SH2 domain and structural differences between tandem and single domains. The BMRB accession number is 27165.

SH2 Binding Site Protection Assay: A Method for Identification of SH2 Domain Interaction Partners by Exploiting SH2 Mediated Phosphosite Protection.

Science.gov (United States)

Jadwin, Joshua A

2017-01-01

Over the last two decades there has been a significant effort in the field to characterize the phosphosite binding specificities of SH2 domains with the goal of deciphering the pY signaling code. Although high throughput studies in various formats using most SH2 domains have collectively provided a rich resource of in vitro SH2-pTyr site specificity maps, this data can only be used approximate what is happening in the cell where protein concentrations and localization are not homogenous, as they are for in vitro experiments. Here we describe an in vivo approach, SH2 site protection assay, which can capture the pTyr binding specificity of SH2 domains in the cell. The basis of this approach is SH2-pY site protection, the ability of SH2 domains to prevent the PTP-dependent dephosphorylation of their pY site binding partners. We overexpress a tracer SH2 domain in cells and quantify the change in abundance of tyrosine phosphorylated sites using MS. Since the method is performed in vivo, it has the advantage of identifying SH2-pY interactions as they occur within in the cell.

MeSH Now: automatic MeSH indexing at PubMed scale via learning to rank.

Science.gov (United States)

Mao, Yuqing; Lu, Zhiyong

2017-04-17

MeSH indexing is the task of assigning relevant MeSH terms based on a manual reading of scholarly publications by human indexers. The task is highly important for improving literature retrieval and many other scientific investigations in biomedical research. Unfortunately, given its manual nature, the process of MeSH indexing is both time-consuming (new articles are not immediately indexed until 2 or 3 months later) and costly (approximately ten dollars per article). In response, automatic indexing by computers has been previously proposed and attempted but remains challenging. In order to advance the state of the art in automatic MeSH indexing, a community-wide shared task called BioASQ was recently organized. We propose MeSH Now, an integrated approach that first uses multiple strategies to generate a combined list of candidate MeSH terms for a target article. Through a novel learning-to-rank framework, MeSH Now then ranks the list of candidate terms based on their relevance to the target article. Finally, MeSH Now selects the highest-ranked MeSH terms via a post-processing module. We assessed MeSH Now on two separate benchmarking datasets using traditional precision, recall and F 1 -score metrics. In both evaluations, MeSH Now consistently achieved over 0.60 in F-score, ranging from 0.610 to 0.612. Furthermore, additional experiments show that MeSH Now can be optimized by parallel computing in order to process MEDLINE documents on a large scale. We conclude that MeSH Now is a robust approach with state-of-the-art performance for automatic MeSH indexing and that MeSH Now is capable of processing PubMed scale documents within a reasonable time frame. http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/MeSHNow/ .

Diversity in peptide recognition by the SH2 domain of SH2B1.

Science.gov (United States)

McKercher, Marissa A; Guan, Xiaoyang; Tan, Zhongping; Wuttke, Deborah S

2018-02-01

SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity. © 2017 Wiley Periodicals, Inc.

Identification of SH2B2β as an Inhibitor for SH2B1- and SH2B2α-Promoted Janus Kinase-2 Activation and Insulin Signaling

OpenAIRE

Li, Minghua; Li, Zhiqin; Morris, David L.; Rui, Liangyou

2007-01-01

The SH2B family has three members (SH2B1, SH2B2, and SH2B3) that contain conserved dimerization (DD), pleckstrin homology, and SH2 domains. The DD domain mediates the formation of homo- and heterodimers between members of the SH2B family. The SH2 domain of SH2B1 (previously named SH2-B) or SH2B2 (previously named APS) binds to phosphorylated tyrosines in a variety of tyrosine kinases, including Janus kinase-2 (JAK2) and the insulin receptor, thereby promoting the activation of JAK2 or the ins...

NuSTAR Search for Hard X-ray Emission from the Star Formation Regions in Sh2-104

Science.gov (United States)

Gotthelf, Eric V.

2016-04-01

We present NuSTAR hard X-ray observations of Sh2-104, a compact Hii region containing several young massive stellar clusters (YMSCs). We have detected distinct hard X-ray sources coincident with localized VERITAS TeV emission recently resolved from the giant gamma-ray complex MGRO J2019+37 in the Cygnus region. Faint, diffuse X-ray emission coincident with the eastern YMSC in Sh2-104 is likely the result of colliding winds of component stars. Just outside the radio shell of Sh2-104 lies 3XMM J201744.7+365045 and nearby nebula NuSTAR J201744.3+364812, whose properties are most consistent with extragalactic objects. The combined XMM-Newton and NuSTAR spectrum of 3XMM J201744.7+365045 is well-fit to an absorbed power-law model with NH = (3.1+/-1.0)E22 1/cm^2 and photon index Gamma = 2.1+/-0.1. Based on possible long-term flux variation and lack of detected pulsations (Sh2-104 will help identify the nature of the X-ray sources and their relation to MGRO J2019+37.

The Abl SH2-kinase linker naturally adopts a conformation competent for SH3 domain binding.

Science.gov (United States)

Chen, Shugui; Brier, Sébastien; Smithgall, Thomas E; Engen, John R

2007-04-01

The core of the Abelson tyrosine kinase (c-Abl) is structurally similar to Src-family kinases where SH3 and SH2 domains pack against the backside of the kinase domain in the down-regulated conformation. Both kinase families depend upon intramolecular association of SH3 with the linker joining the SH2 and kinase domains for suppression of kinase activity. Hydrogen deuterium exchange (HX) and mass spectrometry (MS) were used to probe intramolecular interaction of the c-Abl SH3 domain with the linker in recombinant constructs lacking the kinase domain. Under physiological conditions, the c-Abl SH3 domain undergoes partial unfolding, which is stabilized by ligand binding, providing a unique assay for SH3:linker interaction in solution. Using this approach, we observed dynamic association of the SH3 domain with the linker in the absence of the kinase domain. Truncation of the linker before W254 completely prevented cis-interaction with SH3, while constructs containing amino acids past this point showed SH3:linker interactions. The observation that the Abl linker sequence exhibits SH3-binding activity in the absence of the kinase domain is unique to Abl and was not observed with Src-family kinases. These results suggest that SH3:linker interactions may have a more prominent role in Abl regulation than in Src kinases, where the down-regulated conformation is further stabilized by a second intramolecular interaction between the C-terminal tail and the SH2 domain.

Meshable: searching PubMed abstracts by utilizing MeSH and MeSH-derived topical terms.

Science.gov (United States)

Kim, Sun; Yeganova, Lana; Wilbur, W John

2016-10-01

Medical Subject Headings (MeSH(®)) is a controlled vocabulary for indexing and searching biomedical literature. MeSH terms and subheadings are organized in a hierarchical structure and are used to indicate the topics of an article. Biologists can use either MeSH terms as queries or the MeSH interface provided in PubMed(®) for searching PubMed abstracts. However, these are rarely used, and there is no convenient way to link standardized MeSH terms to user queries. Here, we introduce a web interface which allows users to enter queries to find MeSH terms closely related to the queries. Our method relies on co-occurrence of text words and MeSH terms to find keywords that are related to each MeSH term. A query is then matched with the keywords for MeSH terms, and candidate MeSH terms are ranked based on their relatedness to the query. The experimental results show that our method achieves the best performance among several term extraction approaches in terms of topic coherence. Moreover, the interface can be effectively used to find full names of abbreviations and to disambiguate user queries. https://www.ncbi.nlm.nih.gov/IRET/MESHABLE/ CONTACT: sun.kim@nih.gov Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

The environment and star formation of H II region Sh2-163: a multi-wavelength study

Science.gov (United States)

Yu, Naiping; Wang, Jun-Jie; Li, Nan

2014-12-01

To investigate the environment of H II region Sh2-163 and search for evidence of triggered star formation in this region, we performed a multi-wavelength study of this H II region. Most of our data were taken from large-scale surveys: 2MASS, CGPS, MSX and SCUBA. We also made CO molecular line observations, using the 13.7-m telescope. The ionized region of Sh2-163 is detected by both the optical and radio continuum observations. Sh2-163 is partially bordered by an arc-like photodissociation region (PDR), which is coincident with the strongest optical and radio emissions, indicating interactions between the H II region and the surrounding interstellar medium. Two molecular clouds were discovered on the border of the PDR. The morphology of these two clouds suggests they are compressed by the expansion of Sh2-163. In cloud A, we found two molecular clumps. And it seems star formation in clump A2 is much more active than in clump A1. In cloud B, we found new outflow activities and massive star(s) are forming inside. Using 2MASS photometry, we tried to search for embedded young stellar object (YSO) candidates in this region. The very good agreement between CO emission, infrared shell and YSOs suggest that it is probably a star formation region triggered by the expansion of Sh2-163. We also found the most likely massive protostar related to IRAS 23314+6033.

Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.

Science.gov (United States)

Groveman, Bradley R; Xue, Sheng; Marin, Vedrana; Xu, Jindong; Ali, Mohammad K; Bienkiewicz, Ewa A; Yu, Xian-Min

2011-02-01

Previous studies demonstrated that intra-domain interactions between Src family kinases (SFKs), stabilized by binding of the phosphorylated C-terminus to the SH2 domain and/or binding of the SH2 kinase linker to the SH3 domain, lock the molecules in a closed conformation, disrupt the kinase active site, and inactivate SFKs. Here we report that the up-regulation of N-methyl-D-aspartate receptors (NMDARs) induced by expression of constitutively active neuronal Src (n-Src), in which the C-terminus tyrosine is mutated to phenylalanine (n-Src/Y535F), is significantly reduced by dysfunctions of the SH2 and/or SH3 domains of the protein. Furthermore, we found that dysfunctions of SH2 and/or SH3 domains reduce auto-phosphorylation of the kinase activation loop, depress kinase activity, and decrease NMDAR phosphorylation. The SH2 domain plays a greater regulatory role than the SH3 domain. Our data also show that n-Src binds directly to the C-terminus of the NMDAR NR2A subunit in vitro, with a K(D) of 108.2 ± 13.3 nM. This binding is not Src kinase activity-dependent, and dysfunctions of the SH2 and/or SH3 domains do not significantly affect the binding. These data indicate that the SH2 and SH3 domains may function to promote the catalytic activity of active n-Src, which is important in the regulation of NMDAR functions. © 2010 The Authors Journal compilation © 2010 FEBS.

Optical and millimeter wavelength study of the complex Sh2-147/Sh2-153

International Nuclear Information System (INIS)

Heydari-Malayeri, M.; Testor, G.; Kahane, C.; Lucas, R.

1982-01-01

Sh2-147/Sh2-153 is a vast HII region-molecular cloud complex of dimension 1 0 .5 located in the Perseus arm at l approximately 109 0 . This cloud embodies the HII regions Sh2-147, 148, 149, 152 and 153. In this direction were detected several H 2 O and OH masers, a number of infrared sources, and a supernova remnant. The authors present the 13 CO map and also optical results on two of the HII regions: Sh2-152 and 148. (Auth.)

Synthesis of porous MnCo₂O₄microspheres with yolk–shell structure induced by concentration gradient and the effect on their performance in electrochemical energy storage

DEFF Research Database (Denmark)

Huang, Guoyong; Yang, Yue; Sun, Hongyu

2016-01-01

In this study, novel spherical yolk–shell MnCo2O4 powders with concentration gradient have been synthesized. The porous microspheres with yolk–shell structure (2.00–3.00 μm in average diameter, ∼200 nm in thickness of shell) are built up by irregular nanoparticles attached to each other. It is sh...

The effect of channel height on bubble nucleation in superhydrophobic microchannels due to subcritical heating

Science.gov (United States)

Cowley, Adam; Maynes, Daniel; Crockett, Julie; Iverson, Brian

2017-11-01

This work experimentally investigates the effects of heating on laminar flow in high aspect ratio superhydrophobic (SH) microchannels. When water that is saturated with dissolved air is used, the unwetted cavities of the SH surfaces act as nucleation sites and air effervesces out of solution onto the surfaces. The microchannels consist of a rib/cavity structured SH surface, that is heated, and a glass surface that is utilized for flow visualization. Two channel heights of nominally 183 and 366 μm are considered. The friction factor-Reynolds product (fRe) is obtained via pressure drop and volumetric flow rate measurements and the temperature profile along the channel is obtained via thermocouples embedded in an aluminum block below the SH surface. Five surface types/configurations are investigated: smooth hydrophilic, smooth hydrophobic, SH with ribs perpendicular to the flow, SH with ribs parallel to the flow, and SH with both ribs parallel to the flow and sparse ribs perpendicular to the flow. Depending on the surface type/configuration, large bubbles can form and adversely affect fRe and lead to higher temperatures along the channel. Once bubbles grow large enough, they are expelled from the channel. The channel size greatly effects the residence time of the bubbles and consequently fRe and the channel temperature. This research was supported by the National Science Foundation (NSF) (Grant No. CBET-1235881) and the Utah NASA Space Grant Consortium (NASA Grant NNX15A124H).

The effects of Anadara granosa shell-Stichopus hermanni on bFGF expressions and blood vessel counts in the bone defect healing process of Wistar rats

Directory of Open Access Journals (Sweden)

Rima Parwati Sari

2017-12-01

Full Text Available Background: Bone damage can be caused by various factors with treatment usually involving graft materials being applied to the defective area. Moreover, in the bone defect healing process, blood vessels are also considered to be an important energy source for cell proliferation. One of the angiogenic factors playing an important role in blood vessel formation is basic fibroblast growth factor (bFGF. Furthermore, synthesized hydroxyapatite derived from Anadara granosa (AG shells constitutes one of the potential materials for use in bone graft. The gold sea cucumber genus Stichopus hermanni (SH possesses the ability to stimulate endothelial progenitor cells inducing bFGF. Purpose: This study aims to investigate the effects of AG shells and SH on bFGF expressions and blood vessel counts within the bone healing process. Methods: Twenty four male Wistar rats were divided into three groups, namely: a control group (C, a treatment group was administered with blood cockle shell (AG, and a treatment group with blood cockle shell and golden sea cucumber (AG+SH. Defects were made on their femurs measuring half the diameter of a circular, no. 018. bur These rats were subsequently sacrificed on day 7 after surgery. The expressions of bFGF were measured by means of IHC technique, while the number of blood vessels was quantified using HE technique. The resulting data was subjected to statistical analysis using an Anova test followed by an LSD test (p < 0.05. Results: The one-way Anova test results combined with those of an LSD test showed there to be significant differences in bFGF expressions and blood vessel counts between the control group (K and the treatment group (AG as well as between the treatment group (AG and the treatment group (AG+SH. Conclusions: A combination of Anadara granosa shell and Stichopus hermanni can increase the expression of bFGF and the number of blood vessels on day 7 during the bone healing process in Wistar rats.

SH2 Domain Histochemistry.

Science.gov (United States)

Buhs, Sophia; Nollau, Peter

2017-01-01

Among posttranslational modifications, the phosphorylation of tyrosine residues is a key modification in cell signaling. Because of its biological importance, characterization of the cellular state of tyrosine phosphorylation is of great interest. Based on the unique properties of endogenously expressed SH2 domains recognizing tyrosine phosphorylated signaling proteins with high specificity we have developed an alternative approach, coined SH2 profiling, enabling us to decipher complex patterns of tyrosine phosphorylation in various normal and cancerous tissues. So far, SH2 profiling has largely been applied for the analysis of protein extracts with the limitation that information on spatial distribution and intensity of tyrosine phosphorylation within a tissue is lost. Here, we describe a novel SH2 domain based strategy for differential characterization of the state of tyrosine phosphorylation in formaldehyde-fixed and paraffin-embedded tissues. This approach demonstrates that SH2 domains may serve as very valuable tools for the analysis of the differential state of tyrosine phosphorylation in primary tissues fixed and processed under conditions frequently applied by routine pathology laboratories.

Design criteria of launching rockets for burst aerial shells

Energy Technology Data Exchange (ETDEWEB)

Kuwahara, T.; Takishita, Y.; Onda, T.; Shibamoto, H.; Hosaya, F. [Hosaya Kako Co. Ltd (Japan); Kubota, N. [Mitsubishi Electric Corporation (Japan)

2000-04-01

Rocket motors attached to large-sized aerial shells are proposed to compensate for the increase in the lifting charge in the mortar and the thickness of the shell wall. The proposal is the result of an evaluation of the performance of solid propellants to provide information useful in designing launch rockets for large-size shells. The propellants composed of ammonium perchlorate and hydroxy-terminated polybutadiene were used to evaluate the ballistic characteristics such as the relationship between propellant mass and trajectories of shells and launch rockets. In order to obtain an optimum rocket design, the evaluation also included a study of the velocity and height of the rocket motor and shell separation. A launch rocket with a large-sized shell (84.5 cm in diameter) was designed to verify the effectiveness of this class of launch system. 2 refs., 6 figs.

Magnetic and structural investigations on La{sub 0.6}Sr{sub 0.4}MnO{sub 3} nanostructured manganite: Evidence of a ferrimagnetic shell

Energy Technology Data Exchange (ETDEWEB)

Andrade, V.M.; Caraballo-Vivas, R.J. [Instituto de Física, Universidade Federal Fluminense, 24210-340 Niterói, RJ (Brazil); Costas-Soares, T. [Instituto de Física, Universidade Federal Fluminense, 24210-340 Niterói, RJ (Brazil); IF Sudeste MG, Campus Juiz de Fora - Núcleo de Física, 36080-001 Juiz de Fora, MG (Brazil); Pedro, S.S. [Instituto de Física, Universidade Federal Fluminense, 24210-340 Niterói, RJ (Brazil); Rocco, D.L., E-mail: rocco@if.uff.br [Instituto de Física, Universidade Federal Fluminense, 24210-340 Niterói, RJ (Brazil); Reis, M.S. [Instituto de Física, Universidade Federal Fluminense, 24210-340 Niterói, RJ (Brazil); Campos, A.P.C. [Divisão de Metrologia de Materiais, Instituto Nacional de Metrologia, Qualidade e Tecnologia, 25250-020 Duque de Caxias, RJ (Brazil); Coelho, A.A. [Instituto de Física “Gleb Wataghin”, Universidade Estadual de Campinas, Caixa Postal 6165, 13083-859 Campinas, SP (Brazil)

2014-11-15

This paper presents the structural and magnetic properties of La{sub 0.6}Sr{sub 0.4}MnO{sub 3} nanoparticles with sizes from 21 to 106 nm, which have been prepared using the sol–gel method. The reduction of the nanoparticles' size tends to broaden the paramagnetic to ferromagnetic transition, as well as to promote magnetic hysteresis and a remarkable change on the magnetic saturation. In order to better understand the magnetic behavior of those nanoparticles, a simple model based on a ferromagnetic core and a ferrimagnetic shell was considered, where the magnetization was described in terms of the standard mean-field Brillouin function. This model matches the experimental data, leading to conclusion the nanoparticles with size <40nm are single magnetic domain. In addition, the output fitting parameters give information on the Landé factor of the core and shell. - Graphical abstract: Core–shell model: The core has a ferromagnetic character, while the shell is ferrimagnetic. Each one has two sub-lattices (Mn{sup 3+} and Mn{sup 4+}) that interact through a mean-field (see Eq. (6)). Interactions strength and signals are also represented in this figure. In this figure the arrows (or vectors) represent the magnetic moment of ions Mn{sup 3+} (s=2) and Mn{sup 4+} (s=3/2). βλ's describe the ferromagnetic interaction between Mn{sup 4+} ions into the core (βλ{sub co}) and into the shell (βλ{sub sh}), while αλ's represent ferromagnetic interaction between Mn{sup 3+} ions into the core (αλ{sub co}) and into the shell (αλ{sub sh}). The −λ{sub sh} and +λ{sub co}co are associated to the mean field parameter of interaction between Mn{sup 3+} and Mn{sup 4+} sub-lattices in the shell (ferrimagnetic, negative sign) and core (ferromagnetic, positive sign), respectively. - Highlights: • Evidences of ferromagnetic shell in La{sub 0.6}Sr{sub 0.4}MnO{sub 3} ferromagnetic nanoparticles. • Core(ferromagnetic)–shell(ferromagnetic) model for

Crystal structure of Src-like adaptor protein 2 reveals close association of SH3 and SH2 domains through β-sheet formation.

Science.gov (United States)

Wybenga-Groot, Leanne E; McGlade, C Jane

2013-12-01

The Src-like adaptor proteins (SLAP/SLAP2) are key components of Cbl-dependent downregulation of antigen receptor, cytokine receptor, and receptor tyrosine kinase signaling in hematopoietic cells. SLAP and SLAP2 consist of adjacent SH3 and SH2 domains that are most similar in sequence to Src family kinases (SFKs). Notably, the SH3-SH2 connector sequence is significantly shorter in SLAP/SLAP2 than in SFKs. To understand the structural implication of a short SH3-SH2 connector sequence, we solved the crystal structure of a protein encompassing the SH3 domain, SH3-SH2 connector, and SH2 domain of SLAP2 (SLAP2-32). While both domains adopt typical folds, the short SH3-SH2 connector places them in close association. Strand βe of the SH3 domain interacts with strand βA of the SH2 domain, resulting in the formation of a continuous β sheet that spans the length of the protein. Disruption of the SH3/SH2 interface through mutagenesis decreases SLAP-32 stability in vitro, consistent with inter-domain binding being an important component of SLAP2 structure and function. The canonical peptide binding pockets of the SH3 and SH2 domains are fully accessible, in contrast to other protein structures that display direct interaction between SH3 and SH2 domains, in which either peptide binding surface is obstructed by the interaction. Our results reveal potential sites of novel interaction for SH3 and SH2 domains, and illustrate the adaptability of SH2 and SH3 domains in mediating interactions. As well, our results suggest that the SH3 and SH2 domains of SLAP2 function interdependently, with implications on their mode of substrate binding. © 2013.

Evidence for motivational effects elicited by activation of GABA-A or dopamine receptors in the nucleus accumbens shell.

Science.gov (United States)

Wirtshafter, David; Stratford, Thomas R

2010-09-01

Microinjections of the inhibitory GABA-A receptor agonist muscimol into the shell region of the nucleus accumbens (AcbSh) have been reported to induce large increases in food intake, but the effect of these injections on motivational processes is less clear. In the current study, bilateral injections of saline, muscimol (50ng/side) or d-amphetamine (10mug/side) were made into the AcbSh of rats trained to lever press on a progressive ratio schedule for food reward. Injections of both muscimol and amphetamine were found to produce a large increase in the breaking point relative to saline injections. This result suggests that inactivation of the AcbSh does not simply drive ingestive behavior, but also affects motivational processes assessed by the progressive ratio schedule. Breaking points were also increased by injections of amphetamine into the AcbSh. Copyright 2010 Elsevier Inc. All rights reserved.

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase.

Science.gov (United States)

Meiselbach, Heike; Sticht, Heinrich

2011-08-01

The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence remain poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck in which the SH3-SH2 domain linker is replaced by the corresponding sequence from the homologous kinase Lck. These simulations reveal that linker replacement not only affects the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or in fine-tuning the activation process itself.

X-ray backlighting requirements for the double-shell target

International Nuclear Information System (INIS)

Larsen, J.T.

1980-01-01

We have analyzed one specific NOVA double-shell target design and have determined the x-ray energies required for probing the performance of the implosion. It is virtually impossible to study the compression of the fuel or the motion of the inner pusher. An x-ray energy of about 9 keV appears to be ideal for measuring the behavior of the outer TaCOH shell for the majority of its travel. However, it would be advantageous to have an x-ray source of about 25 keV to measure the contact between the two shells. Development of narrowband x-ray line sources are more desirable than broadband continuum sources since the intensity per keV is many times greater in the line. Intensities of the probes are determined by the self-emission levels of the target capsule. For the 9 keV line source, an intensity of upwards to 10 15 keV/keV/sh/cm 2 /sr is required with a source area of about 0.01 cm 2

Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila.

Science.gov (United States)

Raabe, T; Olivier, J P; Dickson, B; Liu, X; Gish, G D; Pawson, T; Hafen, E

1995-06-01

The Drk SH3-SH2-SH3 adaptor protein has been genetically identified in a screen for rate-limiting components acting downstream of the Sevenless (Sev) receptor tyrosine kinase in the developing eye of Drosophila. It provides a link between the activated Sev receptor and Sos, a guanine nucleotide release factor that activates Ras1. We have used a combined biochemical and genetic approach to study the interactions between Sev, Drk and Sos. We show that Tyr2546 in the cytoplasmic tail of Sev is required for Drk binding, probably because it provides a recognition site for the Drk SH2 domain. Interestingly, a mutation at this site does not completely block Sev function in vivo. This may suggest that Sev can signal in a Drk-independent, parallel pathway or that Drk can also bind to an intermediate docking protein. Analysis of the Drk-Sos interaction has identified a high affinity binding site for Drk SH3 domains in the Sos tail. We show that the N-terminal Drk SH3 domain is primarily responsible for binding to the tail of Sos in vitro, and for signalling to Ras in vivo.

The SH2 Domain Interaction Landscape

Directory of Open Access Journals (Sweden)

Michele Tinti

2013-04-01

Full Text Available Members of the SH2 domain family modulate signal transduction by binding to short peptides containing phosphorylated tyrosines. Each domain displays a distinct preference for the sequence context of the phosphorylated residue. We have developed a high-density peptide chip technology that allows for probing of the affinity of most SH2 domains for a large fraction of the entire complement of tyrosine phosphopeptides in the human proteome. Using this technique, we have experimentally identified thousands of putative SH2-peptide interactions for more than 70 different SH2 domains. By integrating this rich data set with orthogonal context-specific information, we have assembled an SH2-mediated probabilistic interaction network, which we make available as a community resource in the PepspotDB database. A predicted dynamic interaction between the SH2 domains of the tyrosine phosphatase SHP2 and the phosphorylated tyrosine in the extracellular signal-regulated kinase activation loop was validated by experiments in living cells.

Protein-phosphotyrosine proteome profiling by superbinder-SH2 domain affinity purification mass spectrometry, sSH2-AP-MS.

Science.gov (United States)

Tong, Jiefei; Cao, Biyin; Martyn, Gregory D; Krieger, Jonathan R; Taylor, Paul; Yates, Bradley; Sidhu, Sachdev S; Li, Shawn S C; Mao, Xinliang; Moran, Michael F

2017-03-01

Recently, "superbinder" SH2 domain variants with three amino acid substitutions (sSH2) were reported to have 100-fold or greater affinity for protein-phosphotyrosine (pY) than natural SH2 domains. Here we report a protocol in which His-tagged Src sSH2 efficiently captures pY-peptides from protease-digested HeLa cell total protein extracts. Affinity purification of pY-peptides by this method shows little bias for pY-proximal amino acid sequences, comparable to that achieved by using antibodies to pY, but with equal or higher yield. Superbinder-SH2 affinity purification mass spectrometry (sSH2-AP-MS) therefore provides an efficient and economical approach for unbiased pY-directed phospho-proteome profiling without the use of antibodies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular dissection of the interaction between the SH3 domain and the SH2-Kinase Linker region in PTK6.

Science.gov (United States)

Kim, Han Ie; Jung, Jinwon; Lee, Eun-Saem; Kim, Yong-Chul; Lee, Weontae; Lee, Seung-Taek

2007-11-03

PTK6 (also known as Brk) is an intracellular tyrosine kinase that contains SH3, SH2, and tyrosine kinase catalytic (Kinase) domains. The SH3 domain of PTK6 interacts with the N-terminal half of the linker (Linker) region between the SH2 and Kinase domains. Site-directed mutagenesis and surface plasmon resonance studies showed that a tryptophan residue (Trp44) in the SH3 domain and proline residues in the Linker region, in the order of Pro177, Pro175, and Pro179, contribute to the interaction. The three-dimensional modeled structure of the SH3-Linker complex was in agreement with the biochemical data. Disruption of the intramolecular interaction between the SH3 domain and the Linker region by mutation of Trp44, Pro175, Pro177, and Pro179 markedly increased the catalytic activity of PTK6 in HEK 293 cells. These results demonstrate that Trp44 in the SH3 domain and Pro177, Pro175, and Pro179 in the N-terminal half of the Linker region play important roles in the SH3-Linker interaction to maintain the protein in an inactive conformation along with the phosphorylated Tyr447-SH2 interaction.

The SH2 domain interaction landscape.

Science.gov (United States)

Tinti, Michele; Kiemer, Lars; Costa, Stefano; Miller, Martin L; Sacco, Francesca; Olsen, Jesper V; Carducci, Martina; Paoluzi, Serena; Langone, Francesca; Workman, Christopher T; Blom, Nikolaj; Machida, Kazuya; Thompson, Christopher M; Schutkowski, Mike; Brunak, Søren; Mann, Matthias; Mayer, Bruce J; Castagnoli, Luisa; Cesareni, Gianni

2013-04-25

Members of the SH2 domain family modulate signal transduction by binding to short peptides containing phosphorylated tyrosines. Each domain displays a distinct preference for the sequence context of the phosphorylated residue. We have developed a high-density peptide chip technology that allows for probing of the affinity of most SH2 domains for a large fraction of the entire complement of tyrosine phosphopeptides in the human proteome. Using this technique, we have experimentally identified thousands of putative SH2-peptide interactions for more than 70 different SH2 domains. By integrating this rich data set with orthogonal context-specific information, we have assembled an SH2-mediated probabilistic interaction network, which we make available as a community resource in the PepspotDB database. A predicted dynamic interaction between the SH2 domains of the tyrosine phosphatase SHP2 and the phosphorylated tyrosine in the extracellular signal-regulated kinase activation loop was validated by experiments in living cells. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Accumbens Shell AMPA Receptors Mediate Expression of Extinguished Reward Seeking through Interactions with Basolateral Amygdala

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Millan, E. Zayra; McNally, Gavan P.

2011-01-01

Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B).…

Linker length dependent binding of a focal adhesion kinase derived peptide to the Src SH3-SH2 domains.

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Lindfors, Hanna E; Venkata, Bharat Somireddy; Drijfhout, Jan W; Ubbink, Marcellus

2011-02-18

The interaction between a peptide encompassing the SH3 and SH2 binding motifs of focal adhesion kinase (FAK) and the Src SH3-SH2 domains has been investigated with NMR spectroscopy and calorimetry. The binding to both motifs is anti-cooperative. Reduction of the long linker connecting the motifs does not lead to cooperativity. Short linkers that do not allow simultaneous intramolecular binding of the peptide to both motifs cause peptide-mediated dimerisation, even with a linker of only three amino acids. The role of the SH3 binding motif is discussed in view of the independent nature of the SH interactions. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Electron-impact excitation of diatomic hydride cations II: OH+ and SH+

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Hamilton, James R.; Faure, Alexandre; Tennyson, Jonathan

2018-05-01

R-matrix calculations combined with the adiabatic-nuclei-rotation and Coulomb-Born approximations are used to compute electron-impact rotational rate coefficients for two open-shell diatomic cations of astrophysical interest: the hydoxyl and sulphanyl ions, OH+ and SH+. Hyperfine resolved rate coefficients are deduced using the infinite-order-sudden approximation. The propensity rule ΔF = Δj = ΔN = ±1 is observed, as is expected for cations with a large dipole moment. A model for OH+ excitation in the Orion Bar photon-dominated region is presented which nicely reproduces Herschel observations for an electron fraction xe = 10-4 and an OH+ column density of 3 × 1013 cm-2. Electron-impact electronic excitation cross-sections and rate coefficients for the ions are also presented.

Two-state dynamics of the SH3-SH2 tandem of Abl kinase and the allosteric role of the N-cap.

Science.gov (United States)

Corbi-Verge, Carles; Marinelli, Fabrizio; Zafra-Ruano, Ana; Ruiz-Sanz, Javier; Luque, Irene; Faraldo-Gómez, José D

2013-09-03

The regulation and localization of signaling enzymes is often mediated by accessory modular domains, which frequently function in tandems. The ability of these tandems to adopt multiple conformations is as important for proper regulation as the individual domain specificity. A paradigmatic example is Abl, a ubiquitous tyrosine kinase of significant pharmacological interest. SH3 and SH2 domains inhibit Abl by assembling onto the catalytic domain, allosterically clamping it in an inactive state. We investigate the dynamics of this SH3-SH2 tandem, using microsecond all-atom simulations and differential scanning calorimetry. Our results indicate that the Abl tandem is a two-state switch, alternating between the conformation observed in the structure of the autoinhibited enzyme and another configuration that is consistent with existing scattering data for an activated form. Intriguingly, we find that the latter is the most probable when the tandem is disengaged from the catalytic domain. Nevertheless, an amino acid stretch preceding the SH3 domain, the so-called N-cap, reshapes the free-energy landscape of the tandem and favors the interaction of this domain with the SH2-kinase linker, an intermediate step necessary for assembly of the autoinhibited complex. This allosteric effect arises from interactions between N-cap and the SH2 domain and SH3-SH2 connector, which involve a phosphorylation site. We also show that the SH3-SH2 connector plays a determinant role in the assembly equilibrium of Abl, because mutations thereof hinder the engagement of the SH2-kinase linker. These results provide a thermodynamic rationale for the involvement of N-cap and SH3-SH2 connector in Abl regulation and expand our understanding of the principles of modular domain organization.

Morphology of the shell of Happiella cf. insularis (Gastropoda: Heterobranchia: Systrophiidae from three forest areas on Ilha Grande, Southeast Brazil

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Amilcar Brum Barbosa

2014-06-01

Full Text Available We conducted a study on shell morphology variation among three populations of Happiella cf. insularis (Boëttger, 1889 inhabiting different areas (Jararaca, Caxadaço, and Parnaioca trails at Vila Dois Rios, Ilha Grande, Angra dos Reis, state of Rio de Janeiro, Brazil. Linear and angular measurements, shell indices representing shell shape, and whorl counts were obtained from images drawn using a stereomicroscope coupled with a camera lucida. The statistical analysis based on ANOVA (followed by Bonferroni's test, Pearson's correlation matrix, and discriminant analysis enabled discrimination among the populations studied. The variable that most contributed to discriminate among groups was shell height. Mean shell height was greatest for specimens collected from Jararaca, probably reflecting the better conservation status of that area. Good conservation is associated with enhanced shell growth. Mean measurements were smallest for specimens from Parnaioca, the most disturbed area surveyed. Mean aperture height was smallest for specimens from Parnaioca, which may represent a strategy to prevent excessive water loss. Discriminant analysis revealed that the snails from Jararaca differ the most from snails collected in the two other areas, reflecting the different conservation status of these areas: shells reach larger sizes in the localities where the humidity is higher. The similarities in shell morphology were greater between areas that are more similar environmentally (Caxadaço and Parnaioca, suggesting that conchological differences may correspond to adaptations to the environment.

Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila.

OpenAIRE

Raabe, T; Olivier, J P; Dickson, B J; Liu, X; Gish, G D; Pawson, T; Hafen, E

1995-01-01

The Drk SH3-SH2-SH3 adaptor protein has been genetically identified in a screen for rate-limiting components acting downstream of the Sevenless (Sev) receptor tyrosine kinase in the developing eye of Drosophila. It provides a link between the activated Sev receptor and Sos, a guanine nucleotide release factor that activates Ras1. We have used a combined biochemical and genetic approach to study the interactions between Sev, Drk and Sos. We show that Tyr2546 in the cytoplasmic tail of Sev is r...

The influence of MOVPE growth conditions on the shell of core-shell GaN microrod structures

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Schimpke, Tilman; Avramescu, Adrian; Koller, Andreas; Fernando-Saavedra, Amalia; Hartmann, Jana; Ledig, Johannes; Waag, Andreas; Strassburg, Martin; Lugauer, Hans-Jürgen

2017-05-01

A core-shell geometry is employed for most next-generation, three-dimensional opto-electric devices based on III-V semiconductors and grown by metal organic vapor phase epitaxy (MOVPE). Controlling the shape of the shell layers is fundamental for device optimization, however no detailed analysis of the influence of growth conditions has been published to date. We study homogeneous arrays of gallium nitride core-shell microrods with height and diameter in the micrometer range and grown in a two-step selective area MOVPE process. Changes in shell shape and homogeneity effected by deliberately altered shell growth conditions were accurately assessed by digital analysis of high-resolution scanning electron microscope images. Most notably, two temperature regimes could be established, which show a significantly different behavior with regard to material distribution. Above 900 °C of wafer carrier temperature, the shell thickness along the growth axis of the rods was very homogeneous, however variations between vicinal rods increase. In contrast, below 830 °C the shell thickness is higher close to the microrod tip than at the base of the rods, while the lateral homogeneity between neighboring microrods is very uniform. This temperature effect could be either amplified or attenuated by changing the remaining growth parameters such as reactor pressure, structure distance, gallium precursor, carrier gas composition and dopant materials. Possible reasons for these findings are discussed with respect to GaN decomposition as well as the surface and gas phase diffusion of growth species, leading to an improved control of the functional layers in next-generation 3D V-III devices.

SH2 domains: modulators of nonreceptor tyrosine kinase activity.

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Filippakopoulos, Panagis; Müller, Susanne; Knapp, Stefan

2009-12-01

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation.

Preferred SH3 domain partners of ADAM metalloproteases include shared and ADAM-specific SH3 interactions.

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Iivari Kleino

Full Text Available A disintegrin and metalloproteinases (ADAMs constitute a protein family essential for extracellular signaling and regulation of cell adhesion. Catalytic activity of ADAMs and their predicted potential for Src-homology 3 (SH3 domain binding show a strong correlation. Here we present a comprehensive characterization of SH3 binding capacity and preferences of the catalytically active ADAMs 8, 9, 10, 12, 15, 17, and 19. Our results revealed several novel interactions, and also confirmed many previously reported ones. Many of the identified SH3 interaction partners were shared by several ADAMs, whereas some were ADAM-specific. Most of the ADAM-interacting SH3 proteins were adapter proteins or kinases, typically associated with sorting and endocytosis. Novel SH3 interactions revealed in this study include TOCA1 and CIP4 as preferred partners of ADAM8, and RIMBP1 as a partner of ADAM19. Our results suggest that common as well as distinct mechanisms are involved in regulation and execution of ADAM signaling, and provide a useful framework for addressing the pathways that connect ADAMs to normal and aberrant cell behavior.

Two-state dynamics of the SH3–SH2 tandem of Abl kinase and the allosteric role of the N-cap

Science.gov (United States)

Corbi-Verge, Carles; Marinelli, Fabrizio; Zafra-Ruano, Ana; Ruiz-Sanz, Javier; Luque, Irene; Faraldo-Gómez, José D.

2013-01-01

The regulation and localization of signaling enzymes is often mediated by accessory modular domains, which frequently function in tandems. The ability of these tandems to adopt multiple conformations is as important for proper regulation as the individual domain specificity. A paradigmatic example is Abl, a ubiquitous tyrosine kinase of significant pharmacological interest. SH3 and SH2 domains inhibit Abl by assembling onto the catalytic domain, allosterically clamping it in an inactive state. We investigate the dynamics of this SH3–SH2 tandem, using microsecond all-atom simulations and differential scanning calorimetry. Our results indicate that the Abl tandem is a two-state switch, alternating between the conformation observed in the structure of the autoinhibited enzyme and another configuration that is consistent with existing scattering data for an activated form. Intriguingly, we find that the latter is the most probable when the tandem is disengaged from the catalytic domain. Nevertheless, an amino acid stretch preceding the SH3 domain, the so-called N-cap, reshapes the free-energy landscape of the tandem and favors the interaction of this domain with the SH2-kinase linker, an intermediate step necessary for assembly of the autoinhibited complex. This allosteric effect arises from interactions between N-cap and the SH2 domain and SH3–SH2 connector, which involve a phosphorylation site. We also show that the SH3–SH2 connector plays a determinant role in the assembly equilibrium of Abl, because mutations thereof hinder the engagement of the SH2-kinase linker. These results provide a thermodynamic rationale for the involvement of N-cap and SH3–SH2 connector in Abl regulation and expand our understanding of the principles of modular domain organization. PMID:23959873

Expression and Production of SH2 Domain Proteins.

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Liu, Bernard A; Ogiue-Ikeda, Mari; Machida, Kazuya

2017-01-01

The Src Homology 2 (SH2) domain lies at the heart of phosphotyrosine signaling, coordinating signaling events downstream of receptor tyrosine kinases (RTKs), adaptors, and scaffolds. Over a hundred SH2 domains are present in mammals, each having a unique specificity which determines its interactions with multiple binding partners. One of the essential tools necessary for studying and determining the role of SH2 domains in phosphotyrosine signaling is a set of soluble recombinant SH2 proteins. Here we describe methods, based on a broad experience with purification of all SH2 domains, for the production of SH2 domain proteins needed for proteomic and biochemical-based studies such as peptide arrays, mass-spectrometry, protein microarrays, reverse-phase microarrays, and high-throughput fluorescence polarization (HTP-FP). We describe stepwise protocols for expression and purification of SH2 domains using GST or poly His-tags, two widely adopted affinity tags. In addition, we address alternative approaches, challenges, and validation studies for assessing protein quality and provide general characteristics of purified human SH2 domains.

Kinase activation through dimerization by human SH2-B.

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Nishi, Masahiro; Werner, Eric D; Oh, Byung-Chul; Frantz, J Daniel; Dhe-Paganon, Sirano; Hansen, Lone; Lee, Jongsoon; Shoelson, Steven E

2005-04-01

The isoforms of SH2-B, APS, and Lnk form a family of signaling proteins that have been described as activators, mediators, or inhibitors of cytokine and growth factor signaling. We now show that the three alternatively spliced isoforms of human SH2-B readily homodimerize in yeast two-hybrid and cellular transfections assays, and this is mediated specifically by a unique domain in its amino terminus. Consistent with previous reports, we further show that the SH2 domains of SH2-B and APS bind JAK2 at Tyr813. These findings suggested a model in which two molecules of SH2-B or APS homodimerize with their SH2 domains bound to two JAK2 molecules, creating heterotetrameric JAK2-(SH2-B)2-JAK2 or JAK2-(APS)2-JAK2 complexes. We further show that APS and SH2-B isoforms heterodimerize. At lower levels of SH2-B or APS expression, dimerization approximates two JAK2 molecules to induce transactivation. At higher relative concentrations of SH2-B or APS, kinase activation is blocked. SH2-B or APS homodimerization and SH2-B/APS heterodimerization thus provide direct mechanisms for activating and inhibiting JAK2 and other kinases from the inside of the cell and for potentiating or attenuating cytokine and growth factor receptor signaling when ligands are present.

Cut-off frequencies of circumferential horizontal shear waves in various functionally graded cylinder shells.

Science.gov (United States)

Shen, Xiaoqin; Ren, Dawei; Cao, Xiaoshan; Wang, Ji

2018-03-01

In this study, cut-off frequencies of the circumferential SH waves in functionally graded piezoelectric-piezomagnetic material (FGPPM) cylinder shells with traction free, electrical and magnetic open boundary conditions are investigated analytically. The Wentzel-Kramers-Brillouin (WKB) method is employed for solving differential equations with variable coefficients for general cases. For comparison, Bessel functions and Kummer functions are used for solving cut-off frequency problems in homogenous and ideal FGPPM cylinder shells. It is shown that the WKB solution for the cut-off frequencies has good precise. The set of cut-off frequencies is a series of approximate arithmetic progressions, for which the difference is a function of the density and the effective elastic parameter. The relationship between the difference and the gradient coefficient is described. These results provide theoretical guidance for the non-destructive evaluation of curved shells based on the cut-off frequencies. Copyright © 2017 Elsevier B.V. All rights reserved.

Introduction: History of SH2 Domains and Their Applications.

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Liu, Bernard A; Machida, Kazuya

2017-01-01

The Src Homology 2 (SH2) domain is the prototypical protein interaction module that lies at the heart of phosphotyrosine signaling. Since its serendipitous discovery, there has been a tremendous advancement in technologies and an array of techniques available for studying SH2 domains and phosphotyrosine signaling. In this chapter, we provide a glimpse of the history of SH2 domains and describe many of the tools and techniques that have been developed along the way and discuss future directions for SH2 domain studies. We highlight the gist of each chapter in this volume in the context of: the structural biology and phosphotyrosine binding; characterizing SH2 specificity and generating prediction models; systems biology and proteomics; SH2 domains in signal transduction; and SH2 domains in disease, diagnostics, and therapeutics. Many of the individual chapters provide an in-depth approach that will allow scientists to interrogate the function and role of SH2 domains.

Bioaccumulative and conchological assessment of heavy metal transfer in a soil-plant-snail food chain

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Nica Dragos V

2012-06-01

Full Text Available Abstract Background Copper (Cu, zinc (Zn, cadmium (Cd, and lead (Pb can pose serious threats to environmental health because they tend to bioaccumulate in terrestrial ecosystems. We investigated under field conditions the transfer of these heavy metals in a soil-plant-snail food chain in Banat area, Romania. The main goal of this paper was to assess the Roman snail (Helix pomatia usefulness in environmental monitoring as bioindicator of heavy metal accumulation. Eight sampling sites, selected by different history of heavy metal (HM exposure, were chosen to be sampled for soil, nettle leaves, and newly matured snails. This study also aimed to identify the putative effects of HM accumulation in the environment on phenotypic variability in selected shell features, which included shell height (SH, relative shell height (RSH, and whorl number (WN. Results Significantly higher amounts of HMs were accumulated in snail hepatopancreas and not in foot. Cu, Zn, and Cd have biomagnified in the snail body, particularly in the hepatopancreas. In contrast, Pb decreased when going up into the food chain. Zn, Cd, and Pb correlated highly with each other at all levels of the investigated food chain. Zn and Pb exhibited an effective soil–plant transfer, whereas in the snail body only foot Cu concentration was correlated with that in soil. There were significant differences among sampling sites for WN, SH, and RSH when compared with reference snails. WN was strongly correlated with Cd and Pb concentrations in nettle leaves but not with Cu and Zn. SH was independent of HM concentrations in soil, snail hepatopancreas, and foot. However, SH correlated negatively with nettle leaves concentrations for each HM except Cu. In contrast, RSH correlated significantly only with Pb concentration in hepatopancreas. Conclusions The snail hepatopancreas accumulates high amounts of HMs, and therefore, this organ can function as a reliable biomarker for tracking HM bioavailability

SH3 domain tyrosine phosphorylation--sites, role and evolution.

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Zuzana Tatárová

Full Text Available BACKGROUND: SH3 domains are eukaryotic protein domains that participate in a plethora of cellular processes including signal transduction, proliferation, and cellular movement. Several studies indicate that tyrosine phosphorylation could play a significant role in the regulation of SH3 domains. RESULTS: To explore the incidence of the tyrosine phosphorylation within SH3 domains we queried the PhosphoSite Plus database of phosphorylation sites. Over 100 tyrosine phosphorylations occurring on 20 different SH3 domain positions were identified. The tyrosine corresponding to c-Src Tyr-90 was by far the most frequently identified SH3 domain phosphorylation site. A comparison of sequences around this tyrosine led to delineation of a preferred sequence motif ALYD(Y/F. This motif is present in about 15% of human SH3 domains and is structurally well conserved. We further observed that tyrosine phosphorylation is more abundant than serine or threonine phosphorylation within SH3 domains and other adaptor domains, such as SH2 or WW domains. Tyrosine phosphorylation could represent an important regulatory mechanism of adaptor domains. CONCLUSIONS: While tyrosine phosphorylation typically promotes signaling protein interactions via SH2 or PTB domains, its role in SH3 domains is the opposite - it blocks or prevents interactions. The regulatory function of tyrosine phosphorylation is most likely achieved by the phosphate moiety and its charge interfering with binding of polyproline helices of SH3 domain interacting partners.

Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes.

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Urstadt, Kevin R; Kally, Peter; Zaidi, Sana F; Stanley, B Glenn

2013-04-01

The nucleus accumbens shell (AcbSh) and the lateral hypothalamus (LH) are both involved in the control of food intake. Activation of GABA(A) receptors or blockade of AMPA and kainate receptors within the AcbSh induces feeding, as does blockade of GABA(A) receptors or activation of NMDA receptors in the LH. Further, evidence suggests that feeding induced via the AcbSh can be suppressed by LH inhibition. However, it is unclear if this suppression is specific to feeding. Adult male Sprague-Dawley rats with 3 intracranial guide cannulas, one unilaterally into the AcbSh and two bilaterally into the LH, were used to explore this issue. DNQX (1.25 μg) or muscimol (100 ng) infused into the AcbSh unilaterally elicited feeding, and this elicited intake was suppressed by bilateral LH injection of d-AP5 (2 μg) or muscimol (25 ng). The effectiveness of d-AP5 or muscimol infusion into either the LH site ipsilateral or contralateral to the AcbSh injection was compared. Ipsilateral LH injection of d-AP5 or muscimol was significantly more effective than contralateral injection in suppressing food intake initiated by AcbSh injection of DNQX or muscimol. These results add to the prior evidence that inhibition of the LH through pharmacological modulation of NMDA or GABA(A) receptors specifically suppresses feeding initiated by AcbSh inhibition, and that these two regions communicate via an ipsilateral circuit to specifically regulate feeding. Copyright © 2012 Elsevier Ltd. All rights reserved.

Probing SH2-domains using Inhibitor Affinity Purification (IAP).

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Höfener, Michael; Heinzlmeir, Stephanie; Kuster, Bernhard; Sewald, Norbert

2014-01-01

Many human diseases are correlated with the dysregulation of signal transduction processes. One of the most important protein interaction domains in the context of signal transduction is the Src homology 2 (SH2) domain that binds phosphotyrosine residues. Hence, appropriate methods for the investigation of SH2 proteins are indispensable in diagnostics and medicinal chemistry. Therefore, an affinity resin for the enrichment of all SH2 proteins in one experiment would be desirable. However, current methods are unable to address all SH2 proteins simultaneously with a single compound or a small array of compounds. In order to overcome these limitations for the investigation of this particular protein family in future experiments, a dipeptide-derived probe has been designed, synthesized and evaluated. This probe successfully enriched 22 SH2 proteins from mixed cell lysates which contained 50 SH2 proteins. Further characterization of the SH2 binding properties of the probe using depletion and competition experiments indicated its ability to enrich complexes consisting of SH2 domain bearing regulatory PI3K subunits and catalytic phosphoinositide 3-kinase (PI3K) subunits that have no SH2 domain. The results make this probe a promising starting point for the development of a mixed affinity resin with complete SH2 protein coverage. Moreover, the additional findings render it a valuable tool for the evaluation of PI3K complex interrupting inhibitors.

Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice.

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Morris, David L; Cho, Kae Won; Rui, Liangyou

2010-08-01

SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. Here we generated three lines of mice to analyze the role of the SH2 domain of SH2B1 in the central nervous system. Transgenic mice expressing wild-type, SH2 domain-defective (R555E), or SH2 domain-alone (DeltaN503) forms of SH2B1 specifically in neurons were crossed with SH2B1 knockout mice to generate KO/SH2B1, KO/R555E, or KO/DeltaN503 compound mutant mice. R555E had a replacement of Arg(555) with Glu within the SH2 domain. DeltaN503 contained an intact SH2 domain but lacked amino acids 1-503. Neuron-specific expression of recombinant SH2B1, but not R555E or DeltaN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. Neuron-specific expression of R555E in wild-type mice promoted obesity and insulin resistance. These results indicate that in addition to the SH2 domain, N-terminal regions of neuronal SH2B1 are also required for the maintenance of normal body weight and glucose metabolism. Additionally, mutations in the SH2 domain of SH2B1 may increase the susceptibility to obesity and type 2 diabetes in a dominant-negative manner.

Abl N-terminal cap stabilization of SH3 domain dynamics.

Science.gov (United States)

Chen, Shugui; Dumitrescu, Teodora Pene; Smithgall, Thomas E; Engen, John R

2008-05-27

Crystal structures and other biochemical data indicate that the N-terminal cap (NCap) region of the Abelson tyrosine kinase (c-Abl) is important for maintaining the downregulated conformation of the kinase domain. The exact contributions that the NCap makes in stabilizing the various intramolecular interactions within c-Abl are less clear. While the NCap appears to be important for locking the SH3 and SH2 domains to the back of the kinase domain, there may be other more subtle elements of regulation. Hydrogen exchange (HX) and mass spectrometry (MS) were used to determine if the NCap contributes to intramolecular interactions involving the Abl SH3 domain. Under physiological conditions, the Abl SH3 domain underwent partial unfolding and its unfolding half-life was slowed during binding to the SH2 kinase linker, providing a unique assay for testing NCap-induced stabilization of the SH3 domain in various constructs. The results showed that the NCap stabilizes the dynamics of the SH3 domain in certain constructs but does not increase the relative affinity of the SH3 domain for the native SH2 kinase linker. The stabilization effect was absent in constructs of just the NCap and SH3 but was obvious when the SH2 domain and the SH2 kinase linker were present. These results suggest that interactions between the NCap and the SH3 domain can contribute to c-Abl stabilization in constructs that contain at least the SH2 domain, an effect that may partially compensate for the absence of the negative regulatory C-terminal tail found in the related Src family of kinases.

Classification and Lineage Tracing of SH2 Domains Throughout Eukaryotes.

Science.gov (United States)

Liu, Bernard A

2017-01-01

Today there exists a rapidly expanding number of sequenced genomes. Cataloging protein interaction domains such as the Src Homology 2 (SH2) domain across these various genomes can be accomplished with ease due to existing algorithms and predictions models. An evolutionary analysis of SH2 domains provides a step towards understanding how SH2 proteins integrated with existing signaling networks to position phosphotyrosine signaling as a crucial driver of robust cellular communication networks in metazoans. However organizing and tracing SH2 domain across organisms and understanding their evolutionary trajectory remains a challenge. This chapter describes several methodologies towards analyzing the evolutionary trajectory of SH2 domains including a global SH2 domain classification system, which facilitates annotation of new SH2 sequences essential for tracing the lineage of SH2 domains throughout eukaryote evolution. This classification utilizes a combination of sequence homology, protein domain architecture and the boundary positions between introns and exons within the SH2 domain or genes encoding these domains. Discrete SH2 families can then be traced across various genomes to provide insight into its origins. Furthermore, additional methods for examining potential mechanisms for divergence of SH2 domains from structural changes to alterations in the protein domain content and genome duplication will be discussed. Therefore a better understanding of SH2 domain evolution may enhance our insight into the emergence of phosphotyrosine signaling and the expansion of protein interaction domains.

Progress towards the development of SH2 domain inhibitors.

Science.gov (United States)

Kraskouskaya, Dziyana; Duodu, Eugenia; Arpin, Carolynn C; Gunning, Patrick T

2013-04-21

Src homology 2 (SH2) domains are 100 amino acid modular units, which recognize and bind to tyrosyl-phosphorylated peptide sequences on their target proteins, and thereby mediate intracellular protein-protein interactions. This review summarizes the progress towards the development of synthetic agents that disrupt the function of the SH2 domains in different proteins as well as the clinical relevance of targeting a specific SH2 domain. Since 1986, SH2 domains have been identified in over 110 human proteins, including kinases, transcription factors, and adaptor proteins. A number of these proteins are over-activated in many diseases, including cancer, and their function is highly dependent on their SH2 domain. Thus, inhibition of a protein's function through disrupting that of its SH2 domain has emerged as a promising approach towards the development of novel therapeutic modalities. Although targeting the SH2 domain is a challenging task in molecular recognition, the progress reported here demonstrates the feasibility of such an approach.

Deformation Behavior of Press Formed Shell by Indentation and Its Numerical Simulation

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Minoru Yamashita

2015-01-01

Full Text Available Deformation behavior and energy absorbing performance of the press formed aluminum alloy A5052 shells were investigated to obtain the basic information regarding the mutual effect of the shell shape and the indentor. Flat top and hemispherical shells were indented by the flat- or hemispherical-headed indentor. Indentation force in the rising stage was sharper for both shell shapes when the flat indentor was used. Remarkable force increase due to high in-plane compressive stress arisen by the appropriate tool constraint was observed in the early indentation stage, where the hemispherical shell was deformed with the flat-headed indentor. This aspect is preferable for energy absorption performance per unit mass. Less fluctuation in indentation force was achieved in the combination of the hemispherical shell and similar shaped indentor. The consumed energy in the travel length of the indentor equal to the shell height was evaluated. The increase ratio of the energy is prominent when the hemispherical indentor is replaced by a flat-headed one in both shell shapes. Finite element simulation was also conducted. Deformation behaviors were successfully predicted when the kinematic hardening plasticity was introduced in the material model.

SH2 domains: modulators of nonreceptor tyrosine kinase activity

OpenAIRE

Filippakopoulos, Panagis; Müller, Susanne; Knapp, Stefan

2009-01-01

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed ...

GABA(A) and dopamine receptors in the nucleus accumbens shell differentially influence performance of a water-reinforced progressive ratio task.

Science.gov (United States)

Covelo, Ignacio R; Wirtshafter, David; Stratford, Thomas R

2012-03-01

Several authors have shown that injections of the GABA(A) agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh) result in large increases in food, but not water, intake. In previous studies we demonstrated that intra-AcbSh injections of either muscimol or of the indirect dopamine agonist amphetamine increase response output on a food-reinforced progressive ratio schedule. In the current experiment we extended these observations by examining the effects of muscimol and amphetamine injections on the performance of a water-reinforced progressive ratio task in mildly deprived animals. We found that muscimol did not affect the number of responses made in the water-reinforced task, even though a marked increase in responding was observed after amphetamine. Muscimol did, however, significantly increase food intake in the same animals. The results suggest that the enhancing effects of intra-AcbSh muscimol differ from those of amphetamine in that they are selective for food-reinforced behaviors. Copyright © 2011. Published by Elsevier Inc.

Optical absorption of carbon-gold core-shell nanoparticles

Science.gov (United States)

Wang, Zhaolong; Quan, Xiaojun; Zhang, Zhuomin; Cheng, Ping

2018-01-01

In order to enhance the solar thermal energy conversion efficiency, we propose to use carbon-gold core-shell nanoparticles dispersed in liquid water. This work demonstrates theoretically that an absorbing carbon (C) core enclosed in a plasmonic gold (Au) nanoshell can enhance the absorption peak while broadening the absorption band; giving rise to a much higher solar absorption than most previously studied core-shell combinations. The exact Mie solution is used to evaluate the absorption efficiency factor of spherical nanoparticles in the wavelength region from 300 nm to 1100 nm as well as the electric field and power dissipation profiles inside the nanoparticles at specified wavelengths (mostly at the localized surface plasmon resonance wavelength). The field enhancement by the localized plasmons at the gold surfaces boosts the absorption of the carbon particle, resulting in a redshift of the absorption peak with increased peak height and bandwidth. In addition to spherical nanoparticles, we use the finite-difference time-domain method to calculate the absorption of cubic core-shell nanoparticles. Even stronger enhancement can be achieved with cubic C-Au core-shell structures due to the localized plasmonic resonances at the sharp edges of the Au shell. The solar absorption efficiency factor can exceed 1.5 in the spherical case and reach 2.3 in the cubic case with a shell thickness of 10 nm. Such broadband absorption enhancement is in great demand for solar thermal applications including steam generation.

Critical Role of the Src Homology 2 (SH2) Domain of Neuronal SH2B1 in the Regulation of Body Weight and Glucose Homeostasis in Mice

OpenAIRE

Morris, David L.; Cho, Kae Won; Rui, Liangyou

2010-01-01

SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines ...

SH2 dependent autophosphorylation within the Tec family kinase Itk

Science.gov (United States)

Joseph, Raji E.; Severin, Andrew; Min, Lie; Fulton, D. Bruce; Andreotti, Amy H.

2009-01-01

The Tec family kinase, Itk, undergoes an in cis autophosphorylation on Y180 within its SH3 domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening SH2 domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the βD strand. These results are extended into Btk, a Tec family kinase linked to the B cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA causing mutations might impair Btk phosphorylation. PMID:19523959

Uranium contents and 234U/238U activity ratios of modern and fossil marine bivalle molluscan shells

International Nuclear Information System (INIS)

Mitsuda, Hiroshi

1984-01-01

Uranium contents and 234 U/ 238 U activity ratios in modern and fossil marine bivalle molluscan shells were measured by alpha-spectrometry. Uranium contents and 234 U/ 238 U activity ratios in modern shells were averaged to be 0.266 (dpm/g), and 1.18, respectively and those in fossil shells were averaged to be 0.747 (dpm/g), and 1.19, respectivily. Uranium contents in fossil shells were obviously higher than those in modern shells. It can be explained by the addition of uranium to shell during the deposition. In fossil shells, 234 U/ 238 U activity ratio decreases as 238 U content increases the same tendency is not found in modern shells. The author proposed a mechanism of selective loss of 238 U from the fossil shells for the explanation of this tendency. The height activity ratio of 234 U/ 238 U measured on the fossil shells than that measured on the modern shells, also support the selective loss of 238 U from the fossil shells. (author)

Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

Science.gov (United States)

Crofton, Elizabeth J.; Nenov, Miroslav N.; Zhang, Yafang; Scala, Federico; Page, Sean A.; McCue, David L.; Li, Dingge; Hommel, Jonathan D.; Laezza, Fernanda; Green, Thomas A.

2017-01-01

Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types. PMID:28126496

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity.

Science.gov (United States)

Lorenz, Sonja; Deng, Patricia; Hantschel, Oliver; Superti-Furga, Giulio; Kuriyan, John

2015-06-01

Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies have indicated that an interaction between the SH2 (Src-homology 2) domain and the N-lobe (N-terminal lobe) of the c-Abl kinase domain (KD) has a critical role in leukaemogenesis [Grebien et al. (2011) Cell 147, 306-319; Sherbenou et al. (2010) Blood 116, 3278-3285]. To dissect the structural basis of this phenomenon, we studied c-Abl constructs comprising the SH2 and KDs in vitro. We present a crystal structure of an SH2-KD construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the KD. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2/N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the KD. That the effects are small compared with the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the auto-inhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.

SH2-dependent autophosphorylation within the Tec family kinase Itk.

Science.gov (United States)

Joseph, Raji E; Severin, Andrew; Min, Lie; Fulton, D Bruce; Andreotti, Amy H

2009-08-07

The Tec family kinase, Itk (interleukin-2 tyrosine kinase), undergoes an in cis autophosphorylation on Y180 within its Src homology 3 (SH3) domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening Src homology 2 (SH2) domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full-length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the betaD strand. These results are extended into Btk (Bruton's tyrosine kinase), a Tec family kinase linked to the B-cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA-causing mutations might impair Btk phosphorylation.

Subclinical hyperthyroidism (Sh) in atomic-bomb survivors in Japan

International Nuclear Information System (INIS)

Ashizawa, K.; Imaizumi, M.; Usa, T.; Tominaga, T.; Hida, A.; Ejima, E.; Neriishi, K.; Soda, M.; Fujiwara, S.; Maeda, R.; Akahoshi, M.; Nagataki, S.; Eguchi, K.

2005-01-01

Full text: Purpose/Background Subclinical hyperthyroidism (Sh) is defined as a biochemical abnormality characterized by a subnormal level of TSH with otherwise normal thyroid tests (F T 3 , F T 4 ) and no clinical symptoms. There are only a small number of cross-sectional studies on the prevalence of Sh. With the improvement of the sensitivity of TSH assay, it has become possible to survey the clinical significance of Sh. With regard to both Sh and subclinical hypothyroidism, discussions are being focused on such as the necessity of treatment. In order to elucidate the clinical significance of Sh, examination data of A-bomb survivors in Hiroshima and Nagasaki were analyzed. Subjects and Method Between 2000 and 2003, of 4,090 A-bomb survivors (1,352 males and 2,738 females with average age of 70.7), 75 individuals (1.83%) with Sh were found who had normal Free T 4 (0.71∼1.51 ng/dL) and TSH<0.45 m U/L. Analysis was limited to those who had not taken antithyroid drugs or thyroxin, and the Sh group (n=35; 9 males and 26 females) was compared with a control group with TSH:0.45∼4.5 m U/L (Group C; N=3,243; 1,109 males and 2,134 females). Result: Nine individuals had TSH<0.1 m U/L. In the Sh group, six individuals were TPO antibody-positive (17%) and 14 were TG antibody-positive (40%); hence, TG antibody-positive was significantly greater in number (p=0.0096). Hematological biochemical tests showed no significant difference between the two groups. Electrocardiograms indicated that more individuals had atrial fibrillation [p=0.028; Odds ratio (OR)=3.98; 95% Confidential interval (CI)=1.2-13.7] or ventricular premature contraction [p=0.016; OR=3.29; 95% CI=1.3-8.6] in the Sh group. In terms of the presence or absence of diabetes, dyslipidemia, hypertension, and hyperuricemia, there was no difference between the two groups. One individual from the Sh group was confirmed to have Graves' disease two years later. Conclusion: Since more individuals in the Sh group were

In-Solution SH2 Domain Binding Assay Based on Proximity Ligation.

Science.gov (United States)

Machida, Kazuya

2017-01-01

Protein-protein interactions mediated by SH2 domains confer specificity in tyrosine kinase pathways. Traditional assays for assessing interactions between an SH2 domain and its interacting protein such as far-Western and pull-down are inherently low throughput. We developed SH2-PLA, an in-solution SH2 domain binding assay, that takes advantage of the speed and sensitivity of proximity ligation and real-time PCR. SH2-PLA allows for rapid assessment of SH2 domain binding to a target protein using only a few microliters of cell lysate, thereby making it an attractive new tool to study tyrosine kinase signaling.

Neuronal SH2B1 is essential for controlling energy and glucose homeostasis.

Science.gov (United States)

Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

2007-02-01

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

Effects of mechanical properties and geometric conditions on stiffness of Hyperboloid Shallow Shell

Directory of Open Access Journals (Sweden)

Zhao Lihong

2015-01-01

Full Text Available The experiment models based on the hyperboloid shallow shells that represent automobile panel's surface features are established. The effects of material properties and geometric conditions condition on the stiffness of hyperboloid shallow shell are investigated experimentally. The influences of panel thickness and geometric conditions on stiffness are very obvious. Stiffness increases with increasing of the panel thickness, and stiffness doubled as increasing in thickness with 0.1 mm. The effect of thickness on stiffness is far greater than that of blank holding force. The greater the arc height of punch, the greater the stiffness. And stiffness increases nearly by five times with arc height of punch is from 3mm to 9mm. The effect of arc height of punch on stiffness is far greater than that of materials mechanical properties. The stiffness is varied with different panel material properties by the same forming and stiffness test conditions. The decrease of yield strength is beneficial to the panel stiffness. The appropriate choice of materials and forming process condition is important in meeting necessary requirements for the energy-saving, lightweight and reducing wind resistance design in automotive industry.

SH2B1 regulation of energy balance, body weight, and glucose metabolism

OpenAIRE

Rui, Liangyou

2014-01-01

The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and...

Descending projections from the nucleus accumbens shell excite activity of taste-responsive neurons in the nucleus of the solitary tract in the hamster.

Science.gov (United States)

Li, Cheng-Shu; Lu, Da-Peng; Cho, Young K

2015-06-01

The nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN) are the first and second relays in the rodent central taste pathway. A series of electrophysiological experiments revealed that spontaneous and taste-evoked activities of brain stem gustatory neurons are altered by descending input from multiple forebrain nuclei in the central taste pathway. The nucleus accumbens shell (NAcSh) is a key neural substrate of reward circuitry, but it has not been verified as a classical gustatory nucleus. A recent in vivo electrophysiological study demonstrated that the NAcSh modulates the spontaneous and gustatory activities of hamster pontine taste neurons. In the present study, we investigated whether activation of the NAcSh modulates gustatory responses of the NST neurons. Extracellular single-unit activity was recorded from medullary neurons in urethane-anesthetized hamsters. After taste response was confirmed by delivery of sucrose, NaCl, citric acid, and quinine hydrochloride to the anterior tongue, the NAcSh was stimulated bilaterally with concentric bipolar stimulating electrodes. Stimulation of the ipsilateral and contralateral NAcSh induced firings from 54 and 37 of 90 medullary taste neurons, respectively. Thirty cells were affected bilaterally. No inhibitory responses or antidromic invasion was observed after NAcSh activation. In the subset of taste cells tested, high-frequency electrical stimulation of the NAcSh during taste delivery enhanced taste-evoked neuronal firing. These results demonstrate that two-thirds of the medullary gustatory neurons are under excitatory descending influence from the NAcSh, which is a strong indication of communication between the gustatory pathway and the mesolimbic reward pathway. Copyright © 2015 the American Physiological Society.

Application of the biosurfactants produced by Bacillus spp. (SH 20 ...

African Journals Online (AJOL)

Application of the biosurfactants produced by Bacillus spp. (SH 20 and SH 26) and P. aeruginosa SH 29 isolated from the rhizosphere soil of an Egyptian salt marsh plant for the cleaning of oil - contaminataed vessels and enhancing the biodegradat.

Subclinical hyperthyroidism (Sh) in atomic-bomb survivors in Japan

Energy Technology Data Exchange (ETDEWEB)

Ashizawa, K; Imaizumi, M; Usa, T; Tominaga, T; Hida, A; Ejima, E; Neriishi, K; Soda, M; Fujiwara, S; Maeda, R; Akahoshi, M; Nagataki, S; Eguchi, K [Radiation Effects Research Foundation, Nagasaki (Japan). Nagasaki Branch

2005-07-01

Full text: Purpose/Background Subclinical hyperthyroidism (Sh) is defined as a biochemical abnormality characterized by a subnormal level of TSH with otherwise normal thyroid tests (F T{sub 3}, F T{sub 4}) and no clinical symptoms. There are only a small number of cross-sectional studies on the prevalence of Sh. With the improvement of the sensitivity of TSH assay, it has become possible to survey the clinical significance of Sh. With regard to both Sh and subclinical hypothyroidism, discussions are being focused on such as the necessity of treatment. In order to elucidate the clinical significance of Sh, examination data of A-bomb survivors in Hiroshima and Nagasaki were analyzed. Subjects and Method Between 2000 and 2003, of 4,090 A-bomb survivors (1,352 males and 2,738 females with average age of 70.7), 75 individuals (1.83%) with Sh were found who had normal Free T{sub 4} (0.71{approx}1.51 ng/dL) and TSH<0.45 m U/L. Analysis was limited to those who had not taken antithyroid drugs or thyroxin, and the Sh group (n=35; 9 males and 26 females) was compared with a control group with TSH:0.45{approx}4.5 m U/L (Group C; N=3,243; 1,109 males and 2,134 females). Result: Nine individuals had TSH<0.1 m U/L. In the Sh group, six individuals were TPO antibody-positive (17%) and 14 were TG antibody-positive (40%); hence, TG antibody-positive was significantly greater in number (p=0.0096). Hematological biochemical tests showed no significant difference between the two groups. Electrocardiograms indicated that more individuals had atrial fibrillation [p=0.028; Odds ratio (OR)=3.98; 95% Confidential interval (CI)=1.2-13.7] or ventricular premature contraction [p=0.016; OR=3.29; 95% CI=1.3-8.6] in the Sh group. In terms of the presence or absence of diabetes, dyslipidemia, hypertension, and hyperuricemia, there was no difference between the two groups. One individual from the Sh group was confirmed to have Graves' disease two years later. Conclusion: Since more individuals in

Traces (ichnospecies Oichnus paraboloides of predatory gastropods on bivalve shells from the Seogwipo Formation, Jejudo, Korea

Directory of Open Access Journals (Sweden)

Dal-Yong Kong

2015-12-01

Full Text Available Circular to subcircular drill holes were identified on the bivalve shells collected from the Seogwipo Formation, Jejudo, Korea. A great majority of the drill holes (>70% were found on the surfaces of a bivalve species Glycymeris rotunda. They are characterized by a beveled sharp edge and paraboloid in cross section with larger outer borehole diameter (OBD; mean 4.21 mm and smaller inner borehole diameter (mean 2.94 mm. Walls of the drill holes are generally smooth, and walls ornamented with etched relief-like structures were also recognized. A slightly raised central boss observed in an incomplete specimen may indicate a failure of predator’s attack. All drill holes collected are classified as a single ichnospecies Oichnus paraboloides Bromley, 1981. They are interpreted as boring traces produced by predatory gastropods, particularly naticid gastropods. Most O. paraboloides boreholes are observed in the central area of shell surfaces; a few boreholes lie marginally, which may reflect a borehole-site selectivity. No correlation between size of prey (shell height and size of predator (OBD is recognized. It is likely, however, that drilled shells of about 30 mm in height represent optimal prey size for naticid predators that lived in a benthic Seogwipo community.

Determination of the optimum commercial size for the mangrove oyster (Crassostrea rhizophorae) in Todos os Santos Bay, Brazil

OpenAIRE

Nascimento, Iracema Andrade; Pereira, Solange Andrade; Souza, Raymundo Costa e

1980-01-01

Texto completo. Acesso restrito. p. 1 – 8 Pilot studies were conducted in 1977-1978 on the cultivation of mangrove oysters in the Jacuruna River estuary at Todos OS Santos Bay, Salvador, Brazil. Growth characteristics were studied by comparing the relationships between total live weight, volume of the shell cavity fluid and yield of meat, and dry body weight to size (height). The most economically feasible proposition was production of approximately 7 cm high oysters for the sh...

SH2 Ligand Prediction-Guidance for In-Silico Screening.

Science.gov (United States)

Li, Shawn S C; Li, Lei

2017-01-01

Systematic identification of binding partners for SH2 domains is important for understanding the biological function of the corresponding SH2 domain-containing proteins. Here, we describe two different web-accessible computer programs, SMALI and DomPep, for predicting binding ligands for SH2 domains. The former was developed using a Scoring Matrix method and the latter based on the Support Vector Machine model.

Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell

Directory of Open Access Journals (Sweden)

Regina A. Mangieri

2017-08-01

Full Text Available Anaplastic lymphoma kinase (ALK is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD. Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh medium spiny neurons (MSNs, and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO mice consumed greater doses of ethanol, relative to wild-type (AlkWT mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs, we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity – long-term depression of evoked EPSCs – in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.

Structural insights into the intertwined dimer of fyn SH2.

Science.gov (United States)

Huculeci, Radu; Garcia-Pino, Abel; Buts, Lieven; Lenaerts, Tom; van Nuland, Nico

2015-12-01

Src homology 2 domains are interaction modules dedicated to the recognition of phosphotyrosine sites incorporated in numerous proteins found in intracellular signaling pathways. Here we provide for the first time structural insight into the dimerization of Fyn SH2 both in solution and in crystalline conditions, providing novel crystal structures of both the dimer and peptide-bound structures of Fyn SH2. Using nuclear magnetic resonance chemical shift analysis, we show how the peptide is able to eradicate the dimerization, leading to monomeric SH2 in its bound state. Furthermore, we show that Fyn SH2's dimer form differs from other SH2 dimers reported earlier. Interestingly, the Fyn dimer can be used to construct a completed dimer model of Fyn without any steric clashes. Together these results extend our understanding of SH2 dimerization, giving structural details, on one hand, and suggesting a possible physiological relevance of such behavior, on the other hand. © 2015 The Protein Society.

Understanding the Steric Height Long Term Variability at the Bermuda Atlantic Time-Series Study (BATS) Site with a Neutral Density Approach

Science.gov (United States)

Goncalves Neto, A.; Johnson, R. J.; Bates, N. R.

2016-02-01

Rising sea level is one of the main concerns for human life in a scenario with global atmosphere and ocean warming, which is of particular concern for oceanic islands. Bermuda, located in the center of the Sargasso Sea, provides an ideal location to investigate sea level rise since it has a long term tide gauge (1933-present) and is in close proximity to deep ocean time-series sites, namely, Hydrostation `S' (1954-present) and the Bermuda Atlantic Time-Series Study site (1988-present). In this study, we use the monthly CTD deep casts at BATS to compute the contribution of steric height (SH) to the local sea surface height (SSH) for the past 24 years. To determine the relative contribution from the various water masses we first define 8 layers (Surface Layer, Upper Thermocline, Subtropical Mode-Water, Lower Thermocline, Antarctic Intermediate Water, Labrador Sea Water, Iceland-Scotland Overflow Water, Denmark Strait Overflow Water) based on neutral density criteria for which SH is computed. Additionally, we calculate the thermosteric and halosteric components for each of the defined neutral density layers. Surprisingly, the results show that, despite a 3.3mm/yr sea level rise observed at the Bermuda tide gauge, the steric contribution to the SSH at BATS has decreased at a rate of -1.1mm/yr during the same period. The thermal component is found to account for the negative trend in the steric height (-4.4mm/yr), whereas the halosteric component (3.3mm/yr) partially compensates the thermal signal and can be explained by an overall cooling and freshening at the BATS site. Although the surface layer and the upper thermocline waters are warming, all the subtropical and polar water masses, which represent most of the local water column, are cooling and therefore drive the overall SH contribution to the local SSH. Hence, it suggests that the mass contribution to the local SSH plays an important role in the sea level rise, for which we investigate with GRACE data.

Kit W-sh Mutation Prevents Cancellous Bone Loss during Calcium Deprivation.

Science.gov (United States)

Lotinun, Sutada; Suwanwela, Jaijam; Poolthong, Suchit; Baron, Roland

2018-01-01

Calcium is essential for normal bone growth and development. Inadequate calcium intake increases the risk of osteoporosis and fractures. Kit ligand/c-Kit signaling plays an important role in regulating bone homeostasis. Mice with c-Kit mutations are osteopenic. The present study aimed to investigate whether impairment of or reduction in c-Kit signaling affects bone turnover during calcium deprivation. Three-week-old male WBB6F1/J-Kit W /Kit W-v /J (W/W v ) mice with c-Kit point mutation, Kit W-sh /HNihrJaeBsmJ (W sh /W sh ) mice with an inversion mutation in the regulatory elements upstream of the c-Kit promoter region, and their wild-type controls (WT) were fed either a normal (0.6% calcium) or a low calcium diet (0.02% calcium) for 3 weeks. μCT analysis indicated that both mutants fed normal calcium diet had significantly decreased cortical thickness and cancellous bone volume compared to WT. The low calcium diet resulted in a comparable reduction in cortical bone volume and cortical thickness in the W/W v and W sh /W sh mice, and their corresponding controls. As expected, the low calcium diet induced cancellous bone loss in the W/W v mice. In contrast, W sh /W sh cancellous bone did not respond to this diet. This c-Kit mutation prevented cancellous bone loss by antagonizing the low calcium diet-induced increase in osteoblast and osteoclast numbers in the W sh /W sh mice. Gene expression profiling showed that calcium deficiency increased Osx, Ocn, Alp, type I collagen, c-Fms, M-CSF, and RANKL/OPG mRNA expression in controls; however, the W sh mutation suppressed these effects. Our findings indicate that although calcium restriction increased bone turnover, leading to osteopenia, the decreased c-Kit expression levels in the W sh /W sh mice prevented the low calcium diet-induced increase in cancellous bone turnover and bone loss but not the cortical bone loss.

Large Steel Tank Fails and Rockets to Height of 30 meters - Rupture Disc Installed Incorrectly

DEFF Research Database (Denmark)

Hedlund, Frank Huess; Selig, Robert Simon; Kragh, Eva K.

2016-01-01

At a brewery, the base plate-to-shell weld seam of a 90-m3 vertical cylindrical steel tank failed catastrophically. The 4 ton tank “took off” like a rocket leaving its contents behind, and landed on a van, crushing it. The top of the tank reached a height of 30 m. The internal overpressure...

Evidence of site-specific fragmentation on thioacetic acid, CH3C(O)SH, irradiated with synchrotron radiation around the S 2p and O 1s regions.

Science.gov (United States)

Erben, Mauricio F; Geronés, Mariana; Romano, Rosana M; Della Védova, Carlos O

2006-01-26

Site-specific fragmentations following S 2p and O 1s photoexcitation of thioacetic acid, CH3C(O)SH, have been studied by means of synchrotron radiation. Total ion yield (TIY) spectra were measured and multicoincidence techniques, which include photoelectron-photoion coincidence (PEPICO) and photoelectron-photoion-photoion coincidence (PEPIPICO) time-of-flight mass spectrometry, were applied. The equivalent-core approximation was employed in order to estimate ionization transition values, and the observed peaks were tentatively assigned. A site-specific fragmentation is moderately observed by comparing the mass spectra collected at resonant energies around the inner and shallow inner shell S 2p and O 1s ionization edges. Beside H+ ion, the most abundant ions observed at the S 2p edge excitation were CH3CO+, SH+, S+, and CH3+. At the O 1s region the large CH3CO+ fragment was depressed, and small CHx+ (x = 0, 1, 2, 3), S+, and SH+ fragments were dominant. The dissociation dynamic for the main ion-pair production has been discussed. Two- and three-body dissociation channels have been observed in the PEPIPICO spectra, and the dissociation mechanisms were proposed.

Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

OpenAIRE

Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

2007-01-01

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (α, β, γ, and/or δ) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1β was specifically expressed in neural tissue in SH2B1-tran...

Distributed microscopic actuation analysis of paraboloidal membrane shells of different geometric parameters

Science.gov (United States)

Yue, Honghao; Lu, Yifan; Deng, Zongquan; Tzou, Hornsen

2018-03-01

Paraboloidal membrane shells of revolution are commonly used as key components for advanced aerospace structures and aviation mechanical systems. Due to their high flexibility and low damping property, active vibration control is of significant importance for these in-orbit membrane structures. To explore the dynamic control behavior of space flexible paraboloidal membrane shells, precision distributed actuation and control effectiveness of free-floating paraboloidal membrane shells with piezoelectric actuators are investigated. Governing equations of the shell structronic system are presented first. Then, distributed control forces and control actions are formulated. A transverse mode shape function of the paraboloidal shell based on the membrane approximation theory and specified boundary condition is assumed in the modal control force analysis. The actuator induced modal control forces on the paraboloidal shell are derived. The expressions of microscopic local modal control forces are obtained by shrinking the actuator area into infinitesimal and the four control components are investigated respectively to predict the spatial microscopic actuation behavior. Geometric parameter (height-radius ratio and shell thickness) effects on the modal actuation behavior are explored when evaluating the micro-control efficiency. Four different cases are discussed and the results reveal the fact that shallow (e.g., antennas/reflectors) and deep (e.g., rocket/missile fairing) paraboloidal shells exhibit totally different modal actuation behaviors due to their curvature differences. Analytical results in this paper can serve as guidelines for optimal actuator placement for vibration control of different paraboloidal structures.

SH2B Regulation of Growth, Metabolism, and Longevity in Both Insects and Mammals

OpenAIRE

Song, Wei; Ren, Decheng; Li, Wenjun; Jiang, Lin; Cho, Kae Won; Huang, Ping; Fan, Chen; Song, Yiyun; Liu, Yong; Rui, Liangyou

2010-01-01

SH2B1 is a key regulator of body weight in mammals. Here we identified dSH2B as the Drosophila homolog of SH2B1. dSH2B bound to Chico and directly promoted insulin-like signaling. Disruption of dSH2B decreased insulin-like signaling and somatic growth in flies. dSH2B deficiency also increased hemolymph carbohydrate levels, whole body lipid levels, lifespan, and resistance to starvation and oxidative stress. Systemic overexpression of dSH2B resulted in opposite phenotypes. dSH2B overexpression...

Characterization of breakpoint cluster region kinase and SH2-binding activities.

Science.gov (United States)

Afar, D E; Witte, O N

1995-01-01

BCR is an interesting signaling protein, whose cellular function is currently unknown. Its biochemical properties include serine kinase activity, SH2-binding activity, and a GTPase-activating activity. The SH2-binding activity is particularly interesting because it may link BCR to signaling pathways involving SH2-containing molecules. Since tyrosine phosphorylation of BCR has been detected in CML-derived cell lines and since tyrosine-phosphorylated BCR shows increased affinity toward certain SH2 domains, it seems particularly important to further characterize this activity. This chapter described a simple purification scheme for partial purification of BCR, which can be used to assess in vitro kinase and SH2-binding activities.

Sexual Orientation, Objective Height, and Self-Reported Height.

Science.gov (United States)

Skorska, Malvina N; Bogaert, Anthony F

2017-01-01

Studies that have used mostly self-reported height have found that androphilic men and women are shorter than gynephilic men and women, respectively. This study examined whether an objective height difference exists or whether a psychosocial account (e.g., distortion of self-reports) may explain these putative height differences. A total of 863 participants, recruited at a Canadian university, the surrounding region, and through lesbian, gay, bisexual, and transgender (LGBT) events across Canada, self-reported their height and had their height measured. Androphilic men were shorter, on average, than gynephilic men. There was no objective height difference between gynephilic, ambiphilic, and androphilic women. Self-reported height, statistically controlling for objective height, was not related to sexual orientation. These findings are the first to show an objective height difference between androphilic and gynephilic men. Also, the findings suggest that previous studies using self-reported height found part of a true objective height difference between androphilic and gynephilic men. These findings have implications for existing biological theories of men's sexual orientation development.

Thermally Stable Gold Nanoparticles with a Crosslinked Diblock Copolymer Shell

Science.gov (United States)

Jang, Se Gyu; Khan, Anzar; Hawker, Craig J.; Kramer, Edward J.

2010-03-01

The use of polymer-coated Au nanoparticles prepared using oligomeric- or polymeric-ligands tethered by Au-S bonds for incorporation into block copolymer templates under thermal processing has been limited due to dissociation of the Au-S bond at T > 100^oC where compromises their colloidal stability. We report a simple route to prepare sub-5nm gold nanoparticles with a thermally stable polymeric shell. An end-functional thiol ligand consisting of poly(styrene-b-1,2&3,4-isoprene-SH) is synthesized by anionic polymerization. After a standard thiol ligand synthesis of Au nanoparticles, the inner PI block is cross-linked through reaction with 1,1,3,3-tetramethyldisiloxane. Gold nanoparticles with the cross-linked shell are stable in organic solvents at 160^oC as well as in block copolymer films of PS-b-P2VP annealed in vacuum at 170^oC for several days. These nanoparticles can be designed to strongly segregate to the PS-P2VP interface resulting in very large Au nanoparticle volume fractions φp without macrophase separation as well as transitions between lamellar and bicontinuous morphologies as φp increases.

Interproximal grooving in the Atapuerca-SH hominid dentitions.

Science.gov (United States)

Bermúdez de Castro, J M; Arsuaga, J L; Pérez, P J

1997-03-01

The dental sample recovered from the Sima de los Huesos (SH) Middle Pleistocene cave site of the Sierra de Atapuerca (Spain) includes 296 specimens. Interproximal wear grooves have been observed in 20 maxillary and mandibular posterior teeth belonging to at least five of the 32 individuals identified so far in the SH hypodigm. Interproximal grooving affected only the adults, and at an age between 25 and 40 years. The appearance, morphology, and location pattern of the SH wear grooves are similar to those reported in other fossil hominids and in more recent human populations. Two alternative proposals, the toothpicking and the fiber or sinew processing hypotheses, compete for explaining the formation of this anomalous wear. The characteristics observed in the wear grooves of the SH teeth are compatible only with the habitual probing of interdental spaces by means of hard and inflexible objects. Dietary grit may also have contributed to the abrasion of the root walls during the motion of the dental probes.

Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein.

Science.gov (United States)

Garrity, P A; Rao, Y; Salecker, I; McGlade, J; Pawson, T; Zipursky, S L

1996-05-31

Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type-specific expression of dock transgenes demonstrate dock is required in R cells for proper innervation. Dock protein contains one SH2 and three SH3 domains, implicating it in tyrosine kinase signaling, and is highly related to the human proto-oncogene Nck. Dock expression is detected in R cell growth cones in the target region. We propose Dock transmits signals in the growth cone in response to guidance and targeting cues. These findings provide an important step for dissection of signaling pathways regulating growth cone motility.

Evolution of SH2 domains and phosphotyrosine signalling networks

Science.gov (United States)

Liu, Bernard A.; Nash, Piers D.

2012-01-01

Src homology 2 (SH2) domains mediate selective protein–protein interactions with tyrosine phosphorylated proteins, and in doing so define specificity of phosphotyrosine (pTyr) signalling networks. SH2 domains and protein-tyrosine phosphatases expand alongside protein-tyrosine kinases (PTKs) to coordinate cellular and organismal complexity in the evolution of the unikont branch of the eukaryotes. Examination of conserved families of PTKs and SH2 domain proteins provides fiduciary marks that trace the evolutionary landscape for the development of complex cellular systems in the proto-metazoan and metazoan lineages. The evolutionary provenance of conserved SH2 and PTK families reveals the mechanisms by which diversity is achieved through adaptations in tissue-specific gene transcription, altered ligand binding, insertions of linear motifs and the gain or loss of domains following gene duplication. We discuss mechanisms by which pTyr-mediated signalling networks evolve through the development of novel and expanded families of SH2 domain proteins and the elaboration of connections between pTyr-signalling proteins. These changes underlie the variety of general and specific signalling networks that give rise to tissue-specific functions and increasingly complex developmental programmes. Examination of SH2 domains from an evolutionary perspective provides insight into the process by which evolutionary expansion and modification of molecular protein interaction domain proteins permits the development of novel protein-interaction networks and accommodates adaptation of signalling networks. PMID:22889907

Physical and functional interactions between SH2 and SH3 domains of the Src family protein tyrosine kinase p59fyn

NARCIS (Netherlands)

Panchamoorthy, G.; Fukazawa, T.; Stolz, L.; Payne, G.; Reedquist, K.; Shoelson, S.; Songyang, Z.; Cantley, L.; Walsh, C.; Band, H.

1994-01-01

The Src family protein tyrosine kinases participate in signalling through cell surface receptors that lack intrinsic tyrosine kinase domains. All nine members of this family possess adjacent Src homology (SH2 and SH3) domains, both of which are essential for repression of the enzymatic activity. The

NIF Double Shell outer/inner shell collision experiments

Science.gov (United States)

Merritt, E. C.; Loomis, E. N.; Wilson, D. C.; Cardenas, T.; Montgomery, D. S.; Daughton, W. S.; Dodd, E. S.; Desjardins, T.; Renner, D. B.; Palaniyappan, S.; Batha, S. H.; Khan, S. F.; Smalyuk, V.; Ping, Y.; Amendt, P.; Schoff, M.; Hoppe, M.

2017-10-01

Double shell capsules are a potential low convergence path to substantial alpha-heating and ignition on NIF, since they are predicted to ignite and burn at relatively low temperatures via volume ignition. Current LANL NIF double shell designs consist of a low-Z ablator, low-density foam cushion, and high-Z inner shell with liquid DT fill. Central to the Double Shell concept is kinetic energy transfer from the outer to inner shell via collision. The collision determines maximum energy available for compression and implosion shape of the fuel. We present results of a NIF shape-transfer study: two experiments comparing shape and trajectory of the outer and inner shells at post-collision times. An outer-shell-only target shot measured the no-impact shell conditions, while an `imaging' double shell shot measured shell conditions with impact. The `imaging' target uses a low-Z inner shell and is designed to perform in similar collision physics space to a high-Z double shell but can be radiographed at 16keV, near the viable 2DConA BL energy limit. Work conducted under the auspices of the U.S. DOE by LANL under contract DE-AC52-06NA25396.

SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family.

Science.gov (United States)

Register, A C; Leonard, Stephen E; Maly, Dustin J

2014-11-11

Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the αC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report αC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and αC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function.

Off-Shell Interactions of Closed-String Tachyons

Energy Technology Data Exchange (ETDEWEB)

Dabholkar, A

2004-04-07

Off-shell interactions for localized closed-string tachyons in C/Z{sub N} superstring backgrounds are analyzed and a conjecture for the effective height of the tachyon potential is elaborated. At large N, some of the relevant tachyons are nearly massless and their interactions can be deduced from the S-matrix. The cubic interactions between these tachyons and the massless fields are computed in a closed form using orbifold CFT techniques. The cubic interaction between nearly-massless tachyons with different charges is shown to vanish and thus condensation of one tachyon does not source the others. It is shown that to leading order in N, the quartic contact interaction vanishes and the massless exchanges completely account for the four point scattering amplitude. This indicates that it is necessary to go beyond quartic interactions or to include other fields to test the conjecture for the height of the tachyon potential.

Genetic loss of SH2B3 in acute lymphoblastic leukemia.

Science.gov (United States)

Perez-Garcia, Arianne; Ambesi-Impiombato, Alberto; Hadler, Michael; Rigo, Isaura; LeDuc, Charles A; Kelly, Kara; Jalas, Chaim; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M; Tallman, Martin S; Paganin, Maddalena; Basso, Giuseppe; Tong, Wei; Chung, Wendy K; Ferrando, Adolfo A

2013-10-03

The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

Designing a dataflow processor using CλaSH

NARCIS (Netherlands)

Niedermeier, A.; Wester, Rinse; Wester, Rinse; Rovers, K.C.; Baaij, C.P.R.; Kuper, Jan; Smit, Gerardus Johannes Maria

2010-01-01

In this paper we show how a simple dataflow processor can be fully implemented using CλaSH, a high level HDL based on the functional programming language Haskell. The processor was described using Haskell, the CλaSH compiler was then used to translate the design into a fully synthesisable VHDL code.

Modeling cometary photopolarimetric characteristics with Sh-matrix method

Science.gov (United States)

Kolokolova, L.; Petrov, D.

2017-12-01

Cometary dust is dominated by particles of complex shape and structure, which are often considered as fractal aggregates. Rigorous modeling of light scattering by such particles, even using parallelized codes and NASA supercomputer resources, is very computer time and memory consuming. We are presenting a new approach to modeling cometary dust that is based on the Sh-matrix technique (e.g., Petrov et al., JQSRT, 112, 2012). This method is based on the T-matrix technique (e.g., Mishchenko et al., JQSRT, 55, 1996) and was developed after it had been found that the shape-dependent factors could be separated from the size- and refractive-index-dependent factors and presented as a shape matrix, or Sh-matrix. Size and refractive index dependences are incorporated through analytical operations on the Sh-matrix to produce the elements of T-matrix. Sh-matrix method keeps all advantages of the T-matrix method, including analytical averaging over particle orientation. Moreover, the surface integrals describing the Sh-matrix elements themselves can be solvable analytically for particles of any shape. This makes Sh-matrix approach an effective technique to simulate light scattering by particles of complex shape and surface structure. In this paper, we present cometary dust as an ensemble of Gaussian random particles. The shape of these particles is described by a log-normal distribution of their radius length and direction (Muinonen, EMP, 72, 1996). Changing one of the parameters of this distribution, the correlation angle, from 0 to 90 deg., we can model a variety of particles from spheres to particles of a random complex shape. We survey the angular and spectral dependencies of intensity and polarization resulted from light scattering by such particles, studying how they depend on the particle shape, size, and composition (including porous particles to simulate aggregates) to find the best fit to the cometary observations.

Separative analyses of a chromatographic column packed with a core-shell adsorbent for lithium isotope separation

International Nuclear Information System (INIS)

Sugiyama, T.; Sugura, K.; Enokida, Y.; Yamamoto, I.

2015-01-01

Lithium-6 is used as a blanket material for sufficient tritium production in DT fueled fusion reactors. A core-shell type adsorbent was proposed for lithium isotope separation by chromatography. The mass transfer model in a chromatographic column consisted of 4 steps, such as convection and dispersion in the column, transfer through liquid films, intra-particle diffusion and and adsorption or desorption at the local adsorption sites. A model was developed and concentration profiles and time variation in the column were numerically simulated. It became clear that core-shell type adsorbents with thin porous shell were saturated rapidly relatively to fully porous one and established a sharp edge of adsorption band. This is very important feature because lithium isotope separation requires long-distance development of adsorption band. The values of HETP (Height Equivalent of a Theoretical Plate) for core-shell adsorbent packed column were estimated by statistical moments of the step response curve. The value of HETP decreased with the thickness of the porous shell. A core-shell type adsorbent is, then, useful for lithium isotope separation. (authors)

Fear of heights and visual height intolerance.

Science.gov (United States)

Brandt, Thomas; Huppert, Doreen

2014-02-01

The aim of this review is, first, to cover the different aspects of visual height intolerance such as historical descriptions, definition of terms, phenomenology of the condition, neurophysiological control of gaze, stance and locomotion, and therapy, and, second, to identify warranted epidemiological and experimental studies. Vivid descriptions of fear of heights can be found in ancient texts from the Greek, Roman, and Chinese classics. The life-time prevalence of visual height intolerance is as high as 28% in the general population, and about 50% of those who are susceptible report an impact on quality of life. When exposed to heights, visual exploration by eye and head movements is restricted, and the velocity of locomotion is reduced. Therapy for fear of heights is dominated by the behavioral techniques applied during real or virtual reality exposure. Their efficacy might be facilitated by the administration of D-cycloserine or glucocorticoids. Visual height intolerance has a considerable impact on daily life and interpersonal interactions. It is much more frequent than fear of heights, which is defined as an environmental subtype of a specific phobia. There is certainly a continuum stretching from acrophobia to a less-pronounced visual height intolerance, to which the categorical distinction of a specific phobia does not apply.

Superbinder SH2 domains act as antagonists of cell signaling.

Science.gov (United States)

Kaneko, Tomonori; Huang, Haiming; Cao, Xuan; Li, Xing; Li, Chengjun; Voss, Courtney; Sidhu, Sachdev S; Li, Shawn S C

2012-09-25

Protein-ligand interactions mediated by modular domains, which often play important roles in regulating cellular functions, are generally of moderate affinities. We examined the Src homology 2 (SH2) domain, a modular domain that recognizes phosphorylated tyrosine (pTyr) residues, to investigate how the binding affinity of a modular domain for its ligand influences the structure and cellular function of the protein. We used the phage display method to perform directed evolution of the pTyr-binding residues in the SH2 domain of the tyrosine kinase Fyn and identified three amino acid substitutions that critically affected binding. We generated three SH2 domain triple-point mutants that were "superbinders" with much higher affinities for pTyr-containing peptides than the natural domain. Crystallographic analysis of one of these superbinders revealed that the superbinder SH2 domain recognized the pTyr moiety in a bipartite binding mode: A hydrophobic surface encompassed the phenyl ring, and a positively charged site engaged the phosphate. When expressed in mammalian cells, the superbinder SH2 domains blocked epidermal growth factor receptor signaling and inhibited anchorage-independent cell proliferation, suggesting that pTyr superbinders might be explored for therapeutic applications and useful as biological research tools. Although the SH2 domain fold can support much higher affinity for its ligand than is observed in nature, our results suggest that natural SH2 domains are not optimized for ligand binding but for specificity and flexibility, which are likely properties important for their function in signaling and regulatory processes.

Evolution of Src Homology 2 (SH2) Domain to Recognize Sulfotyrosine.

Science.gov (United States)

Ju, Tong; Niu, Wei; Guo, Jiantao

2016-09-16

Protein tyrosine O-sulfation is considered as the most common type of post-translational tyrosine modification in nature and plays important roles in extracellular biomolecular interactions. To facilitate the mapping, biological study, and medicinal application of this type of post-translational modification, we seek to evolve a small protein scaffold that recognizes sulfotyrosine with high affinity. We focused our efforts on the engineering of the Src Homology 2 (SH2) domain, which represents the largest class of known phosphotyrosine-recognition domain in nature and has a highly evolvable binding pocket. By using phage display, we successfully engineered the SH2 domain to recognize sulfotyrosine with high affinity. The best mutant, SH2-60.1, displayed more than 1700 fold higher sulfotyrosine-binding affinity than that of the wild-type SH2 domain. We also demonstrated that the evolved SH2 domain mutants could be used to detect sulfoprotein levels on the cell surface. These evolved SH2 domain mutants can be potentially applied to the study of protein tyrosine O-sulfation with proper experimental designs.

Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell.

Science.gov (United States)

Wilden, Jessica A; Qing, Kurt Y; Hauser, Sheketha R; McBride, William J; Irazoqui, Pedro P; Rodd, Zachary A

2014-04-01

There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ-aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8-10 rats/group), after which the animals were placed in operant chambers containing 2 levers--one used to administer water and the other to administer 15% EtOH--to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat's left AcbSh. The animals then received 100 or 200 μA (3-4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism.

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

Science.gov (United States)

Scudiero, Ivan; Mazzone, Pellegrino; D'Andrea, Luca E; Ferravante, Angela; Zotti, Tiziana; Telesio, Gianluca; De Rubis, Gabriele; Reale, Carla; Pizzulo, Maddalena; Muralitharan, Shanmugakonar; Vito, Pasquale; Stilo, Romania

2017-02-23

The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.

Src binds cortactin through an SH2 domain cystine-mediated linkage

Science.gov (United States)

Evans, Jason V.; Ammer, Amanda G.; Jett, John E.; Bolcato, Chris A.; Breaux, Jason C.; Martin, Karen H.; Culp, Mark V.; Gannett, Peter M.; Weed, Scott A.

2012-01-01

Summary Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions. PMID:23097045

Src binds cortactin through an SH2 domain cystine-mediated linkage.

Science.gov (United States)

Evans, Jason V; Ammer, Amanda G; Jett, John E; Bolcato, Chris A; Breaux, Jason C; Martin, Karen H; Culp, Mark V; Gannett, Peter M; Weed, Scott A

2012-12-15

Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions.

Lead reduces shell mass in juvenile garden snails (Helix aspersa)

International Nuclear Information System (INIS)

Beeby, Alan; Richmond, Larry; Herpe, Florian

2002-01-01

A high Pb diet causes differential depression of juvenile shell mass in populations of Helix. - In an earlier paper examining inherited tolerance to Pb, the shell growth of laboratory-bred offspring of Helix aspersa from contaminated sites was compared with that of juveniles from naieve populations on dosed and undosed diets. Eight-week-old snails were fed either 500 μg g -1 Pb or a control food in competitive trials between two populations. In the first series of trials, a parental history of exposure to Pb did not confer any advantage to either of two populations (BI and MI) competing with a naieve population (LE), whether Pb was present in the diet or not. However, in the analysis of their metal concentrations reported here, LE are found to retain higher levels of Pb in the soft tissues than either BI or MI. Compared to their siblings on the unleaded diet, dosed LE and BI juveniles had lower soft tissue concentrations of Ca and Mg. Although the growth in shell height is unaffected by diet, LE and BI juveniles build lighter shells on the Pb-dosed diet, achieving around 75% of the shell mass of their controls. In contrast, the shell weights of dosed MI juveniles are depressed by only 15% and show no change in the essential metal concentrations of their soft tissues. A second experiment using five populations fed only the dosed food show that the shell weight/soft tissue weight ratios are comparable to the dosed snails of the previous experiment. Building a lighter shell thus appears to be the common response of all Helix populations to a high Pb diet, at least amongst juveniles. The reduction in its mass means that less Ca and Mg is added to the shell and, along with the lowered soft tissue concentrations observed in some populations, may be a consequence of an increased effort to excrete Pb. The possibility that the MI population shows a genotypic adaptation, perhaps as some form of modification of its Ca metabolism, is briefly discussed

New investigation on THz spectra of OH and SH radicals (X∏)

Science.gov (United States)

Martin-Drumel, M. A.; Eliet, S.; Pirali, O.; Guinet, M.; Hindle, F.; Mouret, G.; Cuisset, A.

2012-10-01

Pure rotational transitions of OH and SH radicals have been recorded in the THz spectral range using cw-THz and synchrotron-based FT-FIR techniques. Line lists on these radicals have been completed in the three and two lowest vibrational states for OH and SH, respectively. Furthermore, the hyperfine structure of OH and SH has been observed for the first time using infrared IR FT-spectroscopy, and at frequencies higher than 1 THz, respectively. A combined fit has been made for each of these radicals including v = 0, 1 and 2 for OH and v = 0 and 1 for SH.

Effects of GABA ligands injected into the nucleus accumbens shell on fear/anxiety-like and feeding behaviours in food-deprived rats.

Science.gov (United States)

Lopes, Ana Paula Fraga; Ganzer, Laís; Borges, Aline Caon; Kochenborger, Larissa; Januário, Ana Cláudia; Faria, Moacir Serralvo; Marino-Neto, José; Paschoalini, Marta Aparecida

2012-03-01

In an attempt to establish a relationship between food intake and fear/anxiety-related behaviours, the goal of this study was to investigate the effect of bilateral injections of GABAA (Muscimol, MUS, doses 25 and 50ng/side) and GABAB (Baclofen, BAC, doses 32 and 64ng/side) receptor agonists in the nucleus accumbens shell (AcbSh) on the level of fear/anxiety-like and feeding behaviours in 24h food-deprived rats. The antagonists of GABAA (Bicuculline, BIC, doses 75 and 150ng/side) and GABAB (Saclofen, SAC, doses 1.5 and 3μg/side) were also tested. The results indicated that the total number of risk assessment behaviour decreased after the injection of both doses of GABAA agonist (MUS) into the AcbSh of 24h food-deprived rats exposed to elevated plus maze. Similar results were obtained after treatment with both doses of GABAB (BAC) agonist in the AcbSh. These data indicated that the activation of both GABAA and GABAB receptors within the AcbSh caused anxiolysis in 24h food-deprived rats. In addition, feeding behaviour (food intake, feeding latency and feeding duration) remained unchanged after treatment with both GABA agonists. In contrast, both food intake and feeding duration decreased after injections of both doses of BIC (GABAA antagonist), while the feeding latency remained unchanged after treatment with both GABA antagonists in the AcbSh of 24h food-deprived rats. The treatment with SAC (GABAB antagonist) did not affect feeding behaviour. Collectively, these data suggest that emotional changes evoked by pharmacological manipulation of the GABA neurotransmission in the AcbSh are not linked with changes in food intake. Copyright © 2011 Elsevier Inc. All rights reserved.

Characterizing SH2 Domain Specificity and Network Interactions Using SPOT Peptide Arrays.

Science.gov (United States)

Liu, Bernard A

2017-01-01

Src Homology 2 (SH2) domains are protein interaction modules that recognize and bind tyrosine phosphorylated ligands. Their ability to distinguish binding to over thousands of potential phosphotyrosine (pTyr) ligands within the cell is critical for the fidelity of receptor tyrosine kinase (RTK) signaling. Within humans there are over a hundred SH2 domains with more than several thousand potential ligands across many cell types and cell states. Therefore, defining the specificity of individual SH2 domains is critical for predicting and identifying their physiological ligands. Here, in this chapter, I describe the broad use of SPOT peptide arrays for examining SH2 domain specificity. An orientated peptide array library (OPAL) approach can uncover both favorable and non-favorable residues, thus providing an in-depth analysis to SH2 specificity. Moreover, I discuss the application of SPOT arrays for paneling SH2 ligand binding with physiological peptides.

Short Hairpin RNA (shRNA): Design, Delivery, and Assessment of Gene Knockdown

Science.gov (United States)

Moore, Chris B.; Guthrie, Elizabeth H.; Huang, Max Tze-Han; Taxman, Debra J.

2013-01-01

Shortly after the cellular mechanism of RNA interference (RNAi) was first described, scientists began using this powerful technique to study gene function. This included designing better methods for the successful delivery of small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) into mammalian cells. While the simplest method for RNAi is the cytosolic delivery of siRNA oligonucleotides, this technique is limited to cells capable of transfection and is primarily utilized during transient in vitro studies. The introduction of shRNA into mammalian cells through infection with viral vectors allows for stable integration of shRNA and long-term knockdown of the targeted gene; however, several challenges exist with the implementation of this technology. Here we describe some well-tested protocols which should increase the chances of successful design, delivery, and assessment of gene knockdown by shRNA. We provide suggestions for designing shRNA targets and controls, a protocol for sequencing through the secondary structure of the shRNA hairpin structure, and protocols for packaging and delivery of shRNA lentiviral particles. Using real-time PCR and functional assays we demonstrate the successful knockdown of ASC, an inflammatory adaptor molecule. These studies demonstrate the practicality of including two shRNAs with different efficacies of knockdown to provide an additional level of control and to verify dose dependency of functional effects. Along with the methods described here, as new techniques and algorithms are designed in the future, shRNA is likely to include further promising application and continue to be a critical component of gene discovery. PMID:20387148

Towards Antiviral shRNAs Based on the AgoshRNA Design.

Directory of Open Access Journals (Sweden)

Ying Poi Liu

Full Text Available RNA interference (RNAi can be induced by intracellular expression of a short hairpin RNA (shRNA. Processing of the shRNA requires the RNaseIII-like Dicer enzyme to remove the loop and to release the biologically active small interfering RNA (siRNA. Dicer is also involved in microRNA (miRNA processing to liberate the mature miRNA duplex, but recent studies indicate that miR-451 is not processed by Dicer. Instead, this miRNA is processed by the Argonaute 2 (Ago2 protein, which also executes the subsequent cleavage of a complementary mRNA target. Interestingly, shRNAs that structurally resemble miR-451 can also be processed by Ago2 instead of Dicer. The key determinant of these "AgoshRNA" molecules is a relatively short basepaired stem, which avoids Dicer recognition and consequently allows alternative processing by Ago2. AgoshRNA processing yields a single active RNA strand, whereas standard shRNAs produce a duplex with guide and passenger strands and the latter may cause adverse off-target effects. In this study, we converted previously tested active anti-HIV-1 shRNA molecules into AgoshRNA. We tested several designs that could potentially improve AgoshRNA activity, including extension of the complementarity between the guide strand and the mRNA target and reduction of the thermodynamic stability of the hairpins. We demonstrate that active AgoshRNAs can be generated. However, the RNAi activity is reduced compared to the matching shRNAs. Despite reduced RNAi activity, comparison of an active AgoshRNA and the matching shRNA in a sensitive cell toxicity assay revealed that the AgoshRNA is much less toxic.

Dental size variation in the Atapuerca-SH Middle Pleistocene hominids.

Science.gov (United States)

Bermúdez de Castro, J M; Sarmiento, S; Cunha, E; Rosas, A; Bastir, M

2001-09-01

The Middle Pleistocene Atapuerca-Sima de los Huesos (SH) site in Spain has yielded the largest sample of fossil hominids so far found from a single site and belonging to the same biological population. The SH dental sample includes a total of 452 permanent and deciduous teeth, representing a minimum of 27 individuals. We present a study of the dental size variation in these hominids, based on the analysis of the mandibular permanent dentition: lateral incisors, n=29; canines, n=27; third premolars, n=30; fourth premolars, n=34; first molars, n=38; second molars, n=38. We have obtained the buccolingual diameter and the crown area (measured on occlusal photographs) of these teeth, and used the bootstrap method to assess the amount of variation in the SH sample compared with the variation of a modern human sample from the Museu Antropologico of the Universidade of Coimbra (Portugal). The SH hominids have, in general terms, a dental size variation higher than that of the modern human sample. The analysis is especially conclusive for the canines. Furthermore, we have estimated the degree of sexual dimorphism of the SH sample by obtaining male and female dental subsamples by means of sexing the large sample of SH mandibular specimens. We obtained the index of sexual dimorphism (ISD=male mean/female mean) and the values were compared with those obtained from the sexed modern human sample from Coimbra, and with data found in the literature concerning several recent human populations. In all tooth classes the ISD of the SH hominids was higher than that of modern humans, but the differences were generally modest, except for the canines, thus suggesting that canine size sexual dimorphism in Homo heidelbergensis was probably greater than that of modern humans. Since the approach of sexing fossil specimens has some obvious limitations, these results should be assessed with caution. Additional data from SH and other European Middle Pleistocene sites would be necessary to test

Elemental and Isotopic Incorporation into the Aragonitic Shells of Arctica Islandica: Insights from Temperature Controlled Experiments

Science.gov (United States)

Wanamaker, A. D.; Gillikin, D. P.

2014-12-01

The long-lived ocean quahog, Arctica islandica, is a fairly well developed and tested marine proxy archive, however, the utility of elemental ratios in A. islandica shell material as environmental proxies remains questionable. To further evaluate the influence of seawater temperature on elemental and isotopic incorporation during biomineralization, A. islandica shells were grown at constant temperatures under two regimes during a 16-week period from March 27 to July 21, 2011. Seawater from the Darling Marine Center in Walpole, Maine was pumped into temperature and flow controlled tanks that were exposed to ambient food and salinity conditions. A total of 20 individual juvenile clams with an average shell height of 36 mm were stained with calcein (a commonly used biomarker) and cultured at 10.3 ± 0.3 °C for six weeks. After this, shell heights were measured and the clams were again stained with calcein and cultured at 15.0 ± 0.4 °C for an additional 9.5 weeks. The average shell growth during the first phase of the experiment was 2.4 mm with a linear extension rate of 0.40 mm/week. The average shell growth during the second phase of the experiment was 3.2 mm with an extension rate of 0.34 mm/week. Average salinity values were 30.2 ± 0.7 and 30.7 ±0.7 in the first and second phases of the experiment, respectively. Oxygen isotopes from the cultured seawater were collected throughout the experiment and provide the basis for establishing if shells grew in oxygen isotopic equilibrium. Elemental ratios (primarily Ba/Ca, Mg/Ca, Sr/Ca) in the aragonitic shells were determined via laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), while stable oxygen and carbon isotope ratios were measured using continuous flow isotope ratio mass spectrometry. Continuous sampling within and across the temperature conditions (from 10 °C to 15 °C) coupled with the calcein markings provides the ability to place each sample into a precise temporal framework. The

Shell Venster

International Nuclear Information System (INIS)

De Wit, P.; Looijesteijn, B.; Regeer, B.; Stip, B.

1995-03-01

In the bi-monthly issues of 'Shell Venster' (window on Shell) attention is paid to the activities of the multinational petroleum company Shell Nederland and the Koninklijke/Shell Groep by means of non-specialist articles

A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region.

Science.gov (United States)

Moroco, Jamie A; Baumgartner, Matthew P; Rust, Heather L; Choi, Hwan Geun; Hur, Wooyoung; Gray, Nathanael S; Camacho, Carlos J; Smithgall, Thomas E

2015-08-01

The c-Src tyrosine kinase co-operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c-Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c-Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3-SH2 docking sequence, we screened a kinase-biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c-Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH-4-124-2, with nanomolar inhibitory potency and fivefold selectivity for c-Src when bound to the phospho-focal adhesion kinase peptide. Molecular docking studies indicate that WH-4-124-2 may preferentially inhibit the 'DFG-out' conformation of the kinase active site. These findings suggest that interaction of c-Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition. © 2014 John Wiley & Sons A/S.

Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains.

Science.gov (United States)

Pang, Xiaodong; Zhou, Huan-Xiang

2014-05-01

Protein phosphorylation is very common post-translational modification, catalyzed by kinases, for signaling and regulation. Phosphotyrosines frequently target SH2 domains. The spleen tyrosine kinase (Syk) is critical for tyrosine phosphorylation of multiple proteins and for regulation of important pathways. Phosphorylation of both Y342 and Y346 in Syk linker B is required for optimal signaling. The SH2 domains of Vav1 and PLC-γ both bind this doubly phosphorylated motif. Here we used a recently developed method to calculate the effects of Y342 and Y346 phosphorylation on the rate constants of a peptide from Syk linker B binding to the SH2 domains of Vav1 and PLC-γ. The predicted effects agree well with experimental observations. Moreover, we found that the same doubly phosphorylated peptide binds the two SH2 domains via distinct mechanisms, with apparent rigid docking for Vav1 SH2 and dock-and-coalesce for PLC-γ SH2.

Where is the happy Ending of Shāhnāma?

OpenAIRE

بهروز چمن آرا

2015-01-01

The renowned proverb “Shāhnāma axarash xoš ast” has implicit question which its answer may change our understanding of the nature and function of Shāhnāma. The end of Shāhnāma contains numerous tragic events in Sassanid age. Also it does not seem to be normal if the Iranians have deemed the bitter adventure of the Shahs and Pahlavāns as a happy ending like what Firdausi narrates at the end of his Shāhnāma. This article tries to reply the main question using an illustration on the story platfo...

Design of potentially active ligands for SH2 domains by molecular modeling methods

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Hurmach V. V.

2014-07-01

Full Text Available Search for new chemical structures possessing specific biological activity is a complex problem that needs the use of the latest achievements of molecular modeling technologies. It is well known that SH2 domains play a major role in ontogenesis as intermediaries of specific protein-protein interactions. Aim. Developing an algorithm to investigate the properties of SH2 domain binding, search for new potential active compounds for the whole SH2 domains class. Methods. In this paper, we utilize a complex of computer modeling methods to create a generic set of potentially active compounds targeting universally at the whole class of SH2 domains. A cluster analysis of all available three-dimensional structures of SH2 domains was performed and general pharmacophore models were formulated. The models were used for virtual screening of collection of drug-like compounds provided by Enamine Ltd. Results. The design technique for library of potentially active compounds for SH2 domains class was proposed. Conclusions. The original algorithm of SH2 domains research with molecular docking method was developed. Using our algorithm, the active compounds for SH2 domains were found.

Temperature Condition and Spherical Shell Shape Variation of Space Gauge-Alignment Spacecraft

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V. S. Zarubin

2016-01-01

Full Text Available A high precision spherical shell is one of the geometrical shape embodiments of a gaugealignment spacecraft to determine and control a radar channel energy potential of the ground-based complex for the traffic control of space objects. Passive relays of signals and some types of smallsized instrumentation standard reflectors used for radar gauge and alignment have the same shape. Orbits of the considered spacecraft can be either circular with a height of about 1000 km, including those close to the polar, or elliptical with an apogee of up to 2200 km.In case there is no thermal control system in spacecrafts of these types the solar radiation is a major factor to define the thermal state of a spherical shell in the illuminated orbit area. With the shell in fixed position with respect to direction towards the Sun an arising uneven temperature distribution over its surface leads to variation of the spherically ideal shell shape, which may affect the functional characteristics of the spacecraft. The shell rotation about an axis perpendicular to the direction towards the Sun may reduce an unevenness degree of the temperature distribution.The uneven temperature distribution over the spherical shell surface in conditions of the lowEarth space and this unevenness impact on the shell shape variation against its spherical shape can be quantively estimated by the appropriate methods of mathematical modeling using modification of a previously developed mathematical model to describe steady temperature state of such shell on the low-Earth orbit. The paper considers the shell made from a polymeric composite material. Its original spherical shape is defined by rather low internal pressure. It is assumed that equipment in the shell, if any, is quite small-sized. This allows us to ignore its impact on the radiative transfer in the shell cavity. Along with defining the steady temperature distribution over the shell surface at its fixed orientation with respect to

Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

International Nuclear Information System (INIS)

Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet; Quistgaard, Esben M.; Nordlund, Par; Thanabalu, Thirumaran; Torres, Jaume

2015-01-01

The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target

Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

Energy Technology Data Exchange (ETDEWEB)

Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Quistgaard, Esben M. [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Nordlund, Par [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Thanabalu, Thirumaran [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Torres, Jaume, E-mail: jtorres@ntu.edu.sg [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore)

2015-08-15

The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.

Interaction with the Src homology (SH3-SH2) region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment.

Science.gov (United States)

Alvarado, John Jeff; Tarafdar, Sreya; Yeh, Joanne I; Smithgall, Thomas E

2014-10-10

HIV-1 Nef supports high titer viral replication in vivo and is essential for AIDS progression. Nef function depends on interactions with multiple host cell effectors, including Hck and other Src-family kinases. Here we describe the x-ray crystal structure of Nef in complex with the Hck SH3-SH2 regulatory region to a resolution of 1.86 Å. The complex crystallized as a dimer of complexes, with the conserved Nef PXXPXR motif engaging the Hck SH3 domain. A new intercomplex contact was found between SH3 Glu-93, and Nef Arg-105. Mutagenesis of Hck SH3 Glu-93 interfered with Nef·Hck complex formation and kinase activation in cells. The Hck SH2 domains impinge on the N-terminal region of Nef to stabilize a dimer conformation that exposes Asp-123, a residue critical for Nef function. Our results suggest that in addition to serving as a kinase effector for Nef, Hck binding may reorganize the Nef dimer for functional interaction with other signaling partners. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Interaction with the Src Homology (SH3-SH2) Region of the Src-family Kinase Hck Structures the HIV-1 Nef Dimer for Kinase Activation and Effector Recruitment*

Science.gov (United States)

Alvarado, John Jeff; Tarafdar, Sreya; Yeh, Joanne I.; Smithgall, Thomas E.

2014-01-01

HIV-1 Nef supports high titer viral replication in vivo and is essential for AIDS progression. Nef function depends on interactions with multiple host cell effectors, including Hck and other Src-family kinases. Here we describe the x-ray crystal structure of Nef in complex with the Hck SH3-SH2 regulatory region to a resolution of 1.86 Å. The complex crystallized as a dimer of complexes, with the conserved Nef PXXPXR motif engaging the Hck SH3 domain. A new intercomplex contact was found between SH3 Glu-93, and Nef Arg-105. Mutagenesis of Hck SH3 Glu-93 interfered with Nef·Hck complex formation and kinase activation in cells. The Hck SH2 domains impinge on the N-terminal region of Nef to stabilize a dimer conformation that exposes Asp-123, a residue critical for Nef function. Our results suggest that in addition to serving as a kinase effector for Nef, Hck binding may reorganize the Nef dimer for functional interaction with other signaling partners. PMID:25122770

Encoding of Sucrose's Palatability in the Nucleus Accumbens Shell and Its Modulation by Exteroceptive Auditory Cues

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Miguel Villavicencio

2018-05-01

Full Text Available Although the palatability of sucrose is the primary reason for why it is over consumed, it is not well understood how it is encoded in the nucleus accumbens shell (NAcSh, a brain region involved in reward, feeding, and sensory/motor transformations. Similarly, untouched are issues regarding how an external auditory stimulus affects sucrose palatability and, in the NAcSh, the neuronal correlates of this behavior. To address these questions in behaving rats, we investigated how food-related auditory cues modulate sucrose's palatability. The goals are to determine whether NAcSh neuronal responses would track sucrose's palatability (as measured by the increase in hedonically positive oromotor responses lick rate, sucrose concentration, and how it processes auditory information. Using brief-access tests, we found that sucrose's palatability was enhanced by exteroceptive auditory cues that signal the start and the end of a reward epoch. With only the start cue the rejection of water was accelerated, and the sucrose/water ratio was enhanced, indicating greater palatability. However, the start cue also fragmented licking patterns and decreased caloric intake. In the presence of both start and stop cues, the animals fed continuously and increased their caloric intake. Analysis of the licking microstructure confirmed that auditory cues (either signaling the start alone or start/stop enhanced sucrose's oromotor-palatability responses. Recordings of extracellular single-unit activity identified several distinct populations of NAcSh responses that tracked either the sucrose palatability responses or the sucrose concentrations by increasing or decreasing their activity. Another neural population fired synchronously with licking and exhibited an enhancement in their coherence with increasing sucrose concentrations. The population of NAcSh's Palatability-related and Lick-Inactive neurons were the most important for decoding sucrose's palatability. Only the Lick

Fluid free surface effect on the vibration analysis of cylindrical shells

International Nuclear Information System (INIS)

Lakis, A.A.; Brusuc, G.; Toorani, M.

2007-01-01

The present study is to investigate the effect of free surface motion of the fluid on the dynamic behavior of the thin-walled cylindrical shells. This paper outlines a semi-analytical approach to dynamic analysis of the fluid-filled horizontal cylindrical shell taking into account the free surface motion effect. The aim of the method is to provide a general approach that can be used for both analysis and synthesis of fluid structure interaction problems in the horizontal cylindrical shells where the dynamic interaction of a flexible structure and incompressible and inviscid flow is in focus. The approach is very general and allows for dynamic analysis of both uniform and non-uniform cylindrical shell considering the fluid forces including the sloshing effect exerted on the structure. The hybrid method developed in this work is on the basis of a combination of the classical finite element approach and the thin shell theory to determine the specific displacement functions. Mass and stiffness matrices of the shell are determined by precise analytical integration. A potential function is considered to develop the dynamic pressure due to the fluid. The kinetic and potential energies are evaluated for a range of fluid height to find the influence of the fluid on the dynamic responses of the structure. The influence of the physical and geometrical parameters on the fluid-structure system has been considered in the numerical solutions. When these results are compared with corresponding results available in the literature, both theory and experiment, very good agreement is obtained. (authors)

Distinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications.

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Jose L Ortega Roldan

Full Text Available SH3 domains constitute a new type of ubiquitin-binding domains. We previously showed that the third SH3 domain (SH3-C of CD2AP binds ubiquitin in an alternative orientation. We have determined the structure of the complex between first CD2AP SH3 domain and ubiquitin and performed a structural and mutational analysis to decipher the determinants of the SH3-C binding mode to ubiquitin. We found that the Phe-to-Tyr mutation in CD2AP and in the homologous CIN85 SH3-C domain does not abrogate ubiquitin binding, in contrast to previous hypothesis and our findings for the first two CD2AP SH3 domains. The similar alternative binding mode of the SH3-C domains of these related adaptor proteins is characterised by a higher affinity to C-terminal extended ubiquitin molecules. We conclude that CD2AP/CIN85 SH3-C domain interaction with ubiquitin constitutes a new ubiquitin-binding mode involved in a different cellular function and thus changes the previously established mechanism of EGF-dependent CD2AP/CIN85 mono-ubiquitination.

Importance-truncated shell model for multi-shell valence spaces

Energy Technology Data Exchange (ETDEWEB)

Stumpf, Christina; Vobig, Klaus; Roth, Robert [Institut fuer Kernphysik, TU Darmstadt (Germany)

2016-07-01

The valence-space shell model is one of the work horses in nuclear structure theory. In traditional applications, shell-model calculations are carried out using effective interactions constructed in a phenomenological framework for rather small valence spaces, typically spanned by one major shell. We improve on this traditional approach addressing two main aspects. First, we use new effective interactions derived in an ab initio approach and, thus, establish a connection to the underlying nuclear interaction providing access to single- and multi-shell valence spaces. Second, we extend the shell model to larger valence spaces by applying an importance-truncation scheme based on a perturbative importance measure. In this way, we reduce the model space to the relevant basis states for the description of a few target eigenstates and solve the eigenvalue problem in this physics-driven truncated model space. In particular multi-shell valence spaces are not tractable otherwise. We combine the importance-truncated shell model with refined extrapolation schemes to approximately recover the exact result. We present first results obtained in the importance-truncated shell model with the newly derived ab initio effective interactions for multi-shell valence spaces, e.g., the sdpf shell.

Memory for target height is scaled to observer height.

Science.gov (United States)

Twedt, Elyssa; Crawford, L Elizabeth; Proffitt, Dennis R

2012-04-01

According to the embodied approach to visual perception, individuals scale the environment to their bodies. This approach highlights the central role of the body for immediate, situated action. The present experiments addressed whether body scaling--specifically, eye-height scaling--occurs in memory when action is not immediate. Participants viewed standard targets that were either the same height as, taller than, or shorter than themselves. Participants then viewed a comparison target and judged whether the comparison was taller or shorter than the standard target. Participants were most accurate when the standard target height matched their own heights, taking into account postural changes. Participants were biased to underestimate standard target height, in general, and to push standard target height away from their own heights. These results are consistent with the literature on eye-height scaling in visual perception and suggest that body scaling is not only a useful metric for perception and action, but is also preserved in memory.

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.

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Jamie A Moroco

Full Text Available Src-family kinases (SFKs are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12 to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.

Rosette Assay: Highly Customizable Dot-Blot for SH2 Domain Screening.

Science.gov (United States)

Ng, Khong Y; Machida, Kazuya

2017-01-01

With a growing number of high-throughput studies, structural analyses, and availability of protein-protein interaction databases, it is now possible to apply web-based prediction tools to SH2 domain-interactions. However, in silico prediction is not always reliable and requires experimental validation. Rosette assay is a dot blot-based reverse-phase assay developed for the assessment of binding between SH2 domains and their ligands. It is conveniently customizable, allowing for low- to high-throughput analysis of interactions between various numbers of SH2 domains and their ligands, e.g., short peptides, purified proteins, and cell lysates. The binding assay is performed in a 96-well plate (MBA or MWA apparatus) in which a sample spotted membrane is incubated with up to 96 labeled SH2 domains. Bound domains are detected and quantified using a chemiluminescence or near-infrared fluorescence (IR) imaging system. In this chapter, we describe a practical protocol for rosette assay to assess interactions between synthesized tyrosine phosphorylated peptides and a library of GST-tagged SH2 domains. Since the methodology is not confined to assessment of SH2-pTyr interactions, rosette assay can be broadly utilized for ligand and drug screening using different protein interaction domains or antibodies.

Conformational determinants of phosphotyrosine peptides complexed with the Src SH2 domain.

Directory of Open Access Journals (Sweden)

Joseph Nachman

2010-06-01

Full Text Available The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the "two-pronged plug two-hole socket" model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an alpha-helix. In contrast, a beta-turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors.

Childhood height, adult height, and the risk of prostate cancer

DEFF Research Database (Denmark)

Bjerregaard, Lise Geisler; Aarestrup, Julie; Gamborg, Michael

2016-01-01

PURPOSE: We previously showed that childhood height is positively associated with prostate cancer risk. It is, however, unknown whether childhood height exerts its effects independently of or through adult height. We investigated whether and to what extent childhood height has a direct effect...... on the risk of prostate cancer apart from adult height. METHODS: We included 5,871 men with height measured at ages 7 and 13 years in the Copenhagen School Health Records Register who also had adult (50-65 years) height measured in the Danish Diet, Cancer and Health study. Prostate cancer status was obtained...... through linkage to the Danish Cancer Registry. Direct and total effects of childhood height on prostate cancer risk were estimated from Cox regressions. RESULTS: From 1996 to 2012, 429 prostate cancers occurred. Child and adult heights were positively and significantly associated with prostate cancer risk...

MicroShell Minimalist Shell for Xilinx Microprocessors

Science.gov (United States)

Werne, Thomas A.

2011-01-01

MicroShell is a lightweight shell environment for engineers and software developers working with embedded microprocessors in Xilinx FPGAs. (MicroShell has also been successfully ported to run on ARM Cortex-M1 microprocessors in Actel ProASIC3 FPGAs, but without project-integration support.) Micro Shell decreases the time spent performing initial tests of field-programmable gate array (FPGA) designs, simplifies running customizable one-time-only experiments, and provides a familiar-feeling command-line interface. The program comes with a collection of useful functions and enables the designer to add an unlimited number of custom commands, which are callable from the command-line. The commands are parameterizable (using the C-based command-line parameter idiom), so the designer can use one function to exercise hardware with different values. Also, since many hardware peripherals instantiated in FPGAs have reasonably simple register-mapped I/O interfaces, the engineer can edit and view hardware parameter settings at any time without stopping the processor. MicroShell comes with a set of support scripts that interface seamlessly with Xilinx's EDK tool. Adding an instance of MicroShell to a project is as simple as marking a check box in a library configuration dialog box and specifying a software project directory. The support scripts then examine the hardware design, build design-specific functions, conditionally include processor-specific functions, and complete the compilation process. For code-size constrained designs, most of the stock functionality can be excluded from the compiled library. When all of the configurable options are removed from the binary, MicroShell has an unoptimized memory footprint of about 4.8 kB and a size-optimized footprint of about 2.3 kB. Since MicroShell allows unfettered access to all processor-accessible memory locations, it is possible to perform live patching on a running system. This can be useful, for instance, if a bug is

Shear horizontal wave excitation and reception with shear horizontal piezoelectric wafer active sensor (SH-PWAS)

International Nuclear Information System (INIS)

Kamal, A; Giurgiutiu, V

2014-01-01

This article discusses shear horizontal (SH) guided-waves that can be excited with shear type piezoelectric wafer active sensor (SH-PWAS). The paper starts with a review of state of the art SH waves modelling and their importance in non-destructive evaluation (NDE) and structural health monitoring (SHM). The basic piezoelectric sensing and actuation equations for the case of shear horizontal piezoelectric wafer active sensor (SH-PWAS) with electro-mechanical coupling coefficient d 35 are reviewed. Multiphysics finite element modelling (MP-FEM) was performed on a free SH-PWAS to show its resonance modeshapes. The actuation mechanism of the SH-PWAS is predicted by MP-FEM, and modeshapes of excited structure are presented. The structural resonances are compared with experimental measurements and showed good agreement. Analytical prediction of SH waves was performed. SH wave propagation experimental study was conducted between different combinations of SH-PWAS and regular in-plane PWAS transducers. Experimental results were compared with analytical predictions for aluminium plates and showed good agreement. 2D wave propagation effects were studied by MP-FEM. An analytical model was developed for SH wave power and energy. The normal mode expansion (NME) method was used to account for superpositioning multimodal SH waves. Modal participation factors were presented to show the contribution of every mode. Power and energy transfer between SH-PWAS and the structure was analyzed. Finally, we present simulations of our developed wave power and energy analytical models. (paper)

Towards safe and economic seismic design of cooling towers of extreme height

International Nuclear Information System (INIS)

Kraetzig, W.B.; Meskouris, K.

1979-01-01

Nuclear power plants are being increasingly equipped with natural draught cooling towers of heights greater than 160 m. In many arid zones, where high natural draught cooling towers with dry cooling systems are being projected, wind loads are relativelly small while site seismicity is relatively high. Thus the ability of the tower to withstand earthquake induced forces governs its design. On the other hand, most reinforced concrete cooling towers of extreme height built so far were designed to withstand high wind loads and moderate earthquake loads. The effects of special structural measures for obtaining an economic design, such as the introduction of ring stiffened shells, have been studied mainly for those towers. In view of the previous aspects it is the purpose of this paper to analyze the effects of various structural measures and other parameters on the seismic response of such high cooling towers. (orig.)

Creating Transgenic shRNA Mice by Recombinase-Mediated Cassette Exchange

Science.gov (United States)

Premsrirut, Prem K.; Dow, Lukas E.; Park, Youngkyu; Hannon, Gregory J.; Lowe, Scott W.

2014-01-01

RNA interference (RNAi) enables sequence-specific, experimentally induced silencing of virtually any gene by tapping into innate regulatory mechanisms that are conserved among most eukaryotes. The principles that enable transgenic RNAi in cell lines can also be used to create transgenic animals, which express short-hairpin RNAs (shRNAs) in a regulated or tissue-specific fashion. However, RNAi in transgenic animals is somewhat more challenging than RNAi in cultured cells. The activities of promoters that are commonly used for shRNA expression in cell culture can vary enormously in different tissues, and founder lines also typically vary in transgene expression due to the effects of their single integration sites. There are many ways to produce mice carrying shRNA transgenes and the method described here uses recombinase-mediated cassette exchange (RMCE). RMCE permits insertion of the shRNA transgene into a well-characterized locus that gives reproducible and predictable expression in each founder and enhances the probability of potent expression in many cell types. This procedure is more involved and complex than simple pronuclear injection, but if even a few shRNA mice are envisioned, for example, to probe the functions of several genes, the effort of setting up the processes outlined below are well worthwhile. Note that when creating a transgenic mouse, one should take care to use the most potent shRNA possible. As a rule of thumb, the sequence chosen should provide >90% knockdown when introduced into cultured cells at single copy (e.g., on retroviral infection at a multiplicity of ≤0.3). PMID:24003198

Steering elastic SH waves in an anomalous way by metasurface

Science.gov (United States)

Cao, Liyun; Yang, Zhichun; Xu, Yanlong

2018-03-01

Metasurface, which does not exist in nature, has exhibited exotic essence on the manipulation of both electromagnetic and acoustic waves. In this paper, the concept of metasurface is extended to the field of elastic SH waves, and the anomalous refractions of SH waves across the designed elastic SH wave metasurfaces (SHWMs) are demonstrated numerically. Firstly, a SHWM is designed with supercells, each supercell is composed of four subunits. It is demonstrated that this configuration has the ability of deflecting the vertical and oblique incident waves in an arbitrary desired direction. Then, a unique SHWM with supercell composed of only two subunits is designed. Numerical simulation shows its ability of splitting the vertical and oblique incident waves into two tunable transmitted wave beams, respectively. In the process of steering SH waves, it is also found that two kinds of leakages of transmitted waves across the designed SHWM will occur in some particular situations, which will affect the desired transmitted wave. The mechanisms of the leakages, which are different from that of the common high-order diffraction mentioned in existing literatures, are revealed. The current study can offer theoretical guidance not only for designing devices of directional ultrasonic detection and splitting SH waves but also for steering other kinds of classical waves.

Fall from heights: does height really matter?

Science.gov (United States)

Alizo, G; Sciarretta, J D; Gibson, S; Muertos, K; Romano, A; Davis, J; Pepe, A

2018-06-01

Fall from heights is high energy injuries and constitutes a fraction of all fall-related trauma evaluations while bearing an increase in morbidity and mortality. We hypothesize that despite advancements in trauma care, the overall survivability has not improved in this subset of trauma patients. All adult trauma patients treated after sustaining a fall from heights during a 40-month period were retrospectively reviewed. Admission demographics, clinical data, fall height (ft), injury patterns, ISS, GCS, length of stay, and mortality were reviewed. 116 patients sustained a fall from heights, 90.4% accidental. A mean age of 37± 14.7 years, 86% male, and a fall height of 19 ± 10 ft were encountered. Admission GCS was 13 ± 2 with ISS 10 ± 11. Overall LOS was 6.6 ± 14.9 days and an ICU LOS of 2.8 ± 8.9 days. Falls ≥ 25 ft.(16%) had lower GCS 10.4 ± 5.8, increased ISS 22.6 ± 13.8, a fall height 37.9 ± 13.1 ft and associated increased mortality (p < 0.001). Mortality was 5.2%, a mean distance fallen of 39 ± 22 ft. and an ISS of 31.5 ±16.5. Brain injury was the leading cause of death, 50% with open skull fractures. Level of height fallen is a good predictor of overall outcome and survival. Despite advances in trauma care, death rates remain unchanged. Safety awareness and injury prevention programs are needed to reduce the risk of high-level falls.

Ground state energy and wave function of an off-centre donor in spherical core/shell nanostructures: Dielectric mismatch and impurity position effects

Energy Technology Data Exchange (ETDEWEB)

Ibral, Asmaa [Equipe d’Optique et Electronique du Solide, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B.P. 20 El Jadida Principale, El Jadida 24000 (Morocco); Laboratoire d’Instrumentation, Mesure et Contrôle, Département de Physique, Université Chouaïb Doukkali, B.P. 20 El Jadida Principale, El Jadida (Morocco); Zouitine, Asmae [Département de Physique, Ecole Nationale Supérieure d’Enseignement Technique, Université Mohammed V Souissi, B.P. 6207 Rabat-Instituts, Rabat (Morocco); Assaid, El Mahdi, E-mail: eassaid@yahoo.fr [Equipe d’Optique et Electronique du Solide, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B.P. 20 El Jadida Principale, El Jadida 24000 (Morocco); Laboratoire d’Instrumentation, Mesure et Contrôle, Département de Physique, Université Chouaïb Doukkali, B.P. 20 El Jadida Principale, El Jadida (Morocco); Feddi, El Mustapha [Département de Physique, Ecole Nationale Supérieure d’Enseignement Technique, Université Mohammed V Souissi, B.P. 6207 Rabat-Instituts, Rabat (Morocco); and others

2014-09-15

Ground state energy and wave function of a hydrogen-like off-centre donor impurity, confined anywhere in a ZnS/CdSe spherical core/shell nanostructure are determined in the framework of the envelope function approximation. Conduction band-edge alignment between core and shell of nanostructure is described by a finite height barrier. Dielectric constant mismatch at the surface where core and shell materials meet is taken into account. Electron effective mass mismatch at the inner surface between core and shell is considered. A trial wave function where coulomb attraction between electron and off-centre ionized donor is used to calculate ground state energy via the Ritz variational principle. The numerical approach developed enables access to the dependence of binding energy, coulomb correlation parameter, spatial extension and radial probability density with respect to core radius, shell radius and impurity position inside ZnS/CdSe core/shell nanostructure.

Ground state energy and wave function of an off-centre donor in spherical core/shell nanostructures: Dielectric mismatch and impurity position effects

International Nuclear Information System (INIS)

Ibral, Asmaa; Zouitine, Asmae; Assaid, El Mahdi; Feddi, El Mustapha

2014-01-01

Ground state energy and wave function of a hydrogen-like off-centre donor impurity, confined anywhere in a ZnS/CdSe spherical core/shell nanostructure are determined in the framework of the envelope function approximation. Conduction band-edge alignment between core and shell of nanostructure is described by a finite height barrier. Dielectric constant mismatch at the surface where core and shell materials meet is taken into account. Electron effective mass mismatch at the inner surface between core and shell is considered. A trial wave function where coulomb attraction between electron and off-centre ionized donor is used to calculate ground state energy via the Ritz variational principle. The numerical approach developed enables access to the dependence of binding energy, coulomb correlation parameter, spatial extension and radial probability density with respect to core radius, shell radius and impurity position inside ZnS/CdSe core/shell nanostructure

An Efficient Semi-supervised Learning Approach to Predict SH2 Domain Mediated Interactions.

Science.gov (United States)

Kundu, Kousik; Backofen, Rolf

2017-01-01

Src homology 2 (SH2) domain is an important subclass of modular protein domains that plays an indispensable role in several biological processes in eukaryotes. SH2 domains specifically bind to the phosphotyrosine residue of their binding peptides to facilitate various molecular functions. For determining the subtle binding specificities of SH2 domains, it is very important to understand the intriguing mechanisms by which these domains recognize their target peptides in a complex cellular environment. There are several attempts have been made to predict SH2-peptide interactions using high-throughput data. However, these high-throughput data are often affected by a low signal to noise ratio. Furthermore, the prediction methods have several additional shortcomings, such as linearity problem, high computational complexity, etc. Thus, computational identification of SH2-peptide interactions using high-throughput data remains challenging. Here, we propose a machine learning approach based on an efficient semi-supervised learning technique for the prediction of 51 SH2 domain mediated interactions in the human proteome. In our study, we have successfully employed several strategies to tackle the major problems in computational identification of SH2-peptide interactions.

Optical properties of core-shell and multi-shell nanorods

Science.gov (United States)

Mokkath, Junais Habeeb; Shehata, Nader

2018-05-01

We report a first-principles time dependent density functional theory study of the optical response modulations in bimetallic core-shell (Na@Al and Al@Na) and multi-shell (Al@Na@Al@Na and Na@Al@Na@Al: concentric shells of Al and Na alternate) nanorods. All of the core-shell and multi-shell configurations display highly enhanced absorption intensity with respect to the pure Al and Na nanorods, showing sensitivity to both composition and chemical ordering. Remarkably large spectral intensity enhancements were found in a couple of core-shell configurations, indicative that optical response averaging based on the individual components can not be considered as true as always in the case of bimetallic core-shell nanorods. We believe that our theoretical results would be useful in promising applications depending on Aluminum-based plasmonic materials such as solar cells and sensors.

Cold collisions of SH- with He: Potential energy surface and rate coefficients

Science.gov (United States)

Bop, C. T.; Trabelsi, T.; Hammami, K.; Mogren Al Mogren, M.; Lique, F.; Hochlaf, M.

2017-09-01

Collisional energy transfer under cold conditions is of great importance from the fundamental and applicative point of view. Here, we investigate low temperature collisions of the SH- anion with He. We have generated a three-dimensional potential energy surface (PES) for the SH-(X1Σ+)-He(1S) van der Waals complex. The ab initio multi-dimensional interaction PES was computed using the explicitly correlated coupled cluster approach with simple, double, and perturbative triple excitation in conjunction with the augmented-correlation consistent-polarized valence triple zeta Gaussian basis set. The PES presents two minima located at linear geometries. Then, the PES was averaged over the ground vibrational wave function of the SH- molecule and the resulting two-dimensional PES was incorporated into exact quantum mechanical close coupling calculations to study the collisional excitation of SH- by He. We have computed inelastic cross sections among the 11 first rotational levels of SH- for energies up to 2500 cm-1. (De-)excitation rate coefficients were deduced for temperatures ranging from 1 to 300 K by thermally averaging the cross sections. We also performed calculations using the new PES for a fixed internuclear SH- distance. Both sets of results were found to be in reasonable agreement despite differences existing at low temperatures confirming that accurate predictions require the consideration of all internal degrees of freedom in the case of molecular hydrides. The rate coefficients presented here may be useful in interpreting future experimental work on the SH- negative ion colliding with He as those recently done for the OH--He collisional system as well as for possible astrophysical applications in case SH- would be detected in the interstellar medium.

Characterization of the Micro-shell Surface Using Holographic Measurements

Energy Technology Data Exchange (ETDEWEB)

Sandras, F.; Hermerel, C.; Choux, A.; Merillot, P.; Pin, G.; Jeannot, L. [CEA Valduc, Dept Rech Mat Nucl, Serv Microcibles, 21 - Is-sur-Tille (France)

2009-05-15

To characterize the shape, the quality, and the roughness of micro-shells, typically used technologies are scanning electron microscopy, scanning interferometric microscopy, or atomic force microscopy. One of the drawbacks of these techniques is that they are generally slow because of their scanning process. Digital holographic microscopy technology is an innovation that can offer ability adapted to these studies. It captures holograms instead of intensity images, as done by conventional microscopes. The holograms are then digitally interpreted (10 per second) to reconstruct a double image, one for the intensity and another one for the phase. Using a rotation axis, the bump counting for the complete micro-shell surface is possible with a very high speed. Using an image stitching software, mapping can be done in a few minutes. Wavelets such as 'Mexican hat' are used to model the bumps. Each bump can then be characterized on the map by its position, diameter, and height. (authors)

Deciphering Phosphotyrosine-Dependent Signaling Networks in Cancer by SH2 Profiling

Science.gov (United States)

Machida, Kazuya; Khenkhar, Malik

2012-01-01

It has been a decade since the introduction of SH2 profiling, a modular domain-based molecular diagnostics tool. This review covers the original concept of SH2 profiling, different analytical platforms, and their applications, from the detailed analysis of single proteins to broad screening in translational research. Illustrated by practical examples, we discuss the uniqueness and advantages of the approach as well as its limitations and challenges. We provide guidance for basic researchers and oncologists who may consider SH2 profiling in their respective cancer research, especially for those focusing on tyrosine phosphoproteomics. SH2 profiling can serve as an alternative phosphoproteomics tool to dissect aberrant tyrosine kinase pathways responsible for individual malignancies, with the goal of facilitating personalized diagnostics for the treatment of cancer. PMID:23226573

NEAR-INFRARED IMAGING OF THE STAR-FORMING REGIONS SH2-157 AND SH2-152

International Nuclear Information System (INIS)

Chen Yafeng; Yang Ji; Zeng Qin; Yao Yongqiang; Sato, Shuji

2009-01-01

Near-infrared JHK' and H 2 v = 1-0 S (1) imaging observations of the star-forming regions Sh2-157 and Sh2-152 are presented. The data reveal a cluster of young stars associated with H 2 line emission in each region. Additionally, many IR point sources are found in the dense core of each molecular cloud. Most of these sources exhibit infrared color excesses typical of T Tauri stars, Herbig Ae/Be stars, and protostars. Several display the characteristics of massive stars. We calculate histograms of the K'-magnitude and [H - K'] color for all sources, as well as two-color and color-magnitude diagrams. The stellar populations inside and outside the clusters are similar, suggesting that these systems are rather evolved. Shock-driven H 2 emission knots are also detected, which may be related to evident subclusters in an earlier evolutionary stage.

Differential effects of accumbens core vs. shell lesions in a rat concurrent conditioned place preference paradigm for cocaine vs. social interaction.

Science.gov (United States)

Fritz, Michael; El Rawas, Rana; Klement, Sabine; Kummer, Kai; Mayr, Michael J; Eggart, Vincent; Salti, Ahmad; Bardo, Michael T; Saria, Alois; Zernig, Gerald

2011-01-01

A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. Among these activities, social interaction is doubly important because treatment adherence itself depends on it. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male conspecific (i) reversed CPP from cocaine to social interaction despite continuing cocaine training and (ii) prevented the reinstatement of cocaine CPP. In the present study, we investigated if the two subregions of the nucleus accumbens (Acb), i.e., the core (AcbC) and the shell (AcbSh), would differentially affect CPP for cocaine vs social interaction. Animals were concurrently trained for CPP pairing cocaine with one compartment and social interaction with the other (i.e., mutually exclusive stimulus presentation during training). Excitotoxic lesioning of the AcbC or the BLA shifted CPP toward social interaction, whereas AcbSh inactivation shifted CPP toward cocaine. Overall, our findings suggest that inactivation of the AcbC or the BLA is sufficient to shift CPP away from a drug of abuse toward social interaction. Lesioning the AcbSh produced the opposite effect.

Palaeodemography of the Atapuerca-SH Middle Pleistocene hominid sample.

Science.gov (United States)

Bermúdez de Castro, J M; Nicolás, M E

1997-01-01

We report here on the palaeodemographic analysis of the hominid sample recovered to date from the Sima de los Huesos (SH) Middle Pleistocene cave site in the Sierra de Atapuerca (Burgos, Spain). The analysis of the mandibular, maxillary, and dental remains has made it possible to estimate that a minimum of 32 individuals, who probably belonged to the same biological population, are represented in the current SH human hypodigm. The remains of nine-individuals are assigned to males, and nine to females, suggesting that a 1:1 sex ratio characterizes this hominid sample. The survivorship curve shows a low representation of infants and children, a high mortality among the adolescents and prime-age adults, and a low older adult mortality. Longevity was probably no greater than 40 years. This mortality pattern (adolescents and adults); which in some aspects resembles that observed in Neandertals, is quite different from those reported for recent foraging human groups. The adult age-at-death distribution of the SH hominid sample appears to be neither the consequence of underaging the older adults, nor of differential preservation or of the recognition of skeletal remains. Thus if we accept that they had a life history pattern similar to that of modern humans there would appear to be a clear contradiction between the demographic distribution and the demographic viability of the population represented by the SH hominid fossils. The possible representational bias of the SH hominid sample, as well as some aspects of the reproductive biology of the Pleistocene populations are also discussed.

Quality of pharmacy-specific Medical Subject Headings (MeSH) assignment in pharmacy journals indexed in MEDLINE.

Science.gov (United States)

Minguet, Fernando; Salgado, Teresa M; van den Boogerd, Lucienne; Fernandez-Llimos, Fernando

2015-01-01

The Medical Subject Headings (MeSH) is the National Library of Medicine (NLM) controlled vocabulary for indexing articles. Inaccuracies in the MeSH thesaurus have been reported for several areas including pharmacy. To assess the quality of pharmacy-specific MeSH assignment to articles indexed in pharmacy journals. The 10 journals containing the highest number of articles published in 2012 indexed under the MeSH 'Pharmacists' were identified. All articles published over a 5-year period (2008-2012) in the 10 previously selected journals were retrieved from PubMed. MeSH terms used to index these articles were extracted and pharmacy-specific MeSH terms were identified. The frequency of use of pharmacy-specific MeSH terms was calculated across journals. A total of 6989 articles were retrieved from the 10 pharmacy journals, of which 328 (4.7%) were articles not fully indexed and therefore did not contain any MeSH terms assigned. Among the 6661 articles fully indexed, the mean number of MeSH terms was 10.1 (SD = 4.0), being 1.0 (SD = 1.3) considered as Major MeSH. Both values significantly varied across journals. The mean number of pharmacy-specific MeSH terms per article was 0.9 (SD = 1.2). A total of 3490 (52.4%) of the 6661 articles were indexed in pharmacy journals without a single pharmacy-specific MeSH. Of the total 67193 MeSH terms assigned to articles, on average 10.5% (SD = 13.9) were pharmacy-specific MeSH. A statistically significant different pattern of pharmacy-specific MeSH assignment was identified across journals (Kruskal-Wallis P journals can be improved to further enhance evidence gathering in pharmacy. Over half of the articles published in the top-10 journals publishing pharmacy literature were indexed without a single pharmacy-specific MeSH. Copyright © 2015 Elsevier Inc. All rights reserved.

The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1.

Science.gov (United States)

Rozakis-Adcock, M; Fernley, R; Wade, J; Pawson, T; Bowtell, D

1993-05-06

Many tyrosine kinases, including the receptors for hormones such as epidermal growth factor (EGF), nerve growth factor and insulin, transmit intracellular signals through Ras proteins. Ligand binding to such receptors stimulates Ras guanine-nucleotide-exchange activity and increases the level of GTP-bound Ras, suggesting that these tyrosine kinases may activate a guanine-nucleotide releasing protein (GNRP). In Caenorhabditis elegans and Drosophila, genetic studies have shown that Ras activation by tyrosine kinases requires the protein Sem-5/drk, which contains a single Src-homology (SH) 2 domain and two flanking SH3 domains. Sem-5 is homologous to the mammalian protein Grb2, which binds the autophosphorylated EGF receptor and other phosphotyrosine-containing proteins such as Shc through its SH2 domain. Here we show that in rodent fibroblasts, the SH3 domains of Grb2 are bound to the proline-rich carboxy-terminal tail of mSos1, a protein homologous to Drosophila Sos. Sos is required for Ras signalling and contains a central domain related to known Ras-GNRPs. EGF stimulation induces binding of the Grb2-mSos1 complex to the autophosphorylated EGF receptor, and mSos1 phosphorylation. Grb2 therefore appears to link tyrosine kinases to a Ras-GNRP in mammalian cells.

Solution structure of tensin2 SH2 domain and its phosphotyrosine-independent interaction with DLC-1.

Directory of Open Access Journals (Sweden)

Kun Dai

Full Text Available Src homology 2 (SH2 domain is a conserved module involved in various biological processes. Tensin family member was reported to be involved in tumor suppression by interacting with DLC-1 (deleted-in-liver-cancer-1 via its SH2 domain. We explore here the important questions that what the structure of tensin2 SH2 domain is, and how it binds to DLC-1, which might reveal a novel binding mode.Tensin2 SH2 domain adopts a conserved SH2 fold that mainly consists of five β-strands flanked by two α-helices. Most SH2 domains recognize phosphorylated ligands specifically. However, tensin2 SH2 domain was identified to interact with nonphosphorylated ligand (DLC-1 as well as phosphorylated ligand.We determined the solution structure of tensin2 SH2 domain using NMR spectroscopy, and revealed the interactions between tensin2 SH2 domain and its ligands in a phosphotyrosine-independent manner.

Semi-supervised prediction of SH2-peptide interactions from imbalanced high-throughput data.

Science.gov (United States)

Kundu, Kousik; Costa, Fabrizio; Huber, Michael; Reth, Michael; Backofen, Rolf

2013-01-01

Src homology 2 (SH2) domains are the largest family of the peptide-recognition modules (PRMs) that bind to phosphotyrosine containing peptides. Knowledge about binding partners of SH2-domains is key for a deeper understanding of different cellular processes. Given the high binding specificity of SH2, in-silico ligand peptide prediction is of great interest. Currently however, only a few approaches have been published for the prediction of SH2-peptide interactions. Their main shortcomings range from limited coverage, to restrictive modeling assumptions (they are mainly based on position specific scoring matrices and do not take into consideration complex amino acids inter-dependencies) and high computational complexity. We propose a simple yet effective machine learning approach for a large set of known human SH2 domains. We used comprehensive data from micro-array and peptide-array experiments on 51 human SH2 domains. In order to deal with the high data imbalance problem and the high signal-to-noise ration, we casted the problem in a semi-supervised setting. We report competitive predictive performance w.r.t. state-of-the-art. Specifically we obtain 0.83 AUC ROC and 0.93 AUC PR in comparison to 0.71 AUC ROC and 0.87 AUC PR previously achieved by the position specific scoring matrices (PSSMs) based SMALI approach. Our work provides three main contributions. First, we showed that better models can be obtained when the information on the non-interacting peptides (negative examples) is also used. Second, we improve performance when considering high order correlations between the ligand positions employing regularization techniques to effectively avoid overfitting issues. Third, we developed an approach to tackle the data imbalance problem using a semi-supervised strategy. Finally, we performed a genome-wide prediction of human SH2-peptide binding, uncovering several findings of biological relevance. We make our models and genome-wide predictions, for all the 51 SH2

The different effects of high-frequency stimulation of the nucleus accumbens shell and core on food consumption are possibly associated with different neural responses in the lateral hypothalamic area.

Science.gov (United States)

Wei, N; Wang, Y; Wang, X; He, Z; Zhang, M; Zhang, X; Pan, Y; Zhang, J; Qin, Z; Zhang, K

2015-08-20

Obesity may result from dysfunction of the reward system, especially in the nucleus accumbens (Acb). Based on this hypothesis, many researchers have tested the effect of high-frequency stimulation (HFS) of the Acb shell (Acb-Sh) and/or core (Acb-Co) on ingestive behaviors, but few studies have explored the possible mechanisms involved in the differences between the Acb-Sh and Acb-Co. The present study tested effects of HFS of the Acb-Sh and Acb-Co on high-fat food (HFF) consumption in rats after 24h of food deprivation. Microdialysis and electrophysiological experiments were carried out in awake rats to explore potential mechanisms. The results showed that the Acb-Sh decreased HFF consumption after food deprivation both during and post-HFS. However, HFS of the Acb-Co did not induce similar changes in food consumption. HFS of the Acb-Sh (Sh-HFS) induced an increase in GABA level in the lateral hypothalamic area (LHA) during both phases, whereas HFS of the Acb-Co (Co-HFS) did not exhibit similar effects. The electrophysiological experiment showed that nearly all the LHA neurons were inhibited by Sh-HFS, and the mean firing rate decreased significantly both during and post-HFS. In contrast, the mean firing rate of the LHA neurons did not exhibit clear changes during Co-HFS, although some individual neurons appeared to exhibit responses to Co-HFS. Considering all the data, we postulated that Sh-HFS, rather than Co-HFS, might inhibit palatable food consumption after food deprivation by decreasing the reward value of that food, which suggested that it might also disturb the process of developing obesity. The mechanisms involved in the different effects of Sh-HFS and Co-HFS on food consumption may be associated with different neural responses in the LHA. The Acb-Sh has abundant GABAergic projections to the LHA, whereas the Acb-Co has few or no GABAergic innervations to the LHA. Thus, neural activity in the LHA exhibits different responses to Sh-HFS and Co-HFS. Copyright �

Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

Energy Technology Data Exchange (ETDEWEB)

Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

2017-05-01

The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

ExoMol molecular line lists - XXVI: spectra of SH and NS

Science.gov (United States)

Yurchenko, Sergei N.; Bond, Wesley; Gorman, Maire N.; Lodi, Lorenzo; McKemmish, Laura K.; Nunn, William; Shah, Rohan; Tennyson, Jonathan

2018-07-01

Line lists for the sulphur-containing molecules SH (the mercapto radical) and NS are computed as part of the ExoMol project. These line lists consider transitions within the X2Π ground state for 32SH, 33SH, 34SH,36SH and, 32SD, and 14N32S, 14N33S, 14N34S, 14N36S, and 15N32S. Ab initio potential energy (PEC) and spin-orbit coupling (SOC) curves are computed and then improved by fitting to experimentally observed transitions. Fully ab initio dipole moment curves (DMCs) computed at high level of theory are used to produce the final line lists. For SH, our fit gives a root-mean-square (rms) error of 0.03 cm-1 between the observed (vmax = 4, Jmax = 34.5) and calculated transitions wavenumbers; this is extrapolated such that all X2Π rotational-vibrational-electronic (rovibronic) bound states are considered. For 32SH the resulting line list contains about 81 000 transitions and 2300 rovibronic states, considering levels up to vmax = 14 and Jmax = 60.5. For NS the refinement used a combination of experimentally determined frequencies and energy levels and led to an rms-fitting error of 0.002 cm-1. Each NS-calculated line list includes around 2.8 million transitions and 31 000 rovibronic states with a vibrational range up to v = 53 and rotational range up to J = 235.5, which covers up to 23 000 cm-1. Both line lists should be complete for temperatures up to 5000 K. Example spectra simulated using this line list are shown and comparisons made to the existing data in the CDMS data base. The line lists are available from the CDS (http://cdsarc.u-strasbg.fr) and ExoMol (www.exomol.com) data bases.

A simple and robust vector-based shRNA expression system used for RNA interference.

Science.gov (United States)

Wang, Xue-jun; Li, Ying; Huang, Hai; Zhang, Xiu-juan; Xie, Pei-wen; Hu, Wei; Li, Dan-dan; Wang, Sheng-qi

2013-01-01

RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) has become a powerful genetic tool for conducting functional studies. Previously, vector-based shRNA-expression strategies capable of inducing RNAi in viable cells have been developed, however, these vector systems have some disadvantages, either because they were error-prone or cost prohibitive. In this report we described the development of a simple, robust shRNA expression system utilizing 1 long oligonucleotide or 2 short oligonucleotides for half the cost of conventional shRNA construction methods and with a >95% cloning success rate. The shRNA loop sequence and stem structure were also compared and carefully selected for better RNAi efficiency. Furthermore, an easier strategy was developed based on isocaudomers which permit rapid combination of the most efficient promoter-shRNA cassettes. Finally, using this method, the conservative target sites for hepatitis B virus (HBV) knockdown were systemically screened and HBV antigen expression shown to be successfully suppressed in the presence of connected multiple shRNAs both in vitro and in vivo. This novel design describes an inexpensive and effective way to clone and express single or multiple shRNAs from the same vector with the capacity for potent and effective silencing of target genes.

Infrared Spectra and Band Strengths of CH3SH, an Interstellar Molecule

Science.gov (United States)

Hudson, R. L.

2016-01-01

Three solid phases of CH3SH (methanethiol or methyl mercaptan) have been prepared and their mid-infrared spectra recorded at 10-110 degrees Kelvin, with an emphasis on the 17-100 degrees Kelvin region. Refractive indices have been measured at two temperatures and used to estimate ice densities and infrared band strengths. Vapor pressures for the two crystalline phases of CH3SH at 110 degrees Kelvin are estimated. The behavior of amorphous CH3SH on warming is presented and discussed in terms of Ostwald's step rule. Comparisons to CH3OH under similar conditions are made, and some inconsistencies and ambiguities in the CH3SH literature are examined and corrected.

SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins.

Science.gov (United States)

Park, Mi-Jeong; Sheng, Ren; Silkov, Antonina; Jung, Da-Jung; Wang, Zhi-Gang; Xin, Yao; Kim, Hyunjin; Thiagarajan-Rosenkranz, Pallavi; Song, Seohyeon; Yoon, Youngdae; Nam, Wonhee; Kim, Ilshin; Kim, Eui; Lee, Dong-Gyu; Chen, Yong; Singaram, Indira; Wang, Li; Jang, Myoung Ho; Hwang, Cheol-Sang; Honig, Barry; Ryu, Sungho; Lorieau, Justin; Kim, You-Me; Cho, Wonhwa

2016-04-07

The Src-homology 2 (SH2) domain is a protein interaction domain that directs myriad phosphotyrosine (pY)-signaling pathways. Genome-wide screening of human SH2 domains reveals that ∼90% of SH2 domains bind plasma membrane lipids and many have high phosphoinositide specificity. They bind lipids using surface cationic patches separate from pY-binding pockets, thus binding lipids and the pY motif independently. The patches form grooves for specific lipid headgroup recognition or flat surfaces for non-specific membrane binding and both types of interaction are important for cellular function and regulation of SH2 domain-containing proteins. Cellular studies with ZAP70 showed that multiple lipids bind its C-terminal SH2 domain in a spatiotemporally specific manner and thereby exert exquisite spatiotemporal control over its protein binding and signaling activities in T cells. Collectively, this study reveals how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY-signaling pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Bayesian modeling of the yeast SH3 domain interactome predicts spatiotemporal dynamics of endocytosis proteins.

Directory of Open Access Journals (Sweden)

Raffi Tonikian

2009-10-01

Full Text Available SH3 domains are peptide recognition modules that mediate the assembly of diverse biological complexes. We scanned billions of phage-displayed peptides to map the binding specificities of the SH3 domain family in the budding yeast, Saccharomyces cerevisiae. Although most of the SH3 domains fall into the canonical classes I and II, each domain utilizes distinct features of its cognate ligands to achieve binding selectivity. Furthermore, we uncovered several SH3 domains with specificity profiles that clearly deviate from the two canonical classes. In conjunction with phage display, we used yeast two-hybrid and peptide array screening to independently identify SH3 domain binding partners. The results from the three complementary techniques were integrated using a Bayesian algorithm to generate a high-confidence yeast SH3 domain interaction map. The interaction map was enriched for proteins involved in endocytosis, revealing a set of SH3-mediated interactions that underlie formation of protein complexes essential to this biological pathway. We used the SH3 domain interaction network to predict the dynamic localization of several previously uncharacterized endocytic proteins, and our analysis suggests a novel role for the SH3 domains of Lsb3p and Lsb4p as hubs that recruit and assemble several endocytic complexes.

The SH2D2A gene and susceptibility to multiple sclerosis

DEFF Research Database (Denmark)

Lorentzen, A.R.; Smestad, C.; Lie, B.A.

2008-01-01

We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid...... that the SH2D2A gene may contribute to susceptibility to MS Udgivelsesdato: 2008/7/15...

SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes.

Science.gov (United States)

Choi, Youn Kyung; Cho, Sung-Gook; Choi, Yu-Jeong; Yun, Yee Jin; Lee, Kang Min; Lee, Kangwook; Yoo, Hye-Hyun; Shin, Yong Cheol; Ko, Seong-Gyu

2017-10-24

Drug markets revisits herbal medicines, as historical usages address their therapeutic efficacies with less adverse effects. Moreover, herbal medicines save both cost and time in development. SH003, a modified version of traditional herbal medicine extracted from Astragalus membranaceus (Am), Angelica gigas (Ag), and Trichosanthes Kirilowii Maximowicz (Tk) with 1:1:1 ratio (w/w) has been revealed to inhibit tumor growth and metastasis on highly metastatic breast cancer cells, both in vivo and in vitro with no toxicity. Meanwhile, autophagy is imperative for maintenance cellular homeostasis, thereby playing critical roles in cancer progression. Inhibition of autophagy by pharmacological agents induces apoptotic cell death in cancer cells, resulting in cancer treatment. In this study, we demonstrate that SH003-induced autophagy via inhibiting STAT3 and mTOR results in an induction of lysosomal p62/SQSTM1 accumulation-mediated reactive oxygen species (ROS) generation and attenuates tumor growth. SH003 induced autophagosome and autolysosome formation by inhibiting activation of STAT3- and mTOR-mediated signaling pathways. However, SH003 blocked autophagy-mediated p62/SQSTM1 degradation through reducing of lysosomal proteases, Cathepsins, resulting in accumulation of p62/SQSTM1 in the lysosome. The accumulation of p62/SQSTM1 caused the increase of ROS, which resulted in the induction of apoptotic cell death. Therefore, we conclude that SH003 suppresses breast cancer growth by inducing autophagy. In addition, SH003-induced p62/SQSTM1 could function as an important mediator for ROS generation-dependent cell death suggesting that SH003 may be useful for treating breast cancer.

Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.

Science.gov (United States)

Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

2017-05-05

The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Functional diversity of Csk, Chk, and Src SH2 domains due to a single residue variation.

Science.gov (United States)

Ayrapetov, Marina K; Nam, Nguyen Hai; Ye, Guofeng; Kumar, Anil; Parang, Keykavous; Sun, Gongqin

2005-07-08

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

A simple and robust vector-based shRNA expression system used for RNA interference.

Directory of Open Access Journals (Sweden)

Xue-jun Wang

Full Text Available BACKGROUND: RNA interference (RNAi mediated by small interfering RNAs (siRNAs or short hairpin RNAs (shRNAs has become a powerful genetic tool for conducting functional studies. Previously, vector-based shRNA-expression strategies capable of inducing RNAi in viable cells have been developed, however, these vector systems have some disadvantages, either because they were error-prone or cost prohibitive. RESULTS: In this report we described the development of a simple, robust shRNA expression system utilizing 1 long oligonucleotide or 2 short oligonucleotides for half the cost of conventional shRNA construction methods and with a >95% cloning success rate. The shRNA loop sequence and stem structure were also compared and carefully selected for better RNAi efficiency. Furthermore, an easier strategy was developed based on isocaudomers which permit rapid combination of the most efficient promoter-shRNA cassettes. Finally, using this method, the conservative target sites for hepatitis B virus (HBV knockdown were systemically screened and HBV antigen expression shown to be successfully suppressed in the presence of connected multiple shRNAs both in vitro and in vivo. CONCLUSION: This novel design describes an inexpensive and effective way to clone and express single or multiple shRNAs from the same vector with the capacity for potent and effective silencing of target genes.

Systematic characterization of the specificity of the SH2 domains of cytoplasmic tyrosine kinases.

Science.gov (United States)

Zhao, Bing; Tan, Pauline H; Li, Shawn S C; Pei, Dehua

2013-04-09

Cytoplasmic tyrosine kinases (CTK) generally contain a Src-homology 2 (SH2) domain, whose role in the CTK family is not fully understood. Here we report the determination of the specificity of 25 CTK SH2 domains by screening one-bead-one-compound (OBOC) peptide libraries. Based on the peptide sequences selected by the SH2 domains, we built Support Vector Machine (SVM) models for the prediction of binding ligands for the SH2 domains. These models yielded support for the progressive phosphorylation model for CTKs in which the overlapping specificity of the CTK SH2 and kinase domains has been proposed to facilitate targeting of the CTK substrates with at least two potential phosphotyrosine (pTyr) sites. We curated 93 CTK substrates with at least two pTyr sites catalyzed by the same CTK, and showed that 71% of these substrates had at least two pTyr sites predicted to bind a common CTK SH2 domain. More importantly, we found 34 instances where there was at least one pTyr site predicted to be recognized by the SH2 domain of the same CTK, suggesting that the SH2 and kinase domains of the CTKs may cooperate to achieve progressive phosphorylation of a protein substrate. This article is part of a Special Issue entitled: From protein structures to clinical applications. Copyright © 2012 Elsevier B.V. All rights reserved.

New approaches to high-throughput structure characterization of SH3 complexes: the example of Myosin-3 and Myosin-5 SH3 domains from S. cerevisiae.

Science.gov (United States)

Musi, Valeria; Birdsall, Berry; Fernandez-Ballester, Gregorio; Guerrini, Remo; Salvatori, Severo; Serrano, Luis; Pastore, Annalisa

2006-04-01

SH3 domains are small protein modules that are involved in protein-protein interactions in several essential metabolic pathways. The availability of the complete genome and the limited number of clearly identifiable SH3 domains make the yeast Saccharomyces cerevisae an ideal proteomic-based model system to investigate the structural rules dictating the SH3-mediated protein interactions and to develop new tools to assist these studies. In the present work, we have determined the solution structure of the SH3 domain from Myo3 and modeled by homology that of the highly homologous Myo5, two myosins implicated in actin polymerization. We have then implemented an integrated approach that makes use of experimental and computational methods to characterize their binding properties. While accommodating their targets in the classical groove, the two domains have selectivity in both orientation and sequence specificity of the target peptides. From our study, we propose a consensus sequence that may provide a useful guideline to identify new natural partners and suggest a strategy of more general applicability that may be of use in other structural proteomic studies.

Roles for SH2 and SH3 domains in Lyn kinase association with activated FcepsilonRI in RBL mast cells revealed by patterned surface analysis.

Science.gov (United States)

Hammond, Stephanie; Wagenknecht-Wiesner, Alice; Veatch, Sarah L; Holowka, David; Baird, Barbara

2009-10-01

In mast cells, antigen-mediated cross-linking of IgE bound to its high-affinity surface receptor, FcepsilonRI, initiates a signaling cascade that culminates in degranulation and release of allergic mediators. Antigen-patterned surfaces, in which the antigen is deposited in micron-sized features on a silicon substrate, were used to examine the spatial relationship between clustered IgE-FcepsilonRI complexes and Lyn, the signal-initiating tyrosine kinase. RBL mast cells expressing wild-type Lyn-EGFP showed co-redistribution of this protein with clustered IgE receptors on antigen-patterned surfaces, whereas Lyn-EGFP containing an inhibitory point mutation in its SH2 domain did not significantly accumulate with the patterned antigen, and Lyn-EGFP with an inhibitory point mutation in its SH3 domain exhibited reduced interactions. Our results using antigen-patterned surfaces and quantitative cross-correlation image analysis reveal that both the SH2 and SH3 domains contribute to interactions between Lyn kinase and cross-linked IgE receptors in stimulated mast cells.

Effect of ultrasonic treatment on reduction of Esherichia coli ATCC 25922 and egg quality parameters in experimentally contaminated hens' shell eggs.

Science.gov (United States)

Sert, Durmus; Aygun, Ali; Torlak, Emrah; Mercan, Emin

2013-09-01

In this study, hen eggs which were experimentally contaminated with Esherichia coli ATCC 25922 were used. Contaminated eggs were washed statically (S5 to S30; 0 kHz) and by ultrasonic waves (U5 to U30; 35 kHz) for given applications of time (5, 15 and 30 min), then the eggs were stored at 22°C for 14 days. Depending on the time of ultrasonic application, a significant increase in egg shell strength (P eggs which were washed by ultrasonic waves. Yolk width values of ultrasonic washed eggs diminished. E. coli was completely removed by 30 min of ultrasonic application. During storage E. coli growth was not detected on the eggs which were washed by ultrasonic waves except the eggs in U5 group (2.04 log CFU eggshell⁻¹) on the first day of storage. Depending on the time of ultrasonic application a significant increase in egg quality parameters (shell strength, albumen height, Haugh units, and yolk height) were observed. The application of ultrasound led to a significant reduction in E. coli numbers on egg shells. © 2013 Society of Chemical Industry.

Core-shell microspheres with porous nanostructured shells for liquid chromatography.

Science.gov (United States)

Ahmed, Adham; Skinley, Kevin; Herodotou, Stephanie; Zhang, Haifei

2018-01-01

The development of new stationary phases has been the key aspect for fast and efficient high-performance liquid chromatography separation with relatively low backpressure. Core-shell particles, with a solid core and porous shell, have been extensively investigated and commercially manufactured in the last decade. The excellent performance of core-shell particles columns has been recorded for a wide range of analytes, covering small and large molecules, neutral and ionic (acidic and basic), biomolecules and metabolites. In this review, we first introduce the advance and advantages of core-shell particles (or more widely known as superficially porous particles) against non-porous particles and fully porous particles. This is followed by the detailed description of various methods used to fabricate core-shell particles. We then discuss the applications of common silica core-shell particles (mostly commercially manufactured), spheres-on-sphere particles and core-shell particles with a non-silica shell. This review concludes with a summary and perspective on the development of stationary phase materials for high-performance liquid chromatography applications. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hi shells, supershells, shell-like objects, and ''worms''

International Nuclear Information System (INIS)

Heiles, C.

1984-01-01

We present photographic representations of the combination of two Hi surveys, so as to eliminate the survey boundaries at Vertical BarbVertical Bar = 10 0 . We also present high-contrast photographs for particular velocities to exhibit weak Hi features. All of these photographs were used to prepare a new list of Hi shells, supershells, and shell-like objects. We discuss the structure of three shell-like objects that are associated with high-velocity gas, and with gas at all velocities that is associated with radio continuum loops I, II, and III. We use spatial filtering to find wiggly gas filaments: ''worms'': crawling away from the galactic plane in the inner Galaxy. The ''worms'' are probably parts of shells that are open at the top; such shells should be good sources of hot gas for the galactic halo

Young stellar population and ongoing star formation in the H II complex Sh2-252

Science.gov (United States)

Jose, Jessy; Pandey, A. K.; Samal, M. R.; Ojha, D. K.; Ogura, K.; Kim, J. S.; Kobayashi, N.; Goyal, A.; Chauhan, N.; Eswaraiah, C.

2013-07-01

In this paper, an extensive survey of the star-forming complex Sh2-252 has been undertaken with an aim to explore its hidden young stellar population as well as to understand the structure and star formation history for the first time. This complex is composed of five prominent embedded clusters associated with the subregions A, C, E, NGC 2175s and Teu 136. We used Two Micron All Sky Survey-near-infrared and Spitzer-Infrared Array Camera, Multiband Imaging Photometer for Spitzer photometry to identify and classify the young stellar objects (YSOs) by their infrared (IR) excess emission. Using the IR colour-colour criteria, we identified 577 YSOs, of which, 163 are Class I, 400 are Class II and 14 are transition disc YSOs, suggesting a moderately rich number of YSOs in this complex. Spatial distribution of the candidate YSOs shows that they are mostly clustered around the subregions in the western half of the complex, suggesting enhanced star formation activity towards its west. Using the spectral energy distribution and optical colour-magnitude diagram-based age analyses, we derived probable evolutionary status of the subregions of Sh2-252. Our analysis shows that the region A is the youngest (˜0.5 Myr), the regions B, C and E are of similar evolutionary stage (˜1-2 Myr) and the clusters NGC 2175s and Teu 136 are slightly evolved (˜2-3 Myr). Morphology of the region in the 1.1 mm map shows a semicircular shaped molecular shell composed of several clumps and YSOs bordering the western ionization front of Sh2-252. Our analyses suggest that next generation star formation is currently under way along this border and that possibly fragmentation of the matter collected during the expansion of the H II region as one of the major processes is responsible for such stars. We observed the densest concentration of YSOs (mostly Class I, ˜0.5 Myr) at the western outskirts of the complex, within a molecular clump associated with water and methanol masers and we suggest that it

Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.

Science.gov (United States)

Filippakopoulos, Panagis; Kofler, Michael; Hantschel, Oliver; Gish, Gerald D; Grebien, Florian; Salah, Eidarus; Neudecker, Philipp; Kay, Lewis E; Turk, Benjamin E; Superti-Furga, Giulio; Pawson, Tony; Knapp, Stefan

2008-09-05

The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.

Effects of muscimol, amphetamine, and DAMGO injected into the nucleus accumbens shell on food-reinforced lever pressing by undeprived rats.

Science.gov (United States)

Stratford, Thomas R; Wirtshafter, David

2012-05-01

Previous studies have shown that large increases in food intake in nondeprived animals can be induced by injections of both the GABA(A) agonist muscimol and the μ-opioid agonist DAMGO into the nucleus accumbens shell (AcbSh), while injections of the catecholamine agonist amphetamine have little effect. In the current study we examined whether injections of these drugs are able to increase food-reinforced lever pressing in nondeprived rats. Twelve subjects were trained to lever press on a continuous reinforcement schedule while food deprived and were then tested after being placed back on ad libitum feeding. Under these conditions, responding was markedly increased by injections of either muscimol or DAMGO, although the onset of the effects of the latter drug was delayed by 30-40 min. In contrast, amphetamine injections failed to increase reinforced lever pressing, although they did enhance responding on a non-reinforced lever, presumably reflecting alterations in behavioral activation. These results demonstrate that stimulation of GABA(A) and μ-opioid receptors within the AcbSh is able to promote not only food intake, but also food-directed operant behavior. In contrast, stimulation of AcbSh dopamine receptors may enhance behavioral arousal, but does not appear to specifically potentiate behaviors directed toward food procurement. Copyright © 2012 Elsevier Inc. All rights reserved.

Application of a fiber Fabry-Perot interferometer sensor for receiving SH-EMAT signals

Energy Technology Data Exchange (ETDEWEB)

Lee, Jin Hyuk; Kim, Dae Hyun; Park, Ik Keun [Seoul National University of Technology, Seoul (Korea, Republic of)

2014-04-15

Shear horizontal (SH) waves propagate as a type of plate wave in a thin sheet. The dispersion characteristics of SH waves can be used for signal analysis. Therefore, SH-waves are useful for monitoring the structural health of a thin-sheet-structure. An electromagnetic acoustic transducer (EMAT), which is a non-contact ultrasonic transducer, can generate SH-waves easily by varying the shape and array of magnets and coils. Therefore, an EMAT can be applied to an automated ultrasonic testing system for structural health monitoring. When used as a sensor, however, the EMAT has a weakness in that electromagnetic interference (EMI) noise can occur easily in the automated system because of motors and electric devices. Alternatively, a fiber optic sensor works well in the same environment with EMI noise because it uses a light signal instead of an electric signal. In this paper, a fiber Fabry-Prot interferometer (FFPI) was proposed as a sensor to receive the SH-waves generated by an EMAT. A simple test was performed to verify the performance of the FFPI sensor. It is thus shown that the FFPI can receive SH-wave signals clearly.

Wind rotor power station BONI-ShHV

International Nuclear Information System (INIS)

Bolotov, A.V.

1999-01-01

Wind rotor power station (WRPS) BONI-ShHV has following advantages : the increase of installation stability by rise of wind velocity and rotation speed of rotor due to gyroscopic effect; the absence noise and vibration; the safety for birds and animals; ability of compact installation and creation of series of wind power dams with higher capacity; the simplicity and fast assembling and putting into operation. The price of 1 k W of installing capacity is lower about 2.5-3 times compare to usual WRPS due to simple kinematic scheme. WRPS has high specific output of electrical energy due to use of low and long existing wind velocity and due to short storms, giving greater power. It has ability to be replayed when average annual wind velocity is above 5.5 m/s in comparison with propeller WRPS, which are never repaying. WRPS BONI-ShHV are made on the plants of Republic of Kazakhstan, and tested in wind velocity range up 45 m/s, have experience of 3 years of operation, showing their reliability and effectiveness. The repayment period of individual WRPS BONI-0.5/6 ShHV is from 10 month to 1 year depending on average annual velocity

The MeSH model for hospital-physician joint ventures.

Science.gov (United States)

Anderson, J G

1985-01-01

The MeSH (Medical Staff-Hospital Joint Venture Company) concept has arisen to meet the perceived need for hospital-physician cooperation in a modern age of prospective payment systems, increased supply of health-care providers, cost conscious consumers, corporate health care organizations, and a general trend toward industrialization of health care. Supply and demand economics have created a situation which threatens the autonomy and financial integrity of both hospitals ans physicians, forcing cooperation or mutual destruction. MeSH seeks to preserve the autonomy and financial integrity of both parties through the creation of a free-standing business entity jointly owned by a hospital and those members of its medical staff who choose to participate. This article presents reasons for the need for cooperation, the objectives of MeSH, a description of its structure and operation, and a list of potential projects the program could include.

Flexibility of the myosin heavy chain: direct evidence that the region containing SH/sub 1/ and SH/sub 2/ can move 10 /Angstrom/ under the influence of nucleotide binding

Energy Technology Data Exchange (ETDEWEB)

Huston, E.E.; Grammer, J.C.; Yount, R.G.

1988-12-13

Previous experiments demonstrated that two thiols of skeletal myosin subfragment 1 (SF/sub 1/) could be oxidized to a disulfide bond by treatment with a 2-fold excess of 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) in the presence of MgADP. The resulting characteristic changes in the ATPase activities of SF/sub 1/ and the fact that MgADP was stably trapped at the active site, suggested that the two thiols cross-linked were SH/sub 1/ (Cys-707) and SH/sub 2/ (Cys-697) from the myosin heavy chain. To verify this suggestion, SF/sub 1/, after DTNB treatment as above, was treated with an excess of N-ethylmaleimide to block all accessible thiols. The single protein disulfide produced by DTNB oxidation was reduced with dithioerythritol and the modified SF/sub 1/ internally cross-linked with equimolar (/sup 14/C)p-phenylenedimaleimide (pPDM) in the presence of MgADP. After extensive trypsinization, the major /sup 14/C-labeled peptide was isolated, characterized, and shown to be Cys-Asn-Gly-Val-Leu-Gly-Ile-Arg-Ile-Cys-Arg, in which the two cysteines were cross-linked by pPDM. This peptide is known to contain SH/sub 2/ and SH/sub 1/ in this order and to come from residues 697-708 in the rabbit skeletal myosin heavy chain. Parallel experiments with (/sup 14/C)pPDM and unmodified SF/sub 1/ similar to those above gave an identical SH/sub 1/, SH/sub 2/ tryptic peptide, verifying earlier labeling results. These combined results demonstrate that SH/sub 1/ and SH/sub 2/ cross-linked by pPDM (12-13 /Angstrom/, S to S) or by oxidation with DTNB (2 /Angstrom/, S to S) can move a minimum of 10 /Angstrom/ under the influence of nucleotide binding. Because these residues are separated by only nine amino acids in the primary sequence, this small section of the heavy chain must possess extraordinary flexibility.

In vivo binding properties of SH2 domains from GTPase-activating protein and phosphatidylinositol 3-kinase.

Science.gov (United States)

Cooper, J A; Kashishian, A

1993-01-01

We have used a transient expression system and mutant platelet-derived growth factor (PDGF) receptors to study the binding specificities of the Src homology 2 (SH2) regions of the Ras GTPase-activator protein (GAP) and the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3 kinase). A number of fusion proteins, each tagged with an epitope allowing recognition by a monoclonal antibody, were expressed at levels comparable to those of endogenous GAP. Fusion proteins containing the central SH2-SH3-SH2 region of GAP or the C-terminal region of p85 alpha, which includes two SH2 domains, bound to PDGF receptors in response to PDGF stimulation. Both fusion proteins showed the same requirements for tyrosine phosphorylation sites in the PDGF receptor as the full-length proteins from which they were derived, i.e., binding of the GAP fusion protein was reduced by mutation of Tyr-771, and binding of the p85 fusion protein was reduced by mutation of Tyr-740, Tyr-751, or both residues. Fusion proteins containing single SH2 domains from either GAP or p85 alpha did not bind detectably to PDGF receptors in this system, suggesting that two SH2 domains in a single polypeptide cooperate to raise the affinity of binding. The sequence specificities of individual SH2 domains were deduced from the binding properties of fusion proteins containing one SH2 domain from GAP and another from p85. The results suggest that the C-terminal GAP SH2 domain specifies binding to Tyr-771, the C-terminal p85 alpha SH2 domain binds to either Tyr-740 or Tyr-751, and each protein's N-terminal SH2 domain binds to unidentified phosphorylation sites.(ABSTRACT TRUNCATED AT 250 WORDS) Images PMID:8382774

Structure determination of human Lck unique and SH3 domains by nuclear magnetic resonance spectroscopy

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Willbold Dieter

2003-05-01

Full Text Available Abstract Background Protein tyrosine kinases are involved in signal transduction pathways that regulate cell growth, differentiation, activation and transformation. Human lymphocyte specific kinase (Lck is a 56 kDa protein involved in T-cell- and IL2-receptor signaling. Three-dimensional structures are known for SH3, SH2 and kinase domains of Lck as well as for other tyrosine kinases. No structure is known for the unique domain of any Src-type tyrosine kinase. Results Lck(1–120 comprising unique and SH3 domains was structurally investigated by nuclear magnetic resonance spectroscopy. We found the unique domain, in contrast to the SH3 part, to have basically no defined structural elements. The solution structure of the SH3 part could be determined with very high precision. It does not show significant differences to Lck SH3 in the absence of the unique domain. Minor differences were observed to the X-ray structure of Lck SH3. Conclusion The unique domain of Lck does not contain any defined structure elements in the absence of ligands and membranes. Presence of the unique domain is not relevant to the three-dimensional structure of the Lck SH3 domain.

Modeling and validating HL7 FHIR profiles using semantic web Shape Expressions (ShEx).

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Solbrig, Harold R; Prud'hommeaux, Eric; Grieve, Grahame; McKenzie, Lloyd; Mandel, Joshua C; Sharma, Deepak K; Jiang, Guoqian

2017-03-01

HL7 Fast Healthcare Interoperability Resources (FHIR) is an emerging open standard for the exchange of electronic healthcare information. FHIR resources are defined in a specialized modeling language. FHIR instances can currently be represented in either XML or JSON. The FHIR and Semantic Web communities are developing a third FHIR instance representation format in Resource Description Framework (RDF). Shape Expressions (ShEx), a formal RDF data constraint language, is a candidate for describing and validating the FHIR RDF representation. Create a FHIR to ShEx model transformation and assess its ability to describe and validate FHIR RDF data. We created the methods and tools that generate the ShEx schemas modeling the FHIR to RDF specification being developed by HL7 ITS/W3C RDF Task Force, and evaluated the applicability of ShEx in the description and validation of FHIR to RDF transformations. The ShEx models contributed significantly to workgroup consensus. Algorithmic transformations from the FHIR model to ShEx schemas and FHIR example data to RDF transformations were incorporated into the FHIR build process. ShEx schemas representing 109 FHIR resources were used to validate 511 FHIR RDF data examples from the Standards for Trial Use (STU 3) Ballot version. We were able to uncover unresolved issues in the FHIR to RDF specification and detect 10 types of errors and root causes in the actual implementation. The FHIR ShEx representations have been included in the official FHIR web pages for the STU 3 Ballot version since September 2016. ShEx can be used to define and validate the syntax of a FHIR resource, which is complementary to the use of RDF Schema (RDFS) and Web Ontology Language (OWL) for semantic validation. ShEx proved useful for describing a standard model of FHIR RDF data. The combination of a formal model and a succinct format enabled comprehensive review and automated validation. Copyright © 2017 Elsevier Inc. All rights reserved.

A consensus microsatellite-based linkage map for the hermaphroditic bay scallop (Argopecten irradians and its application in size-related QTL analysis.

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Hongjun Li

Full Text Available Bay scallop (Argopecten irradians is one of the most economically important aquaculture species in China. In this study, we constructed a consensus microsatellite-based genetic linkage map with a mapping panel containing two hybrid backcross-like families involving two subspecies of bay scallop, A. i. irradians and A. i. concentricus. One hundred sixty-one microsatellite and one phenotypic (shell color markers were mapped to 16 linkage groups (LGs, which corresponds to the haploid chromosome number of bay scallop. The sex-specific map was 779.2 cM and 781.6 cM long in female and male, respectively, whereas the sex-averaged map spanned 849.3 cM. The average resolution of integrated map was 5.9 cM/locus and the estimated coverage was 81.3%. The proportion of distorted markers occurred more in the hybrid parents, suggesting that the segregation distortion was possibly resulted from heterospecific interaction between genomes of two subspecies of bay scallop. The overall female-to-male recombination rate was 1.13:1 across all linked markers in common to both parents, and considerable differences in recombination also existed among different parents in both families. Four size-related traits, including shell length (SL, shell height (SH, shell width (SW and total weight (TW were measured for quantitative trait loci (QTL analysis. Three significant and six suggestive QTL were detected on five LGs. Among the three significant QTL, two (qSW-10 and qTW-10, controlling SW and TW, respectively were mapped on the same region near marker AiAD121 on LG10 and explained 20.5% and 27.7% of the phenotypic variance, while the third (qSH-7, controlling SH was located on LG7 and accounted for 15.8% of the phenotypic variance. Six suggestive QTL were detected on four different LGs. The linkage map and size-related QTL obtained in this study may facilitate marker-assisted selection (MAS in bay scallop.

In Vitro Evaluation of Beneficial Properties of Bacteriocinogenic Lactobacillus plantarum ST8Sh.

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Todorov, Svetoslav Dimitrov; Holzapfel, Wilhelm; Nero, Luis Augusto

2017-06-01

Lactobacillus plantarum ST8Sh, isolated from Bulgarian salami "shpek" and previously characterized as bacteriocin producer, was evaluated for its beneficial properties. Based on the PCR analysis, Lb. plantarum ST8Sh was shown to host a gene related to the production of adhesion proteins such as Mab, Mub, EF, and PrgB. Genetic and physiological tests suggest Lb. plantarum ST8Sh to represent a potential probiotic candidate, including survival in the presence of low levels of pH and high levels of ox bile, production of β-galactosidase, bile salt deconjugation, high level of hydrophobicity, functional auto- and co-aggregation properties, and adhesion to cell lines. Application of semi-purified bacteriocin produced by Lb. plantarum ST8Sh in combination with ciprofloxacin presented synergistic effect on inhibition of Listeria monocytogenes Scott A. Based on observed properties, Lb. plantarum ST8Sh can be considered as a potential probiotic candidate with additional bacteriocinogenic properties.

Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain

OpenAIRE

Nelms, Keats; O'Neill, Thomas J.; Li, Shiqing; Hubbard, Stevan R.; Gustafson, Thomas A.; Paul, William E.

1999-01-01

. The SH2-B protein is an SH2-domain-containing molecule that interacts with a number of phosphorylated kinase and receptor molecules including the insulin receptor. Two isoforms of the SH2-B have been identified and have been proposed to arise through alternate splicing. Here we have identified a third isoform of the SH2-B protein, SH2-Bγ, that interacts specifically with the insulin receptor. This interaction required phosphorylation of residue Y1146 in the triple tyrosine motif within the ...

Concordant preferences for actual height and facial cues to height

OpenAIRE

Re, Daniel Edward; Perrett, David I.

2012-01-01

Physical height has a well-documented effect on human mate preferences. In general, both sexes prefer opposite-sex romantic relationships in which the man is taller than the woman, while individual preferences for height are affected by a person’s own height. Research in human mate choice has demonstrated that attraction to facial characteristics, such as facial adiposity, may reflect references for body characteristics. Here, we tested preferences for facial cues to height. In general, incre...

Examining transition metal hydrosulfides: The pure rotational spectrum of ZnSH (X̃2A').

Science.gov (United States)

Bucchino, M P; Adande, G R; Halfen, D T; Ziurys, L M

2017-10-21

The pure rotational spectrum of the ZnSH (X̃ 2 A') radical has been measured using millimeter-wave direct absorption and Fourier transform microwave (FTMW) methods across the frequency range 18-468 GHz. This work is the first gas-phase detection of ZnSH by any spectroscopic technique. Spectra of the 66 ZnSH, 68 ZnSH, and 64 ZnSD isotopologues were also recorded. In the mm-wave study, ZnSH was synthesized in a DC discharge by the reaction of zinc vapor, generated by a Broida-type oven, with H 2 S; for FTMW measurements, the radical was made in a supersonic jet expansion by the same reactants but utilizing a discharge-assisted laser ablation source. Between 7 and 9 rotational transitions were recorded for each isotopologue. Asymmetry components with K a = 0 through 6 were typically measured in the mm-wave region, each split into spin-rotation doublets. In the FTMW spectra, hyperfine interactions were also resolved, arising from the hydrogen or deuterium nuclear spins of I = 1/2 or I = 1, respectively. The data were analyzed using an asymmetric top Hamiltonian, and rotational, spin-rotation, and magnetic hyperfine parameters were determined for ZnSH, as well as the quadrupole coupling constant for ZnSD. The observed spectra clearly indicate that ZnSH has a bent geometry. The r m (1) structure was determined to be r Zn-S = 2.213(5) Å, r S-H = 1.351(3) Å, and θ Zn-S-H = 90.6(1)°, suggesting that the bonding occurs primarily through sulfur p orbitals, analogous to H 2 S. The hyperfine constants indicate that the unpaired electron in ZnSH primarily resides on the zinc nucleus.

Model SH intelligent instrument for thickness measuring

International Nuclear Information System (INIS)

Liu Juntao; Jia Weizhuang; Zhao Yunlong

1995-01-01

The authors introduce Model SH Intelligent Instrument for thickness measuring by using principle of beta back-scattering and its application range, features, principle of operation, system design, calibration and specifications

Activation of PI3K/Akt signaling by n-terminal SH2 domain mutants of the p85α regulatory subunit of PI3K is enhanced by deletion of its c-terminal SH2 domain.

Science.gov (United States)

Hofmann, Bianca T; Jücker, Manfred

2012-10-01

The phosphoinositide 3-kinase (PI3K) is frequently activated in human cancer cells due to gain of function mutations in the catalytic (p110) and the regulatory (p85) subunits. The regulatory subunit consists of an SH3 domain and two SH2 domains. An oncogenic form of p85α named p65 lacking the c-terminal SH2 domain (cSH2) has been cloned from an irradiation-induced murine thymic lymphoma and transgenic mice expressing p65 in T lymphocytes develop a lymphoproliferative disorder. We have recently detected a c-terminal truncated form of p85α named p76α in a human lymphoma cell line lacking most of the cSH2 domain due to a frame shift mutation. Here, we report that the deletion of the cSH2 domain enhances the activating effects of the n-terminal SH2 domain (nSH2) mutants K379E and R340E on the PI3K/Akt pathway and micro tumor formation in a focus assay. Further analysis revealed that this transforming effect is mediated by activation of the catalytic PI3K isoform p110α and downstream signaling through mTOR. Our data further support a mechanistic model in which mutations of the cSH2 domain of p85α can abrogate its negative regulatory function on PI3K activity via the nSH2 domain of p85α. Copyright © 2012 Elsevier Inc. All rights reserved.

Improving MeSH classification of biomedical articles using citation contexts.

Science.gov (United States)

Aljaber, Bader; Martinez, David; Stokes, Nicola; Bailey, James

2011-10-01

Medical Subject Headings (MeSH) are used to index the majority of databases generated by the National Library of Medicine. Essentially, MeSH terms are designed to make information, such as scientific articles, more retrievable and assessable to users of systems such as PubMed. This paper proposes a novel method for automating the assignment of biomedical publications with MeSH terms that takes advantage of citation references to these publications. Our findings show that analysing the citation references that point to a document can provide a useful source of terms that are not present in the document. The use of these citation contexts, as they are known, can thus help to provide a richer document feature representation, which in turn can help improve text mining and information retrieval applications, in our case MeSH term classification. In this paper, we also explore new methods of selecting and utilising citation contexts. In particular, we assess the effect of weighting the importance of citation terms (found in the citation contexts) according to two aspects: (i) the section of the paper they appear in and (ii) their distance to the citation marker. We conduct intrinsic and extrinsic evaluations of citation term quality. For the intrinsic evaluation, we rely on the UMLS Metathesaurus conceptual database to explore the semantic characteristics of the mined citation terms. We also analyse the "informativeness" of these terms using a class-entropy measure. For the extrinsic evaluation, we run a series of automatic document classification experiments over MeSH terms. Our experimental evaluation shows that citation contexts contain terms that are related to the original document, and that the integration of this knowledge results in better classification performance compared to two state-of-the-art MeSH classification systems: MeSHUP and MTI. Our experiments also demonstrate that the consideration of Section and Distance factors can lead to statistically

Crystal Structure of the FERM-SH2 Module of Human Jak2.

Science.gov (United States)

McNally, Randall; Toms, Angela V; Eck, Michael J

2016-01-01

Jak-family tyrosine kinases mediate signaling from diverse cytokine receptors. Binding of Jaks to their cognate receptors is mediated by their N-terminal region, which contains FERM and SH2 domains. Here we describe the crystal structure of the FERM-SH2 region of Jak2 at 3.0Å resolution. The structure reveals that these domains and their flanking linker segments interact intimately to form an integrated structural module. The Jak2 FERM-SH2 structure closely resembles that recently described for Tyk2, another member of the Jak family. While the overall architecture and interdomain orientations are preserved between Jak2 and Tyk2, we identify residues in the putative receptor-binding groove that differ between the two and may contribute to the specificity of receptor recognition. Analysis of Jak mutations that are reported to disrupt receptor binding reveals that they lie in the hydrophobic core of the FERM domain, and are thus expected to compromise the structural integrity of the FERM-SH2 unit. Similarly, analysis of mutations in Jak3 that are associated with severe combined immunodeficiency suggests that they compromise Jak3 function by destabilizing the FERM-SH2 structure.

Characterizing tyrosine phosphorylation signaling in lung cancer using SH2 profiling.

Directory of Open Access Journals (Sweden)

Kazuya Machida

2010-10-01

Full Text Available Tyrosine kinases drive the proliferation and survival of many human cancers. Thus profiling the global state of tyrosine phosphorylation of a tumor is likely to provide a wealth of information that can be used to classify tumors for prognosis and prediction. However, the comprehensive analysis of tyrosine phosphorylation of large numbers of human cancer specimens is technically challenging using current methods.We used a phosphoproteomic method termed SH2 profiling to characterize the global state of phosphotyrosine (pTyr signaling in human lung cancer cell lines. This method quantifies the phosphorylated binding sites for SH2 domains, which are used by cells to respond to changes in pTyr during signaling. Cells could be grouped based on SH2 binding patterns, with some clusters correlated with EGF receptor (EGFR or K-RAS mutation status. Binding of specific SH2 domains, most prominently RAS pathway activators Grb2 and ShcA, correlated with EGFR mutation and sensitivity to the EGFR inhibitor erlotinib. SH2 binding patterns also reflected MET activation and could identify cells driven by multiple kinases. The pTyr responses of cells treated with kinase inhibitors provided evidence of distinct mechanisms of inhibition.This study illustrates the potential of modular protein domains and their proteomic binding profiles as powerful molecular diagnostic tools for tumor classification and biomarker identification.

Free vibration analysis of delaminated composite shells using different shell theories

International Nuclear Information System (INIS)

Nanda, Namita; Sahu, S.K.

2012-01-01

Free vibration response of laminated composite shells with delamination is presented using the finite element method based on first order shear deformation theory. The shell theory used is the extension of dynamic, shear deformable theory according to the Sanders' first approximation for doubly curved shells, which can be reduced to Love's and Donnell's theories by means of tracers. An eight-noded C 0 continuity, isoparametric quadrilateral element with five degrees of freedom per node is used in the formulation. For modeling the delamination, multipoint constraint algorithm is incorporated in the finite element code. The natural frequencies of the delaminated cylindrical (CYL), spherical (SPH) and hyperbolic paraboloid (HYP) shells are determined by using the above mentioned shell theories, namely Sanders', Love's, and Donnell's. The validity of the present approach is established by comparing the authors' results with those available in the literature. Additional studies on free vibration response of CYL, SPH and HYP shells are conducted to assess the effects of delamination size and number of layers considering all three shell theories. It is shown that shell theories according to Sanders and Love always predict practically identical frequencies. Donnell's theory gives reliable results only for shallow shells. Moreover, the natural frequency is found to be very sensitive to delamination size and number of layers in the shell.

Piezo-phototronic effect enhanced UV photodetector based on CuI/ZnO double-shell grown on flexible copper microwire.

Science.gov (United States)

Liu, Jingyu; Zhang, Yang; Liu, Caihong; Peng, Mingzeng; Yu, Aifang; Kou, Jinzong; Liu, Wei; Zhai, Junyi; Liu, Juan

2016-12-01

In this work, we present a facile, low-cost, and effective approach to fabricate the UV photodetector with a CuI/ZnO double-shell nanostructure which was grown on common copper microwire. The enhanced performances of Cu/CuI/ZnO core/double-shell microwire photodetector resulted from the formation of heterojunction. Benefiting from the piezo-phototronic effect, the presentation of piezocharges can lower the barrier height and facilitate the charge transport across heterojunction. The photosensing abilities of the Cu/CuI/ZnO core/double-shell microwire detector are investigated under different UV light densities and strain conditions. We demonstrate the I-V characteristic of the as-prepared core/double-shell device; it is quite sensitive to applied strain, which indicates that the piezo-phototronic effect plays an essential role in facilitating charge carrier transport across the CuI/ZnO heterojunction, then the performance of the device is further boosted under external strain.

Annotating patents with Medline MeSH codes via citation mapping.

Science.gov (United States)

Griffin, Thomas D; Boyer, Stephen K; Councill, Isaac G

2010-01-01

Both patents and Medline are important document collections for discovering new relationships between chemicals and biology, searching for prior art for patent applications and retrieving background knowledge for current research activities. Finding relevance to a topic within patents is often made difficult by poor categorization, badly written descriptions, and even intentional obfuscation. Unlike patents, the Medline corpus has Medical Subject Heading (MeSH) keywords manually added to their articles, giving a medically relevant taxonomy to the 18 million article abstracts. Our work attempts to accurately recognize the citations made in patents to Medline-indexed articles, linking them to their corresponding PubMed ID and exploiting the associated MeSH to enhance patent search by annotating the referencing patents with their Medline citations' MeSH codes. The techniques, system features, and benefits are explained.

SH3 Domains Differentially Stimulate Distinct Dynamin I Assembly Modes and G Domain Activity.

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Sai Krishnan

Full Text Available Dynamin I is a highly regulated GTPase enzyme enriched in nerve terminals which mediates vesicle fission during synaptic vesicle endocytosis. One regulatory mechanism involves its interactions with proteins containing Src homology 3 (SH3 domains. At least 30 SH3 domain-containing proteins bind dynamin at its proline-rich domain (PRD. Those that stimulate dynamin activity act by promoting its oligomerisation. We undertook a systematic parallel screening of 13 glutathione-S-transferase (GST-tagged endocytosis-related SH3 domains on dynamin binding, GTPase activity and oligomerisation. No correlation was found between dynamin binding and their potency to stimulate GTPase activity. There was limited correlation between the extent of their ability to stimulate dynamin activity and the level of oligomerisation, indicating an as yet uncharacterised allosteric coupling of the PRD and G domain. We examined the two variants, dynamin Iab and Ibb, which differ in the alternately splice middle domain α2 helix. They responded differently to the panel of SH3s, with the extent of stimulation between the splice variants varying greatly between the SH3s. This study reveals that SH3 binding can act as a heterotropic allosteric regulator of the G domain via the middle domain α2 helix, suggesting an involvement of this helix in communicating the PRD-mediated allostery. This indicates that SH3 binding both stabilises multiple conformations of the tetrameric building block of dynamin, and promotes assembly of dynamin-SH3 complexes with distinct rates of GTP hydrolysis.

Investigation of phosphotyrosine recognition by the SH2 domain of the Src kinase.

Science.gov (United States)

Bradshaw, J M; Mitaxov, V; Waksman, G

1999-11-05

The binding of tyrosine phosphorylated targets by SH2 domains is required for propagation of many cellular signals in higher eukaryotes; however, the determinants of phosphotyrosine (pTyr) recognition by SH2 domains are not well understood. In order to identify the attributes of pTyr required for high affinity interaction with SH2 domains, the binding of the SH2 domain of the Src kinase (Src SH2 domain) to a dephosphorylated peptide, a phosphoserine-containing peptide, and the amino acid pTyr was studied using titration calorimetry and compared with the binding of a high affinity tyrosyl phosphopeptide. The dephosphorylated peptide and the phosphoserine containing peptide both bind extremely weakly to the Src SH2 domain (DeltaGo (dephosphorylated)=-3.6 kcal/mol, DeltaGo (phosphoserine) >-3.7 kcal/mol); however, the DeltaGo value of pTyr binding is more favorable (-4.7 kcal/mol, or 50 % of the entire binding free energy of a high affinity tyrosyl phosphopeptide). These results indicate that both the phosphate and the tyrosine ring of the pTyr are critical determinants of high affinity binding. Alanine mutagenesis was also used to evaluate the energetic contribution to binding of ten residues located in the pTyr-binding site. Mutation of the strictly conserved Arg betaB5 resulted in a large increase in DeltaGo (DeltaDeltaGo=3.2 kcal/mol) while elimination of the other examined residues each resulted in a significantly smaller (DeltaDeltaGoSH2 domain, surprisingly increased affinity by eightfold (DeltaDeltaGo=-1.1 kcal/mol). Using a double mutant cycle analysis, it was revealed that residues of the pTyr-binding pocket are not coupled to the peptide residues C-terminal to the pTyr. In addition, comparison of each residue's DeltaDeltaGo value upon mutation with that residue's sequence conservation among SH2 domains revealed only a modest correlation between a residue's energetic contribution to pTyr recognition and its conservation throughout evolution. The results of

Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity*

Science.gov (United States)

Jin, Lily L.; Wybenga-Groot, Leanne E.; Tong, Jiefei; Taylor, Paul; Minden, Mark D.; Trudel, Suzanne; McGlade, C. Jane; Moran, Michael F.

2015-01-01

Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y194 impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y194 on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. PMID:25587033

MeSH key terms for validation and annotation of gene expression clusters

Energy Technology Data Exchange (ETDEWEB)

Rechtsteiner, A. (Andreas); Rocha, L. M. (Luis Mateus)

2004-01-01

Integration of different sources of information is a great challenge for the analysis of gene expression data, and for the field of Functional Genomics in general. As the availability of numerical data from high-throughput methods increases, so does the need for technologies that assist in the validation and evaluation of the biological significance of results extracted from these data. In mRNA assaying with microarrays, for example, numerical analysis often attempts to identify clusters of co-expressed genes. The important task to find the biological significance of the results and validate them has so far mostly fallen to the biological expert who had to perform this task manually. One of the most promising avenues to develop automated and integrative technology for such tasks lies in the application of modern Information Retrieval (IR) and Knowledge Management (KM) algorithms to databases with biomedical publications and data. Examples of databases available for the field are bibliographic databases c ntaining scientific publications (e.g. MEDLINE/PUBMED), databases containing sequence data (e.g. GenBank) and databases of semantic annotations (e.g. the Gene Ontology Consortium and Medical Subject Headings (MeSH)). We present here an approach that uses the MeSH terms and their concept hierarchies to validate and obtain functional information for gene expression clusters. The controlled and hierarchical MeSH vocabulary is used by the National Library of Medicine (NLM) to index all the articles cited in MEDLINE. Such indexing with a controlled vocabulary eliminates some of the ambiguity due to polysemy (terms that have multiple meanings) and synonymy (multiple terms have similar meaning) that would be encountered if terms would be extracted directly from the articles due to differing article contexts or author preferences and background. Further, the hierarchical organization of the MeSH terms can illustrate the conceptuallfunctional relationships of genes

Composted oyster shell as lime fertilizer is more effective than fresh oyster shell.

Science.gov (United States)

Lee, Young Han; Islam, Shah Md Asraful; Hong, Sun Joo; Cho, Kye Man; Math, Renukaradhya K; Heo, Jae Young; Kim, Hoon; Yun, Han Dae

2010-01-01

Physio-chemical changes in oyster shell were examined, and fresh and composted oyster shell meals were compared as lime fertilizers in soybean cultivation. Structural changes in oyster shell were observed by AFM and FE-SEM. We found that grains of the oyster shell surface became smoother and smaller over time. FT-IR analysis indicated the degradation of a chitin-like compound of oyster shell. In chemical analysis, pH (12.3+/-0.24), electrical conductivity (4.1+/-0.24 dS m(-1)), and alkaline powder (53.3+/-1.12%) were highest in commercial lime. Besides, pH was higher in composted oyster shell meal (9.9+/-0.53) than in fresh oyster shell meal (8.4+/-0.32). The highest organic matter (1.1+/-0.08%), NaCl (0.54+/-0.03%), and moisture (15.1+/-1.95%) contents were found in fresh oyster shell meal. A significant higher yield of soybean (1.33 t ha(-1)) was obtained by applying composted oyster shell meal (a 21% higher yield than with fresh oyster shell meal). Thus composting of oyster shell increases the utility of oyster shell as a liming material for crop cultivation.

Love and fear of heights: the pathophysiology and psychology of height imbalance.

Science.gov (United States)

Salassa, John R; Zapala, David A

2009-01-01

Individual psychological responses to heights vary on a continuum from acrophobia to height intolerance, height tolerance, and height enjoyment. This paper reviews the English literature and summarizes the physiologic and psychological factors that generate different responses to heights while standing still in a static or motionless environment. Perceptual cues to height arise from vision. Normal postural sway of 2 cm for peripheral objects within 3 m increases as eye-object distance increases. Postural sway >10 cm can result in a fall. A minimum of 20 minutes of peripheral retinal arc is required to detect motion. Trigonometry dictates that a 20-minute peripheral retinal arch can no longer be achieved in a standing position at an eye-object distance of >20 m. At this distance, visual cues conflict with somatosensory and vestibular inputs, resulting in variable degrees of imbalance. Co-occurring deficits in the visual, vestibular, and somatosensory systems can significantly increase height imbalance. An individual's psychological makeup, influenced by learned and genetic factors, can influence reactions to height imbalance. Enhancing peripheral vision and vestibular, proprioceptive, and haptic functions may improve height imbalance. Psychotherapy may improve the troubling subjective sensations to heights.

ExoMol molecular line lists - XXVI: spectra of SH and NS

Science.gov (United States)

Yurchenko, Sergei N.; Bond, Wesley; Gorman, Maire N.; Lodi, Lorenzo; McKemmish, Laura K.; Nunn, William; Shah, Rohan; Tennyson, Jonathan

2018-04-01

Line lists for the sulphur-containing molecules SH (the mercapto radical) and NS are computed as part of the ExoMol project. These line lists consider transitions within the X 2Π ground state for 32SH, 33SH, 34SH and 32SD, and 14N32S, 14N33S, 14N34S, 14N36S and 15N32S. Ab initio potential energy (PEC) and spin-orbit coupling (SOC) curves are computed and then improved by fitting to experimentally observed transitions. Fully ab initio dipole moment curves (DMCs) computed at high level of theory are used to produce the final line lists. For SH, our fit gives a root-mean-square (rms) error of 0.03 cm-1 between the observed (vmax = 4, Jmax = 34.5) and calculated transitions wavenumbers; this is extrapolated such that all X 2Π rotational-vibrational-electronic (rovibronic) bound states are considered. For 32SH the resulting line list contains about 81 000 transitions and 2 300 rovibronic states, considering levels up to vmax = 14 and Jmax = 60.5. For NS the refinement used a combination of experimentally determined frequencies and energy levels and led to an rms fitting error of 0.002 cm-1. Each NS calculated line list includes around 2.8 million transitions and 31 000 rovibronic states with a vibrational range up to v = 53 and rotational range to J = 235.5, which covers up to 23 000 cm-1. Both line lists should be complete for temperatures up to 5000 K. Example spectra simulated using this line list are shown and comparisons made to the existing data in the CDMS database. The line lists are available from the CDS (http://cdsarc.u-strasbg.fr) and ExoMol (www.exomol.com) data bases.

On the core-mass-shell-luminosity relation for shell-burning stars

International Nuclear Information System (INIS)

Jeffery, C.S.; Saint Andrews Univ.

1988-01-01

Core-mass-shell-luminosity relations for several types of shell-burning star have been calculated using simultaneous differential equations derived from simple homology approximations. The principal objective of obtaining a mass-luminosity relation for helium giants was achieved. This relation gives substantially higher luminosities than the equivalent relation for H-shell stars with core masses greater than 1 solar mass. The algorithm for calculating mass-luminosity relations in this fashion was investigated in detail. Most of the assumptions regarding the physics in the shell do not play a critical role in determining the core-mass-shell-luminosity relation. The behaviour of the core-mass-core-radius relation for a growing degenerate core as a single unique function of mass and growth rate needs to be defined before a single core-mass-shell-luminosity relation for all H-shell stars can be obtained directly from the homology approximations. (author)

Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis.

Science.gov (United States)

Grebien, Florian; Hantschel, Oliver; Wojcik, John; Kaupe, Ines; Kovacic, Boris; Wyrzucki, Arkadiusz M; Gish, Gerald D; Cerny-Reiterer, Sabine; Koide, Akiko; Beug, Hartmut; Pawson, Tony; Valent, Peter; Koide, Shohei; Superti-Furga, Giulio

2011-10-14

Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention. Copyright © 2011 Elsevier Inc. All rights reserved.

Variation in Orthologous Shell-Forming Proteins Contribute to Molluscan Shell Diversity.

Science.gov (United States)

Jackson, Daniel J; Reim, Laurin; Randow, Clemens; Cerveau, Nicolas; Degnan, Bernard M; Fleck, Claudia

2017-11-01

Despite the evolutionary success and ancient heritage of the molluscan shell, little is known about the molecular details of its formation, evolutionary origins, or the interactions between the material properties of the shell and its organic constituents. In contrast to this dearth of information, a growing collection of molluscan shell-forming proteomes and transcriptomes suggest they are comprised of both deeply conserved, and lineage specific elements. Analyses of these sequence data sets have suggested that mechanisms such as exon shuffling, gene co-option, and gene family expansion facilitated the rapid evolution of shell-forming proteomes and supported the diversification of this phylum specific structure. In order to further investigate and test these ideas we have examined the molecular features and spatial expression patterns of two shell-forming genes (Lustrin and ML1A2) and coupled these observations with materials properties measurements of shells from a group of closely related gastropods (abalone). We find that the prominent "GS" domain of Lustrin, a domain believed to confer elastomeric properties to the shell, varies significantly in length between the species we investigated. Furthermore, the spatial expression patterns of Lustrin and ML1A2 also vary significantly between species, suggesting that both protein architecture, and the regulation of spatial gene expression patterns, are important drivers of molluscan shell evolution. Variation in these molecular features might relate to certain materials properties of the shells of these species. These insights reveal an important and underappreciated source of variation within shell-forming proteomes that must contribute to the diversity of molluscan shell phenotypes. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Effect of whole body X-irradiation on the NP-SH level of blood in rabbits

International Nuclear Information System (INIS)

Suh, Soo Jhi; Woo, Won Hyung

1972-01-01

In hope to elucidate possible changes in blood NP-SH levels when X-irradiation is made in single or fractionate dose, a whole body X-irradiation was done to rabbits either in single dose of 900 r or in fractionated dose of 300 r per day for three days. The NP-SH was measured at 1, 3, 5, 24 and 48 post-irradiation hours, and the results were compared with the normal value of the blood NP-SH. The results obtained are as follows: 1. The normal value of blood NP-SH in the rabbit was 2.11 ± 0.40 μmol/ml. 2. In the single X-irradiation group, the blood NP-SH decreased most prominently at five hours after-irradiation, and a tendency of recovery to the normal level was observed thereafter. 3. In the fractionated group, the blood NP-SH levels were higher, than in the single irradiation group throughout the experiment, and the levels were also higher than the normal in general

“Girls are dancin’”: shōjo culture and feminism in contemporary Japanese art

Directory of Open Access Journals (Sweden)

Emily Jane Wakeling

2011-12-01

Full Text Available This article explores the gender-transgressive expressions found in shōjo culture in order to highlight the potential for feminist analysis in the prevalence of the shōjo motif in contemporary Japanese art. Shōjo culture is a fascinating cultural space, within contemporary Japanese culture, which fosters creative expressions of gender that negate or make complex hegemonic categories. Departing from stereotypes of Japanese girls, this article will pay particular interest to an emerging wave of figurative contemporary art practices in which the figure of the shōjo is utilised for a new generation of feminist critique. Aoshima Chiho, Kunikata Mahomi, Takano Aya, Sawada Tomoko and Yanagi Miwa are among the current artists who feature the shōjo motif in contexts that foreground female subjectivities found paralleled in shōjo culture. These works will then be contextualised in the greater picture of current trends and themes in global contemporary feminist art.

Off-shell CHY amplitudes

Energy Technology Data Exchange (ETDEWEB)

Lam, C.S., E-mail: Lam@physics.mcgill.ca [Department of Physics, McGill University, Montreal, Q.C., H3A 2T8 (Canada); Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, V6T 1Z1 (Canada); Yao, York-Peng, E-mail: yyao@umich.edu [Department of Physics, The University of Michigan Ann Arbor, MI 48109 (United States)

2016-06-15

The Cachazo–He–Yuan (CHY) formula for on-shell scattering amplitudes is extended off-shell. The off-shell amplitudes (amputated Green's functions) are Möbius invariant, and have the same momentum poles as the on-shell amplitudes. The working principles which drive the modifications to the scattering equations are mainly Möbius covariance and energy momentum conservation in off-shell kinematics. The same technique is also used to obtain off-shell massive scalars. A simple off-shell extension of the CHY gauge formula which is Möbius invariant is proposed, but its true nature awaits further study.

Synthesis and in vitro cytotoxicity of mPEG-SH modified gold nanorods

Science.gov (United States)

Didychuk, Candice L.; Ephrat, Pinhas; Belton, Michelle; Carson, Jeffrey J. L.

2008-02-01

Plasmon-resonant gold nanorods show great potential as an agent for contrast-enhanced biomedical imaging or for phototherapeutics. This is primarily due to the high molar extinction coefficient at the absorption maximum and the dependence of the wavelength of the absorption maximum on the aspect ratio, which is tunable in the near-infrared (NIR) during synthesis. Although gold nanorods can be produced in high-yield through the seed-mediated growth technique, the presence of residual cetyltrimethylammonium bromide (CTAB), a stabilizing surfactant required for nanorod growth, interferes with cell function and causes cytotoxicity. To overcome this potential obstacle to in vivo use, we synthesized gold nanorods and conjugated them to a methoxy (polyethylene glycol)-thiol (mPEG (5000)-SH). This approach yielded mPEG-SH modified gold nanorods with optical and morphometric properties that were similar to raw (CTAB) nanorods. Both the CTAB and mPEG-SH nanorods were tested for cytotoxicity against the HL-60 human leukemia cell line by trypan blue exclusion, and the mPEG-SH modified gold nanorods were also tested against a rat insulinoma (RIN-38) and squamous cell carcinoma (SCCVII) cell line. Cells incubated for 24 h with the mPEG-SH modified nanorods had little change in cell viability compared to cells incubated with vehicle alone. This was in contrast to cytotoxicity of CTAB nanorods on HL-60 cells. These results suggest that mPEG-SH modified gold nanorods are better suited for cell loading protocols and injection into animals and facilitate their use for imaging and phototherapeutic purposes.

New residence times of the Holocene reworked shells on the west coast of Bohai Bay, China

Science.gov (United States)

Shang, Zhiwen; Wang, Fu; Li, Jianfen; Marshall, William A.; Chen, Yongsheng; Jiang, Xingyu; Tian, Lizhu; Wang, Hong

2016-01-01

Shelly cheniers and shell-rich beds found intercalated in near-shore marine muds and sandy sediments can be used to indicate the location of ancient shorelines, and help to estimate the height of sea level. However, dating the deposition of material within cheniers and shell-rich beds is not straightforward because much of this material is transported and re-worked, creating an unknown temporal off-set, i.e., the residence time, between the death of a shell and its subsequent entombment. To quantify the residence time during the Holocene on a section of the northern Chinese coastline a total 47 shelly subsamples were taken from 17 discrete layers identified on the west coast of Bohai Bay. This material was AMS 14C dated and the calibrated ages were systematically compared. The subsamples were categorized by type as articulated and disarticulated bivalves, gastropod shells, and undifferentiated shell-hash. It was found that within most individual layers the calibrated ages of the subsamples got younger relative to the amount of apparent post-mortem re-working the material had been subject to. For examples, the 14C ages of the bivalve samples trended younger in this order: shell-hash → split shells → articulated shells. We propose that the younger subsample age determined within an individual layer will be the closest to the actual depositional age of the material dated. Using this approach at four Holocene sites we find residence times which range from 100 to 1260 cal yrs, with two average values of 600 cal yrs for the original 14C dates older than 1 ka cal BP and 100 cal yrs for the original 14C dates younger than 1 ka cal BP, respectively. Using this semi-empirical estimation of the shell residence times we have refined the existing chronology of the Holocene chenier ridges on the west coast of Bohai Bay.

Energy in elastic fiber embedded in elastic matrix containing incident SH wave

Science.gov (United States)

Williams, James H., Jr.; Nagem, Raymond J.

1989-01-01

A single elastic fiber embedded in an infinite elastic matrix is considered. An incident plane SH wave is assumed in the infinite matrix, and an expression is derived for the total energy in the fiber due to the incident SH wave. A nondimensional form of the fiber energy is plotted as a function of the nondimensional wavenumber of the SH wave. It is shown that the fiber energy attains maximum values at specific values of the wavenumber of the incident wave. The results obtained here are interpreted in the context of phenomena observed in acousto-ultrasonic experiments on fiber reinforced composite materials.

Zero-point energies in the two-center shell model. II

International Nuclear Information System (INIS)

Reinhard, P.-G.

1978-01-01

The zero-point energy (ZPE) contained in the potential-energy surface of a two-center shell model (TCSM) is evaluated. In extension of previous work, the author uses here the full TCSM with l.s force, smoothing and asymmetry. The results show a critical dependence on the height of the potential barrier between the centers. The ZPE turns out to be non-negligible along the fission path for 236 U, and even more so for lighter systems. It is negligible for surface quadrupole motion and it is just on the fringe of being negligible for motion along the asymmetry coordinate. (Auth.)

Rayleigh SAW-Assisted SH-SAW Immunosensor on X-Cut 148-Y LiTaO3.

Science.gov (United States)

Kogai, Takashi; Yatsuda, Hiromi; Kondoh, Jun

2017-09-01

In this paper, we describe a shear horizontal surface acoustic wave (SH-SAW) immunosensor that utilizes induce agitation by a Rayleigh SAW (R-SAW) on an X-cut 148-Y LiTaO 3 substrate. On this substrate, SH-SAWs and R-SAWs with different frequencies can be effectively generated at an interdigital transducer (IDT). First, to consider the power flow angles of SH-SAWs and R-SAWs on this substrate, the 360-MHz delay lines with six different tilt angles were designed and fabricated. From the experiments, an optimal power flow angle of 9° for the SH-SAW on this substrate is obtained. Second, in order to consider the immunoreactions of the SH-SAW immunosensors, a delay line with a tilt angle of 9° was designed and fabricated on this substrate. The delay line, which can generate two SAWs, namely, a 100-MHz SH-SAW and an 88.8-MHz R-SAW, has a propagation area covered with antigens of human serum albumin between transmitting and receiving IDTs. The immunoreactions caused by antigen-antibody binding events on the surface of the delay line were investigated on the basis of the velocity changes of the SH-SAWs for sensing with and without the assistance of an R-SAW. As a result, it was confirmed that the SH-SAW velocity changes due to antigen-antibody reactions can be markedly increased by the assistance of R-SAW agitation.

Structural Characterization of Monomeric/Dimeric State of p59fyn SH2 Domain.

Science.gov (United States)

Huculeci, Radu; Kieken, Fabien; Garcia-Pino, Abel; Buts, Lieven; van Nuland, Nico; Lenaerts, Tom

2017-01-01

Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59 fyn SH2 domain.

Tyrosine phosphorylation of the Lyn Src homology 2 (SH2) domain modulates its binding affinity and specificity.

Science.gov (United States)

Jin, Lily L; Wybenga-Groot, Leanne E; Tong, Jiefei; Taylor, Paul; Minden, Mark D; Trudel, Suzanne; McGlade, C Jane; Moran, Michael F

2015-03-01

Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y(194) impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y(194) on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

On the uncertainties in the shell correction by Strutinsky smearing procedure for certain shapes relevant in fission

International Nuclear Information System (INIS)

Ramamurthy, V.S.; Prakash, M.; Kapoor, S.

1976-01-01

It is found that for level schemes obtained from a folded Yukawa potential, the Strutinsky smearing procedure for the evaluation of the shell correction to the total potential energy of nuclei does not lead to a unique value for nuclear shapes near and beyond the outer fission barrier deformations and consequently introduces uncertainties in the relative fission barrier heights. (author)

Rapid determination of parabens in seafood sauces by high-performance liquid chromatography: A practical comparison of core-shell particles and sub-2 μm fully porous particles.

Science.gov (United States)

Ye, Jing; Cao, Xiaoji; Cheng, Zhuo; Qin, Ye; Lu, Yanbin

2015-12-01

In this work, the chromatographic performance of superficially porous particles (Halo core-shell C18 column, 50 mm × 2.1 mm, 2.7 μm) was compared with that of sub-2 μm fully porous particles (Acquity BEH C18 , 50 mm × 2.1 mm, 1.7 μm). Four parabens, methylparaben, ethylparaben, propylparaben, and butylparaben, were used as representative compounds for calculating the plate heights in a wide flow rate range and analyzed on the basis of the Van Deemter and Knox equations. Theoretical Poppe plots were constructed for each column to compare their kinetic performance. Both phases gave similar minimum plate heights when using nonreduced coordinates. Meanwhile, the flat C-term of the core-shell column provided the possibilities for applying high flow rates without significant loss in efficiency. The low backpressure of core-shell particles allowed this kind of column, especially compatible with conventional high-performance liquid chromatography systems. Based on these factors, a simple high-performance liquid chromatography method was established and validated for the determination of parabens in various seafood sauces using the Halo core-shell C18 column for separation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Time-resolved multimodal analysis of Src Homology 2 (SH2) domain binding in signaling by receptor tyrosine kinases.

Science.gov (United States)

Jadwin, Joshua A; Oh, Dongmyung; Curran, Timothy G; Ogiue-Ikeda, Mari; Jia, Lin; White, Forest M; Machida, Kazuya; Yu, Ji; Mayer, Bruce J

2016-04-12

While the affinities and specificities of SH2 domain-phosphotyrosine interactions have been well characterized, spatio-temporal changes in phosphosite availability in response to signals, and their impact on recruitment of SH2-containing proteins in vivo, are not well understood. To address this issue, we used three complementary experimental approaches to monitor phosphorylation and SH2 binding in human A431 cells stimulated with epidermal growth factor (EGF): 1) phospho-specific mass spectrometry; 2) far-Western blotting; and 3) live cell single-molecule imaging of SH2 membrane recruitment. Far-Western and MS analyses identified both well-established and previously undocumented EGF-dependent tyrosine phosphorylation and binding events, as well as dynamic changes in binding patterns over time. In comparing SH2 binding site phosphorylation with SH2 domain membrane recruitment in living cells, we found in vivo binding to be much slower. Delayed SH2 domain recruitment correlated with clustering of SH2 domain binding sites on the membrane, consistent with membrane retention via SH2 rebinding.

Detection and characterization of partially unfolded oligomers of the SH3 domain of α-Spectrin

NARCIS (Netherlands)

Casares, S.; Sadqi, M.; López-Mayorga, O.; Conejero-Lara, F.; van Nuland, N.A.J.

2004-01-01

For the purpose of equilibrium and kinetic folding-unfolding studies, the SH3 domain of α-spectrin (spc-SH3) has long been considered a classic two-state folding protein. In this work we have indeed observed that the thermal unfolding curves of spc-SH3 measured at pH 3.0 by differential scanning

Association between receptor protein-tyrosine phosphatase RPTPalpha and the Grb2 adaptor. Dual Src homology (SH) 2/SH3 domain requirement and functional consequences

DEFF Research Database (Denmark)

Su, J; Yang, L T; Sap, J

1996-01-01

domain in Grb2 (, ). We show here that association of Grb2 with RPTPalpha also involves a critical function for the C-terminal SH3 domain of Grb2. Furthermore, Grb2 SH3 binding peptides interfere with RPTPalpha-Grb2 association in vitro, and the RPTPalpha protein can dissociate the Grb2-Sos complex...... in vivo. These observations constitute a novel mode of Grb2 association and suggest a model in which association with a tyrosine-phosphorylated protein restricts the repertoire of SH3 binding proteins with which Grb2 can simultaneously interact. The function of the Tyr798 tyrosine phosphorylation/Grb2...... binding site in RPTPalpha was studied further by expression of wild type or mutant RPTPalpha proteins in PC12 cells. In these cells, wild type RPTPalpha interferes with acidic fibroblast growth factor-induced neurite outgrowth; this effect requires both the catalytic activity and the Grb2 binding Tyr798...

New function of the adaptor protein SH2B1 in brain-derived neurotrophic factor-induced neurite outgrowth.

Directory of Open Access Journals (Sweden)

Chien-Hung Shih

Full Text Available Neurite outgrowth is an essential process for the establishment of the nervous system. Brain-derived neurotrophic factor (BDNF binds to its receptor TrkB and regulates axonal and dendritic morphology of neurons through signal transduction and gene expression. SH2B1 is a signaling adaptor protein that regulates cellular signaling in various physiological processes. The purpose of this study is to investigate the role of SH2B1 in the development of the central nervous system. In this study, we show that knocking down SH2B1 reduces neurite formation of cortical neurons whereas overexpression of SH2B1β promotes the development of hippocampal neurons. We further demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth and signaling using the established PC12 cells stably expressing TrkB, SH2B1β or SH2B1β mutants. Our data indicate that overexpressing SH2B1β enhances BDNF-induced MEK-ERK1/2, and PI3K-AKT signaling pathways. Inhibition of MEK-ERK1/2 and PI3K-AKT pathways by specific inhibitors suggest that these two pathways are required for SH2B1β-promoted BDNF-induced neurite outgrowth. Moreover, SH2B1β enhances BDNF-stimulated phosphorylation of signal transducer and activator of transcription 3 at serine 727. Finally, our data indicate that the SH2 domain and tyrosine phosphorylation of SH2B1β contribute to BDNF-induced signaling pathways and neurite outgrowth. Taken together, these findings demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth through enhancing pathways involved MEK-ERK1/2 and PI3K-AKT.

The T-cell-specific adapter protein family: TSAd, ALX, and SH2D4A/SH2D4B.

Science.gov (United States)

Lapinski, Philip E; Oliver, Jennifer A; Bodie, Jennifer N; Marti, Francesc; King, Philip D

2009-11-01

Adapter proteins play key roles in intracellular signal transduction through complex formation with catalytically active signaling molecules. In T lymphocytes, the role of several different types of adapter proteins in T-cell antigen receptor signal transduction is well established. An exception to this is the family of T-cell-specific adapter (TSAd) proteins comprising of TSAd, adapter protein of unknown function (ALX), SH2D4A, and SH2D4B. Only recently has the function of these adapters in T-cell signal transduction been explored. Here, we discuss advances in our understanding of the role of this family of adapter proteins in T cells. Their function as regulators of signal transduction in other cell types is also discussed.

Therapeutic effects of lentivirus-mediated shRNA targeting of cyclin D1 in human gastric cancer

International Nuclear Information System (INIS)

Seo, Jin-Hee; Jeong, Eui-Suk; Choi, Yang-Kyu

2014-01-01

Gastric cancer is the second most common cause of cancer-related death in males and the fourth in females. Traditional treatment has poor prognosis because of recurrence and systemic side effects. Therefore, the development of new therapeutic strategies is an important issue. Lentivirus-mediated shRNA stably inhibits target genes and can efficiently transduce most cells. Since overexpressed cyclin D1 is closely related to human gastric cancer progression, inhibition of cyclin D1 using specific targeting could be an effective treatment method of human gastric cancer. The therapeutic effect of lentivirus-mediated shRNA targeting of cyclin D1 (ShCCND1) was analyzed both in vitro and in vivo experiments. In vitro, NCI-N87 cells with downregulation of cyclin D1 by ShCCND1 showed significant inhibition of cell proliferation, cell motility, and clonogenicity. Downregulation of cyclin D1 in NCI-N87 cells also resulted in significantly increased G1 arrest and apoptosis. In vivo, stable NCI-N87 cells expressing ShCCND1 were engrafted into nude mice. Then, the cancer-growth inhibition effect of lentivirus was confirmed. To assess lentivirus including ShCCND1 as a therapeutic agent, intratumoral injection was conducted. Tumor growth of the lentivirus-treated group was significantly inhibited compared to growth of the control group. These results are in accordance with the in vitro data and lend support to the mitotic figure count and apoptosis analysis of the tumor mass. The lentivirus-mediated ShCCND1 was constructed, which effectively inhibited growth of NCI-N87-derived cancer both in vitro and in vivo. The efficiency of shRNA knockdown and variation in the degree of inhibition is mediated by different shRNA sequences and cancer cell lines. These experimental results suggest the possibility of developing new gastric cancer therapies using lentivirus-mediated shRNA

Dossier Shell Eco-Marathon; Dossier Shell Eco-Marathon

Energy Technology Data Exchange (ETDEWEB)

Matla, P.

2012-05-15

Three articles address subjects concerning the annual race with highly energy efficient cars: the Shell Eco-Marathon. [Dutch] In 3 artikelen wordt aandacht besteed aan de ontwerpen voor de jaarlijkse race met superzuinige auto's, de Shell Eco-Marathon.

Dominant thermogravimetric signatures of lignin in cashew shell as compared to cashew shell cake.

Science.gov (United States)

Gangil, Sandip

2014-03-01

Dominant thermogravimetric signatures related to lignin were observed in cashew shell as compared to these signatures in cashew shell cake. The phenomenon of weakening of lignin from cashew shell to cashew shell cake was explained on the basis of changes in the activation energies. The pertinent temperature regimes responsible for the release of different constituents of both the bio-materials were identified and compared. The activation energies of cashew shell and cashew shell cake were compared using Kissinger-Akahira-Sunose method. Thermogravimetric profiling of cashew shell and cashew shell cake indicated that these were different kinds of bio-materials. Copyright © 2013 Elsevier Ltd. All rights reserved.

Combining biophysical methods to analyze the disulfide bond in SH2 domain of C-terminal Src kinase.

Science.gov (United States)

Liu, Dongsheng; Cowburn, David

2016-01-01

The Src Homology 2 (SH2) domain is a structurally conserved protein domain that typically binds to a phosphorylated tyrosine in a peptide motif from the target protein. The SH2 domain of C-terminal Src kinase (Csk) contains a single disulfide bond, which is unusual for most SH2 domains. Although the global motion of SH2 domain regulates Csk function, little is known about the relationship between the disulfide bond and binding of the ligand. In this study, we combined X-ray crystallography, solution NMR, and other biophysical methods to reveal the interaction network in Csk. Denaturation studies have shown that disulfide bond contributes significantly to the stability of SH2 domain, and crystal structures of the oxidized and C122S mutant showed minor conformational changes. We further investigated the binding of SH2 domain to a phosphorylated peptide from Csk-binding protein upon reduction and oxidation using both NMR and fluorescence approaches. This work employed NMR, X-ray cryptography, and other biophysical methods to study a disulfide bond in Csk SH2 domain. In addition, this work provides in-depth understanding of the structural dynamics of Csk SH2 domain.

Purification of SOCS (Suppressor of Cytokine Signaling) SH2 Domains for Structural and Functional Studies.

Science.gov (United States)

Liau, Nicholas P D; Laktyushin, Artem; Babon, Jeffrey J

2017-01-01

Src Homology 2 (SH2) domains are protein domains which have a high binding affinity for specific amino acid sequences containing a phosphorylated tyrosine residue. The Suppressors of Cytokine Signaling (SOCS) proteins use an SH2 domain to bind to components of certain cytokine signaling pathways to downregulate the signaling cascade. The recombinantly produced SH2 domains of various SOCS proteins have been used to undertake structural and functional studies elucidating the method of how such targeting occurs. Here, we describe the protocol for the recombinant production and purification of SOCS SH2 domains, with an emphasis on SOCS3.

Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism.

Science.gov (United States)

Zhang, Xuxiao; Vadas, Oscar; Perisic, Olga; Anderson, Karen E; Clark, Jonathan; Hawkins, Phillip T; Stephens, Len R; Williams, Roger L

2011-03-04

Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110β/p85β complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit. Mutagenesis of a cSH2 contact residue activates downstream signaling in cells. This inhibitory contact ties up the C-terminal region of the p110β catalytic subunit, which is essential for lipid kinase activity. In vitro, p110β basal activity is tightly restrained by contacts with three p85 domains: the cSH2, nSH2, and iSH2. RTK phosphopeptides relieve inhibition by nSH2 and cSH2 using completely different mechanisms. The binding site for the RTK's pYXXM motif is exposed on the cSH2, requiring an extended RTK motif to reach and disrupt the inhibitory contact with p110β. This contrasts with the nSH2 where the pY-binding site itself forms the inhibitory contact. This establishes an unusual mechanism by which p85 SH2 domains contribute to RTK signaling specificities. Copyright © 2011 Elsevier Inc. All rights reserved.

Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation.

Directory of Open Access Journals (Sweden)

Sulyman Barkho

Full Text Available The Src family of tyrosine kinases (SFKs regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk. Although Csk and SFKs share conserved kinase, SH2 and SH3 domains, they differ considerably in three-dimensional structure, regulatory mechanism, and the intrinsic kinase activities. Although the SH2 and SH3 domains are known to up- or down-regulate tyrosine kinase function, little is known about the global motions in the full-length kinase that govern these catalytic variations. We use a combination of accelerated Molecular Dynamics (aMD simulations and experimental methods to provide a new view of functional motions in the Csk scaffold. These computational studies suggest that high frequency vibrations in the SH2 domain are coupled through the N-terminal lobe of the kinase domain to motions in the SH3 domain. The effects of these reflexive movements on the kinase domain can be viewed using both Deuterium Exchange Mass Spectrometry (DXMS and steady-state kinetic methods. Removal of several contacts, including a crystallographically unobserved N-terminal segment, between the SH3 and kinase domains short-circuit these coupled motions leading to reduced catalytic efficiency and stability of N-lobe motifs within the kinase domain. The data expands the model of Csk's activation whereby separate domains productively interact with two diametrically opposed surfaces of the kinase domain. Such reversible transitions may organize the active structure of the tyrosine kinase domain of Csk.

Giant-Planet Chemistry: Ammonium Hydrosulfide (NH4SH), Its IR Spectra and Thermal and Radiolytic Stabilities

Science.gov (United States)

Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

2015-01-01

Here we present our recent studies of proton-irradiated and unirradiated ammonium hydrosulfide, NH4SH, a compound predicted to be an important tropospheric cloud component of Jupiter and other giant planets. We irradiated both crystalline and amorphous NH4SH at 10-160 K and used IR spectroscopy to observe and identify reaction products in the ice, specifically NH3 and long-chained sulfur-containing ions. Crystalline NH4SH was amorphized during irradiation at all temperatures studied with the rate being the fastest at the lowest temperatures. Irradiation of amorphous NH4SH at approximately 10-75 K showed that 60-80% of the NH4 + remained when equilibrium was reached, and that NH4SH destruction rates were relatively constant within this temperature range. Irradiations at higher temperatures produced different dose dependence and were accompanied by pressure outbursts that, in some cases, fractured the ice. The thermal stability of irradiated NH4SH was found to be greater than that of unirradiated NH4SH, suggesting that an irradiated giant-planet cloud precipitate can exist at temperatures and altitudes not previously considered.

Polarization effects on spectra of spherical core/shell nanostructures: Perturbation theory against finite difference approach

International Nuclear Information System (INIS)

Ibral, Asmaa; Zouitine, Asmaa; Assaid, El Mahdi

2015-01-01

Poisson equation is solved analytically in the case of a point charge placed anywhere in a spherical core/shell nanostructure, immersed in aqueous or organic solution or embedded in semiconducting or insulating matrix. Conduction and valence band-edge alignments between core and shell are described by finite height barriers. Influence of polarization charges induced at the surfaces where two adjacent materials meet is taken into account. Original expressions of electrostatic potential created everywhere in the space by a source point charge are derived. Expressions of self-polarization potential describing the interaction of a point charge with its own image–charge are deduced. Contributions of double dielectric constant mismatch to electron and hole ground state energies as well as nanostructure effective gap are calculated via first order perturbation theory and also by finite difference approach. Dependencies of electron, hole and gap energies against core to shell radii ratio are determined in the case of ZnS/CdSe core/shell nanostructure immersed in water or in toluene. It appears that finite difference approach is more efficient than first order perturbation method and that the effect of polarization charge may in no case be neglected as its contribution can reach a significant proportion of the value of nanostructure gap

Polarization effects on spectra of spherical core/shell nanostructures: Perturbation theory against finite difference approach

Energy Technology Data Exchange (ETDEWEB)

Ibral, Asmaa [Equipe d' Optique et Electronique du Solide, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B. P. 20 El Jadida principale, El Jadida, Royaume du Maroc (Morocco); Laboratoire d' Instrumentation, Mesure et Contrôle, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B. P. 20 El Jadida principale, El Jadida, Royaume du Maroc (Morocco); Zouitine, Asmaa [Département de Physique, Ecole Nationale Supérieure d' Enseignement Technique, Université Mohammed V Souissi, B. P. 6207 Rabat-Instituts, Rabat, Royaume du Maroc (Morocco); Assaid, El Mahdi, E-mail: eassaid@yahoo.fr [Equipe d' Optique et Electronique du Solide, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B. P. 20 El Jadida principale, El Jadida, Royaume du Maroc (Morocco); Laboratoire d' Instrumentation, Mesure et Contrôle, Département de Physique, Faculté des Sciences, Université Chouaïb Doukkali, B. P. 20 El Jadida principale, El Jadida, Royaume du Maroc (Morocco); and others

2015-02-01

Poisson equation is solved analytically in the case of a point charge placed anywhere in a spherical core/shell nanostructure, immersed in aqueous or organic solution or embedded in semiconducting or insulating matrix. Conduction and valence band-edge alignments between core and shell are described by finite height barriers. Influence of polarization charges induced at the surfaces where two adjacent materials meet is taken into account. Original expressions of electrostatic potential created everywhere in the space by a source point charge are derived. Expressions of self-polarization potential describing the interaction of a point charge with its own image–charge are deduced. Contributions of double dielectric constant mismatch to electron and hole ground state energies as well as nanostructure effective gap are calculated via first order perturbation theory and also by finite difference approach. Dependencies of electron, hole and gap energies against core to shell radii ratio are determined in the case of ZnS/CdSe core/shell nanostructure immersed in water or in toluene. It appears that finite difference approach is more efficient than first order perturbation method and that the effect of polarization charge may in no case be neglected as its contribution can reach a significant proportion of the value of nanostructure gap.

Agreement between measured height, and height predicted from ...

African Journals Online (AJOL)

lower limb measurements, such as knee height, as well as upper limb measures ... had with bone injuries/fractures affecting height or ulna length; and n = 1 had a ... and heels, buttocks and upper back in contact with the vertical surface of the .... found striking similarity in linear growth of infants to five-year- olds among all ...

Accuracy of recumbent height measurement.

Science.gov (United States)

Gray, D S; Crider, J B; Kelley, C; Dickinson, L C

1985-01-01

Since many patients requiring specialized nutritional support are bedridden, measurement of height for purposes of nutritional assessment or prescription must often be done with the patient in bed. This study examined the accuracy of measuring body height in bed in the supine position. Two measurements were performed on 108 ambulatory inpatients: (1) standing height using a standard height-weight scale, and (2) bed height using a flexible tape. Patients were divided into four groups based on which of two researchers performed each of the two measurements. Each patient was also weighed and self-reported height, weight, sex, and age were recorded. Bed height was significantly longer than standing height by 3.68 cm, but the two measurements were equally precise. It was believed, however, that this 2% difference was probably not clinically significant in most circumstances. Bed height correlated highly with standing height (r = 0.95), and the regression equation was standing height = 13.82 +/- 0.09 bed height. Patients overestimated their heights. Heights recorded by nurses were more accurate when patients were measured than when asked about their heights, but the patients were more often asked than measured.

Abl N-terminal Cap stabilization of SH3 domain dynamics†

OpenAIRE

Chen, Shugui; Dumitrescu, Teodora Pene; Smithgall, Thomas E.; Engen, John R.

2008-01-01

Crystal structures and other biochemical data indicate that the N-terminal cap (NCap) region of the Abelson tyrosine kinase (c-Abl) is important for maintaining the downregulated conformation of the kinase domain. The exact contributions that NCap makes in stabilizing the various intramolecular interactions within c-Abl are less clear. While the NCap appears important for locking the SH3/SH2 domains to the back of the kinase domain, there may be other more subtle elements of regulation. Hydro...

Shell-like structures

CERN Document Server

Altenbach, Holm

2011-01-01

In this volume, scientists and researchers from industry discuss the new trends in simulation and computing shell-like structures. The focus is put on the following problems: new theories (based on two-dimensional field equations but describing non-classical effects), new constitutive equations (for materials like sandwiches, foams, etc. and which can be combined with the two-dimensional shell equations), complex structures (folded, branching and/or self intersecting shell structures, etc.) and shell-like structures on different scales (for example: nano-tubes) or very thin structures (similar

Interactions of polyomavirus middle T with the SH2 domains of the pp85 subunit of phosphatidylinositol-3-kinase.

Science.gov (United States)

Yoakim, M; Hou, W; Liu, Y; Carpenter, C L; Kapeller, R; Schaffhausen, B S

1992-01-01

The binding of phosphatidylinositol-3-kinase to the polyomavirus middle T antigen is facilitated by tyrosine phosphorylation of middle T on residue 315. The pp85 subunit of phosphatidylinositol-3-kinase contains two SH2 domains, one in the middle of the molecule and one at the C terminus. When assayed by blotting with phosphorylated middle T, the more N-terminal SH2 domain is responsible for binding to middle T. When assayed in solution with glutathione S transferase fusions, both SH2s are capable of binding phosphorylated middle T. While both SH2 fusions can compete with intact pp85 for binding to middle T, the C-terminal SH2 is the more efficient of the two. Interaction between pp85 or its SH2 domains and middle T can be blocked by a synthetic peptide comprising the tyrosine phosphorylation sequence around middle T residue 315. Despite the fact that middle T can interact with both SH2s, these domains are not equivalent. Only the C-terminal SH2-middle T interaction was blocked by anti-SH2 antibody; the two SH2 fusions also interact with different cellular proteins. Images PMID:1380095

Envisioning the Shôjo Aesthetic in Illustrations of Miyazawa Kenji’s Literature.

Directory of Open Access Journals (Sweden)

Helen Claire Kilpatrick

2013-01-01

Full Text Available Despite an ever-growing body of scholarship on the shôjo (girl in manga and anime, little has been written about representations of the ‘girl’ in Japanese picture books. Shôjo literature and culture have grown exponentially in Japan since about the 1980s, but there has been a tendency in popular media to overemphasise the 'cute', disempowering aspects of the ‘girl’. By using Takahara Eiri's (1999 concept of “girl consciousness” and Honda Masuko's (1992 envisioning of the girl’s imagined freedom through a hirahira (fluttering aesthetic, notions of the powerless or mindlessly consuming shôjo can be dispelled. Such concepts help demonstrate that the girl ‘has her own creative, critical and cultural, if not social or political, power’ (Aoyama 2008: 286. This paper examines the shôjo tropes in contemporary illustrations that were produced to accompany two tales by the renowned author Miyazawa Kenji (1896-1933, Futago no Hoshi (Twin Stars and Ginga Tetsudô no Yoru (Night of the Milky Way Railway. Although Kenji (as he is known is not generally considered a shôjo author, some of his works incorporate gently transgressive shôjo themes reminiscent of, for example, Yoshiya Nobuko’s Hana Monogatari (Flower Tales from the 1920s. I argue that the current artwork of two award-winning artists, Makino Suzuko and Azuma Itsuko, reflects and enhances Kenji’s ‘girlish’ verbal images, bringing them to the fore in their accompanying imagery for Futago and Ginga by drawing on shôjo art, manga and literature. The artists thus bring into play intertextual references that occur not only across different historical temporalities but also through relations between the author, the artist, the text(s, the protagonists and the reading/viewing audience. The analysis of their striking artwork shows how they bring Kenji’s 1920s’ works firmly into the arena of the contemporary ‘girl’, expanding the abstract consciousness of the shôjo to

Extensions to a nonlinear finite-element axisymmetric shell model based on Reissner's shell theory

International Nuclear Information System (INIS)

Cook, W.A.

1981-01-01

Extensions to shell analysis not usually associated with shell theory are described in this paper. These extensions involve thick shells, nonlinear materials, a linear normal stress approximation, and a changing shell thickness. A finite element shell-of-revolution model has been developed to analyze nuclear material shipping containers under severe impact conditions. To establish the limits for this shell model, the basic assumptions used in its development were studied; these are listed in this paper. Several extensions were evident from the study of these limits: a thick shell, a plastic hinge, and a linear normal stress

General theory for thermal pulses of finite amplitude in nuclear shell-burnings

Energy Technology Data Exchange (ETDEWEB)

Sugimoto, D [Tokyo Univ. (Japan). Coll. of General Education; Fujimoto, M Y

1978-09-01

Theory for thermal pulses of nuclear shell-burning is advanced to include the case of finite amplitude. The aims are to predict the progress of thermal pulse quantitatively and to obtain the peak values of the temperature and nuclear energy generation rate without making detailed numerical computation of stellar structure. In order to attain them the physical processes involved in the progress of the pulse are clarified using the concepts of the flatness of the shell source, which destabilizes nuclear burning, and the effect of radiation pressure, which stabilizes it. It is shown that the progress of the pulse can be predicted quantitatively when the pressure and the gravitational potential of the burning shell are specified for the onset stage of the pulse. The pulse height is determined mainly by the initial pressure; the higher initial pressure results in the higher pulse. Mass dependence is also obtained by approximating the gravitational potential by that of white dwarfs. The initial pressure is the quantity which is determined in the course of evolution preceding the pulse. The theory is shown to give a satisfactory agreement with numerical computations for a wide variety of the preceding evolutions, i.e., both for the case of the core in red giant stars and of the accreting white dwarfs.

Large Steel Tank Fails and Rockets to Height of 30 meters − Rupture Disc Installed Incorrectly

OpenAIRE

Hedlund, Frank H.; Selig, Robert S.; Kragh, Eva K.

2016-01-01

At a brewery, the base plate-to-shell weld seam of a 90-m3 vertical cylindrical steel tank failed catastrophically. The 4 ton tank “took off” like a rocket leaving its contents behind, and landed on a van, crushing it. The top of the tank reached a height of 30 m. The internal overpressure responsible for the failure was an estimated 60 kPa. A rupture disc rated at <50 kPa provided overpressure protection and thus prevented the tank from being covered by the European Pressure Equipment Dir...

Use of the shrunken-2 (sh2) mutant to study source-sink relations in maize during reproductive development

International Nuclear Information System (INIS)

Ritchie, S.W.

1987-01-01

Leaf metabolism, 14 C-assimilate distribution, and kernel (sink) metabolism were compared in a normal wild-type (homozygous sh2) inbred (Oh43) of maize (Zea mays L.) and a genetically related shrunken-2 (homozygous sh2) inbred of Oh43. In comparison to normal starchy kernels, kernels from the shrunken-2 (sh2) mutant showed highly decreased starch contents and subsequently decreased total kernel dry matter. As measured by dry matter accumulation and 14 C-assimilate distribution patterns, sh2 kernel assimilate demand did not differ from normal kernel assimilate demand throughout most of the early linear grain-fill period. However, sh2 kernel demand began to decrease toward the end of early grain-fill and was highly decreased during all of the middle grain-fill period. During the late grain-fill period, sh2 kernel assimilate demand was non-existent. The initial evidence for decreased sh2 kernel assimilate demand was a change in 14 C label distribution in the sh2 ear tissues (husks, shank, cob, and kernels) toward the end of early grain-fill

Novel high-throughput screening system for identifying STAT3-SH2 antagonists

International Nuclear Information System (INIS)

Uehara, Yutaka; Mochizuki, Masato; Matsuno, Kenji; Haino, Takeharu; Asai, Akira

2009-01-01

Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr-SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr-SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3-SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was observed. Thus, the HTS assay system represented herein may be useful for identifying novel STAT3-SH2 antagonists.

Adsorption of Pb2+ on Thiol-functionalized Mesoporous Silica, SH-MCM-48

Science.gov (United States)

Taba, P.; Mustafa, R. D. P.; Ramang, L. M.; Kasim, A. H.

2018-03-01

Modification of mesoporous silica, MCM-48, by using 3- mercaptopropyltrimethoxysilane has been successfully conducted. MCM-48 and SH-MCM-48 were characterized using XRD and FTIR. SH-MCM-48 was used as an adsorbent of Pb2+ ions from solution. A number of Pb2+ ions adsorbed were studied as the function of time, pH, and concentration. The concentration of the ions after adsorption was determined by an Atomic Absorption Spectrophotometer. The removal of the adsorbed ions from the SH-MCM-48 was also studied using several desorbing agents. The result showed that the optimum time was 20 minutes and optimum pH was 4. The adsorption of Pb(II) ion followed the pseudo-second-order with the rate constant of 0,2632 g•mg-1•min-1. Adsorption of Pb(II) ion fitted the Langmuir isotherm with the adsorption capacity of 0,1088 mmol/g. The best desorbing agent to remove the adsorbed ion from SH-MCM-48 was 0.3 M HCl solution with the desorption percentage of 58.6%.

The Coast Guard Proceedings of the Marine Safety and Security Council. Waterways. Summer 2016

Science.gov (United States)

2016-01-01

Number of Establishments Employment 2012 Revenues ($1,000) Aquaculture 3,093 5,798 1,371,707 Finsh farming and sh hatcheries #N/A #N/A #N/A Shell sh...farming #N/A #N/A #N/A Other aquaculture #N/A #N/A #N/A Fishing 2,259 5,990 5,118,939 Finsh shing 1,288 3,669 #N/A Shell sh shing 925 2,200 #N/A...described above, whereas renewable diesel is produced via hydrotreating or biomass -to-liquid conversion pro- cesses, the results being a fuel that is

Final height in survivors of childhood cancer compared with Height Standard Deviation Scores at diagnosis.

Science.gov (United States)

Knijnenburg, S L; Raemaekers, S; van den Berg, H; van Dijk, I W E M; Lieverst, J A; van der Pal, H J; Jaspers, M W M; Caron, H N; Kremer, L C; van Santen, H M

2013-04-01

Our study aimed to evaluate final height in a cohort of Dutch childhood cancer survivors (CCS) and assess possible determinants of final height, including height at diagnosis. We calculated standard deviation scores (SDS) for height at initial cancer diagnosis and height in adulthood in a cohort of 573 CCS. Multivariable regression analyses were carried out to estimate the influence of different determinants on height SDS at follow-up. Overall, survivors had a normal height SDS at cancer diagnosis. However, at follow-up in adulthood, 8.9% had a height ≤-2 SDS. Height SDS at diagnosis was an important determinant for adult height SDS. Children treated with (higher doses of) radiotherapy showed significantly reduced final height SDS. Survivors treated with total body irradiation (TBI) and craniospinal radiation had the greatest loss in height (-1.56 and -1.37 SDS, respectively). Younger age at diagnosis contributed negatively to final height. Height at diagnosis was an important determinant for height SDS at follow-up. Survivors treated with TBI, cranial and craniospinal irradiation should be monitored periodically for adequate linear growth, to enable treatment on time if necessary. For correct interpretation of treatment-related late effects studies in CCS, pre-treatment data should always be included.

Binding Assays Using Recombinant SH2 Domains: Far-Western, Pull-Down, and Fluorescence Polarization.

Science.gov (United States)

Machida, Kazuya; Liu, Bernard

2017-01-01

Recognition of phosphotyrosine-containing sequences by SH2 domains confers specificity in tyrosine kinase pathways. By assessing interactions between isolated SH2 domains and their binding proteins, it is possible to gain insight into otherwise inaccessible complex cellular systems. Far-Western, pull-down, and fluorescence polarization (FP) have been frequently used for characterization of phosphotyrosine signaling. Here, we outline standard protocols for these established assays using recombinant SH2 domain, emphasizing the importance of appropriate sample preparation and assay controls.

Structure of the SH3 domain of human osteoclast-stimulating factor at atomic resolution

International Nuclear Information System (INIS)

Chen, Liqing; Wang, Yujun; Wells, David; Toh, Diana; Harold, Hunt; Zhou, Jing; DiGiammarino, Enrico; Meehan, Edward J.

2006-01-01

The crystal structure of the SH3 domain of human osteoclast-stimulating factor has been determined and refined to the ultrahigh resolution of 1.07 Å. The structure at atomic resolution provides an accurate framework for structure-based design of its inhibitors. Osteoclast-stimulating factor (OSF) is an intracellular signaling protein, produced by osteoclasts themselves, that enhances osteoclast formation and bone resorption. It is thought to act via an Src-related signaling pathway and contains SH3 and ankyrin-repeat domains which are involved in protein–protein interactions. As part of a structure-based anti-bone-loss drug-design program, the atomic resolution X-ray structure of the recombinant human OSF SH3 domain (hOSF-SH3) has been determined. The domain, residues 12–72, yielded crystals that diffracted to the ultrahigh resolution of 1.07 Å. The overall structure shows a characteristic SH3 fold consisting of two perpendicular β-sheets that form a β-barrel. Structure-based sequence alignment reveals that the putative proline-rich peptide-binding site of hOSF-SH3 consists of (i) residues that are highly conserved in the SH3-domain family, including residues Tyr21, Phe23, Trp49, Pro62, Asn64 and Tyr65, and (ii) residues that are less conserved and/or even specific to hOSF, including Thr22, Arg26, Thr27, Glu30, Asp46, Thr47, Asn48 and Leu60, which might be key to designing specific inhibitors for hOSF to fight osteoporosis and related bone-loss diseases. There are a total of 13 well defined water molecules forming hydrogen bonds with the above residues in and around the peptide-binding pocket. Some of those water molecules might be important for drug-design approaches. The hOSF-SH3 structure at atomic resolution provides an accurate framework for structure-based design of its inhibitors

SH1 leaf rust and bacterial halo blight coffee resistances are genetically independent

Directory of Open Access Journals (Sweden)

Lucas Mateus Rivero Rodrigues

Full Text Available ABSTRACT Coffee resistance to Pseudomonas syringae pv. garcae has been associated to pleiotropic effect of SH1 allele, present in coffee plants resistant to certain races of Hemileia vastatrix, the causal agent of leaf rust, or genetic linkage between resistance alleles to both pathogens. To validate this hypothesis, 63 coffee plants in F2 generation were evaluated for resistance to 2 isolates of H. vastatrix carriers of alleles, respectively, v2, v5 (isolate I/2015 and v1; v2; v5 (isolate II/2015 with the objective to confirm presence of SH1 allele in resistant plants to isolate I/2015. The same coffee plants were evaluated for resistance to a mixture of P. syringae pv. garcae strains highly pathogenic to coffee. Results showed that, among F2 coffee allele SH1 carriers, resistant to isolate I/2015, resistant and susceptible plants to bacterial halo blight were found; the same segregation occurs between F2 homozygous for SH1 allele, susceptible to the same isolate (I/2015 of H. vastatrix. Results also indicate that there is no pleiotropic effect of gene or allele SH1 connection between genes conferring resistance to leaf rust caused by H. vastatrix and bacterial halo blight caused by P. syringae pv. garcae.

Conformation of an Shc-derived phosphotyrosine-containing peptide complexed with the Grb2 SH2 domain

International Nuclear Information System (INIS)

Ogura, Kenji; Tsuchiya, Shigeo; Terasawa, Hiroaki; Yuzawa, Satoru; Hatanaka, Hideki; Mandiyan, Valsan; Schlessinger, Joseph; Inagaki, Fuyuhiko

1997-01-01

We have determined the structure of an Shc-derived phosphotyrosine-containing peptide complexed with Grb2 SH2 based on intra-and intermolecular NOE correlations observed by a series of isotope-filtered NMR experiments using a PFG z-filter. In contrast to an extended conformation of phosphotyrosine-containing peptides bound to Src, Syp and PLC γ SH2s, the Shc-derived peptide formed a turn at the +1 and +2 positions next to the phosphotyrosine residue. Trp 121 , located at the EF1 site of Grb2 SH2, blocked the peptide binding in an extended conformation. The present study confirms that each phosphotyrosine-containing peptide binds to the cognate SH2 with a specific conformation, which gives the structural basis for the binding specificity between SH2s and target proteins

Expression of plasmid-based shRNA against the E1 and nsP1 genes effectively silenced Chikungunya virus replication.

Directory of Open Access Journals (Sweden)

Shirley Lam

Full Text Available BACKGROUND: Chikungunya virus (CHIKV is a re-emerging alphavirus that causes chikungunya fever and persistent arthralgia in humans. Currently, there is no effective vaccine or antiviral against CHIKV infection. Therefore, this study evaluates whether RNA interference which targets at viral genomic level may be a novel antiviral strategy to inhibit the medically important CHIKV infection. METHODS: Plasmid-based small hairpin RNA (shRNA was investigated for its efficacy in inhibiting CHIKV replication. Three shRNAs designed against CHIKV Capsid, E1 and nsP1 genes were transfected to establish stable shRNA-expressing cell clones. Following infection of stable shRNA cells clones with CHIKV at M.O.I. 1, viral plaque assay, Western blotting and transmission electron microscopy were performed. The in vivo efficacy of shRNA against CHIKV replication was also evaluated in a suckling murine model of CHIKV infection. RESULTS: Cell clones expressing shRNAs against CHIKV E1 and nsP1 genes displayed significant inhibition of infectious CHIKV production, while shRNA Capsid demonstrated a modest inhibitory effect as compared to scrambled shRNA cell clones and non-transfected cell controls. Western blot analysis of CHIKV E2 protein expression and transmission electron microscopy of shRNA E1 and nsP1 cell clones collectively demonstrated similar inhibitory trends against CHIKV replication. shRNA E1 showed non cell-type specific anti-CHIKV effects and broad-spectrum silencing against different geographical strains of CHIKV. Furthermore, shRNA E1 clones did not exert any inhibition against Dengue virus and Sindbis virus replication, thus indicating the high specificity of shRNA against CHIKV replication. Moreover, no shRNA-resistant CHIKV mutant was generated after 50 passages of CHIKV in the stable cell clones. More importantly, strong and sustained anti-CHIKV protection was conferred in suckling mice pre-treated with shRNA E1. CONCLUSION: Taken together, these

Isogeometric shell formulation based on a classical shell model

KAUST Repository

Niemi, Antti

2012-09-04

This paper constitutes the first steps in our work concerning isogeometric shell analysis. An isogeometric shell model of the Reissner-Mindlin type is introduced and a study of its accuracy in the classical pinched cylinder benchmark problem presented. In contrast to earlier works [1,2,3,4], the formulation is based on a shell model where the displacement, strain and stress fields are defined in terms of a curvilinear coordinate system arising from the NURBS description of the shell middle surface. The isogeometric shell formulation is implemented using the PetIGA and igakit software packages developed by the authors. The igakit package is a Python package used to generate NURBS representations of geometries that can be utilised by the PetIGA finite element framework. The latter utilises data structures and routines of the portable, extensible toolkit for scientific computation (PETSc), [5,6]. The current shell implementation is valid for static, linear problems only, but the software package is well suited for future extensions to geometrically and materially nonlinear regime as well as to dynamic problems. The accuracy of the approach in the pinched cylinder benchmark problem and present comparisons against the h-version of the finite element method with bilinear elements. Quadratic, cubic and quartic NURBS discretizations are compared against the isoparametric bilinear discretization introduced in [7]. The results show that the quadratic and cubic NURBS approximations exhibit notably slower convergence under uniform mesh refinement as the thickness decreases but the quartic approximation converges relatively quickly within the standard variational framework. The authors future work is concerned with building an isogeometric finite element method for modelling nonlinear structural response of thin-walled shells undergoing large rigid-body motions. The aim is to use the model in a aeroelastic framework for the simulation of flapping wings.

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

International Nuclear Information System (INIS)

Ogura, Kenji; Shiga, Takanori; Yokochi, Masashi; Yuzawa, Satoru; Burke, Terrence R.; Inagaki, Fuyuhiko

2008-01-01

The solution structure of the growth factor receptor-bound protein 2 (Grb2) SH2 domain complexed with a high-affinity inhibitor containing a non-phosphorus phosphate mimetic within a macrocyclic platform was determined by nuclear magnetic resonance (NMR) spectroscopy. Unambiguous assignments of the bound inhibitor and intermolecular NOEs between the Grb2 SH2 domain and the inhibitor was accomplished using perdeuterated Grb2 SH2 protein. The well-defined solution structure of the complex was obtained and compared to those by X-ray crystallography. Since the crystal structure of the Grb2 SH2 domain formed a domain-swapped dimer and several inhibitors were bound to a hinge region, there were appreciable differences between the solution and crystal structures. Based on the binding interactions between the inhibitor and the Grb2 SH2 domain in solution, we proposed a design of second-generation inhibitors that could be expected to have higher affinity

Testing and analysis to determine the shell thickness required to prevent puncture

International Nuclear Information System (INIS)

Ammerman, D.J.; Radloff, H.D.; Eifert, E.J.

1998-05-01

Type B radioactive material packages are required to withstand a hypothetical puncture accident of a free fall from a height of one meter onto a 15 cm diameter mild steel puncture probe. For many packages it is desirable to have this accident event not result in puncture or tearing of the outer shell of the package. The wall thickness necessary to prevent this has historically been determined by test or the use of empirical relations. This technique generally results in overly conservative designs, but the degree of conservatism is uncertain. The use of modem finite element codes to determine package response to puncture accidents can result in designs that are both safe and economical. The work reported in this paper is aimed at developing a method to analytically determine the wall thickness required to prevent puncture. For designers and regulators to have confidence in this analytical method, however, it must be benchmarked against test results. A series of tests has been conducted with differing shell thicknesses, shell materials of mild steel and stainless steel, and shell backing materials of lead, foam, and air. The results of these tests have been compared with pre-test analytical predictions of the response obtained from the nonlinear transient dynamic finite element program PRONTO-2D. From this comparison it can be seen that the finite element method can accurately predict the response of packages to puncture accidents. This implies that an analytical technique based on the finite element method can be used to design packages having known response and margin of safety against tearing of the outer shell. In addition, the analytical technique can accurately predict the deformed shape of the package following the test. This may be important for subsequent calculations, such as external dose and heat input during a thermal event

Social inequalities in height: persisting differences today depend upon height of the parents.

Directory of Open Access Journals (Sweden)

Bruna Galobardes

Full Text Available Substantial increases in height have occurred concurrently with economic development in most populations during the last century. In high-income countries, environmental exposures that can limit genetic growth potential appear to have lessened, and variation in height by socioeconomic position may have diminished. The objective of this study is to investigate inequalities in height in a cohort of children born in the early 1990s in England, and to evaluate which factors might explain any identified inequalities.12,830 children from The Avon Longitudinal Study of Parents and Children (ALSPAC, a population based cohort from birth to about 11.5 years of age, were used in this analysis. Gender- and age-specific z-scores of height at different ages were used as outcome variables. Multilevel models were used to take into account the repeated measures of height and to analyze gender- and age-specific relative changes in height from birth to 11.5 years. Maternal education was the main exposure variable used to examine socioeconomic inequalities. The roles of parental and family characteristics in explaining any observed differences between maternal education and child height were investigated. Children whose mothers had the highest education compared to those with none or a basic level of education, were 0.39 cm longer at birth (95% CI: 0.30 to 0.48. These differences persisted and at 11.5 years the height difference was 1.4 cm (95% CI: 1.07 to 1.74. Several other factors were related to offspring height, but few changed the relationship with maternal education. The one exception was mid-parental height, which fully accounted for the maternal educational differences in offspring height.In a cohort of children born in the 1990s, mothers with higher education gave birth to taller boys and girls. Although height differences were small they persisted throughout childhood. Maternal and paternal height fully explained these differences.

A photoaffinity scan maps regions of the p85 SH2 domain involved in phosphoprotein binding.

Science.gov (United States)

Williams, K P; Shoelson, S E

1993-03-15

Src homology 2 (SH2) domains are modular phosphotyrosine binding pockets found within a wide variety of cytoplasmic signaling molecules. Here we develop a new approach to analyzing protein-protein interfaces termed photoaffinity scanning, and apply the method to map regions of the phosphatidylinositol 3-kinase p85 SH2 domain that participate in phospho-protein binding. Each residue except phosphotyrosine (pY) within a tightly binding, IRS-1-derived phosphopeptide (GNGDpYMPMSPKS) was substituted with the photoactive amino acid, benzoylphenylalanine (Bpa). Whereas most substitutions had little effect on binding affinity, Bpa substitution of either Met (+1 and +3 with respect to pY) reduced affinity 50-100-fold to confirm their importance in the pYMXM recognition motif. In three cases photolysis of SH2 domain/Bpa phosphopeptide complexes led to cross-linking of > 50% of the SH2 domain; cross-link positions were identified by microsequence, amino acid composition, and electrospray mass spectrometric analyses. Bpa-1 cross-links within alpha-helix I, whereas Bpa+1 and Bpa+4 cross-link the SH2 domain within the flexible loop C-terminal to alpha-helix II. Moreover, cross-linking at any position prevents SH2 domain cleavage at a trypsin-sensitive site within the flexible loop between beta-strands 1 and 2. Therefore, at least three distinct SH2 regions in addition to the beta-sheet participate in phosphoprotein binding; the loop cross-linked by phosphopeptide residues C-terminal to pY appears to confer specificity to the phosphoprotein/SH2 domain interaction.

Understanding the role of BAR and SH3 domain-containing proteins in fungi

NARCIS (Netherlands)

Gkourtsa, A.

2017-01-01

This thesis addresses the role of SH3 and BAR domain-containing proteins in different fungal species. SH3 domains are small modules that mediate protein-protein interactions and BAR domains are dimerization domains with membrane binding and bending properties. It is known that the ScRvs167 protein

Three new shRNA expression vectors targeting the CYP3A4 coding sequence to inhibit its expression

Directory of Open Access Journals (Sweden)

Siyun Xu

2014-10-01

Full Text Available RNA interference (RNAi is useful for selective gene silencing. Cytochrome P450 3A4 (CYP3A4, which metabolizes approximately 50% of drugs in clinical use, plays an important role in drug metabolism. In this study, we aimed to develop a short hairpin RNA (shRNA to modulate CYP3A4 expression. Three new shRNAs (S1, S2 and S3 were designed to target the coding sequence (CDS of CYP3A4, cloned into a shRNA expression vector, and tested in different cells. The mixture of three shRNAs produced optimal reduction (55% in CYP3A4 CDS-luciferase activity in both CHL and HEK293 cells. Endogenous CYP3A4 expression in HepG2 cells was decreased about 50% at both mRNA and protein level after transfection of the mixture of three shRNAs. In contrast, CYP3A5 gene expression was not altered by the shRNAs, supporting the selectivity of CYP3A4 shRNAs. In addition, HepG2 cells transfected with CYP3A4 shRNAs were less sensitive to Ginkgolic acids, whose toxic metabolites are produced by CYP3A4. These results demonstrate that vector-based shRNAs could modulate CYP3A4 expression in cells through their actions on CYP3A4 CDS, and CYP3A4 shRNAs may be utilized to define the role of CYP3A4 in drug metabolism and toxicity.

Functional analysis of SH3 domain containing ring finger 2 during the myogenic differentiation of quail myoblast cells

Directory of Open Access Journals (Sweden)

Si Won Kim

2017-08-01

Full Text Available Objective Owing to the public availability of complete genome sequences, including avian species, massive bioinformatics analyses may be conducted for computational gene prediction and the identification of gene regulatory networks through various informatics tools. However, to evaluate the biofunctional activity of a predicted target gene, in vivo and in vitro functional genomic analyses should be a prerequisite. Methods Due to a lack of quail genomic sequence information, we first identified the partial genomic structure and sequences of the quail SH3 domain containing ring finger 2 (SH3RF2 gene. Subsequently, SH3RF2 was knocked out using clustered regularly interspaced short palindromic repeat/Cas9 technology and single cell-derived SH3RF2 mutant sublines were established to study the biofunctional activity of SH3RF2 in quail myoblast (QM7 cells during muscle differentiation. Results Through a T7 endonuclease I assay and genotyping analysis, we established an SH3RF2 knockout (KO QM7#4 subline with 61 and 155 nucleotide deletion mutations in SH3RF2. After the induction of myotube differentiation, the expression profiles were analyzed and compared between regular QM7 and SH3RF2 KO QM7#4 cells by global RNA sequencing and bioinformatics analysis. Conclusion We did not detect any statistically significant role of SH3RF2 during myotube differentiation in QM7 myoblast cells. However, additional experiments are necessary to examine the biofunctional activity of SH3RF2 in cell proliferation and muscle growth.

New Vary-Chap Profile of the Topside Ionosphere Electron Density Distribution for use with the IRI Model and the GIRO Real-Time Data

Science.gov (United States)

Nsumei, Patrick; Reinisch, Bodo W.; Huang, Xueqin; Bilitza, Dieter

2012-01-01

A new Vary-Chap function is introduced for the empirical modeling of the electron density N(h) profile in the topside ionosphere that uses a shape function S(h) in the generalized Chapman function. The Vary-Chap profile extends the bottomside profile that is specified by the IRI model or measured by the Global Ionospheric Radio Observatory (GIRO) to the altitude of the ISIS-2 satellite. Some 80,000 topside profiles, measured by the topside sounder on the ISIS-2 satellite were analyzed, and the shape function S(h) was calculated for each profile. A parameterized function S*(h), composed of two sub-functions S1(h) and S2(h), is fitted to the measured S(h) profile using three free parameters. At altitudes just above the F2 layer peak height hmF2, the shape function S1 controls S(h), and at greater altitudes S2 controls S(h). The height of the intersection of S1 and S2 is defined as the transition height h(sub T) indicating the transition from an O(+) to an H(+)-dominated profile shape. The observed transition heights range from approx.500 km to 800 km.

Molluscan shell colour.

Science.gov (United States)

Williams, Suzanne T

2017-05-01

The phylum Mollusca is highly speciose, and is the largest phylum in the marine realm. The great majority of molluscs are shelled, including nearly all bivalves, most gastropods and some cephalopods. The fabulous and diverse colours and patterns of molluscan shells are widely recognised and have been appreciated for hundreds of years by collectors and scientists alike. They serve taxonomists as characters that can be used to recognise and distinguish species, however their function for the animal is sometimes less clear and has been the focus of many ecological and evolutionary studies. Despite these studies, almost nothing is known about the evolution of colour in molluscan shells. This review summarises for the first time major findings of disparate studies relevant to the evolution of shell colour in Mollusca and discusses the importance of colour, including the effects of visual and non-visual selection, diet and abiotic factors. I also summarise the evidence for the heritability of shell colour in some taxa and recent efforts to understand the molecular mechanisms underpinning synthesis of shell colours. I describe some of the main shell pigments found in Mollusca (carotenoids, melanin and tetrapyrroles, including porphyrins and bile pigments), and their durability in the fossil record. Finally I suggest that pigments appear to be distributed in a phylogenetically relevant manner and that the synthesis of colour is likely to be energetically costly. © 2016 Cambridge Philosophical Society.

Fusion protein based on Grb2-SH2 domain for cancer therapy

International Nuclear Information System (INIS)

Saito, Yuriko; Furukawa, Takako; Arano, Yasushi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2010-01-01

Research highlights: → Grb2 mediates EGFR signaling through binding to phosphorylate EGFR with SH2 domain. → We generated fusion proteins containing 1 or 2 SH2 domains of Grb2 added with TAT. → The one with 2 SH2 domains (TSSF) interfered ERK phosphorylation. → TSSF significantly delayed the growth of EGFR overexpressing tumor in a mouse model. -- Abstract: Epidermal growth factor receptor (EGFR) is one of the very attractive targets for cancer therapy. In this study, we generated fusion proteins containing one or two Src-homology 2 (SH2) domains of growth factor receptor bound protein 2 (Grb2), which bind to phosphorylated EGFR, added with HIV-1 transactivating transcription for cell membrane penetration (termed TSF and TSSF, respectively). We examined if they can interfere Grb2-mediated signaling pathway and suppress tumor growth as expected from the lack of SH3 domain, which is necessary to intermediate EGFR-Grb2 cell signaling, in the fusion proteins. The transduction efficiency of TSSF was similar to that of TSF, but the binding activity of TSSF to EGFR was higher than that of TSF. Treatment of EGFR-overexpressing cells showed that TSSF decreased p42-ERK phosphorylation, while TSF did not. Both the proteins delayed cell growth but did not induce cell death in culture. TSSF also significantly suppressed tumor growth in vivo under consecutive administration. In conclusion, TSSF showed an ability to inhibit EGFR-Grb2 signaling and could have a potential to treat EGFR-activated cancer.

Final height in survivors of childhood cancer compared with Height Standard Deviation Scores at diagnosis

NARCIS (Netherlands)

Knijnenburg, S. L.; Raemaekers, S.; van den Berg, H.; van Dijk, I. W. E. M.; Lieverst, J. A.; van der Pal, H. J.; Jaspers, M. W. M.; Caron, H. N.; Kremer, L. C.; van Santen, H. M.

2013-01-01

Our study aimed to evaluate final height in a cohort of Dutch childhood cancer survivors (CCS) and assess possible determinants of final height, including height at diagnosis. We calculated standard deviation scores (SDS) for height at initial cancer diagnosis and height in adulthood in a cohort of

The development and application of a quantitative peptide microarray platform to SH2 domain specificity space

Science.gov (United States)

Engelmann, Brett Warren

The Src homology 2 (SH2) domains evolved alongside protein tyrosine kinases (PTKs) and phosphatases (PTPs) in metazoans to recognize the phosphotyrosine (pY) post-translational modification. The human genome encodes 121 SH2 domains within 111 SH2 domain containing proteins that represent the primary mechanism for cellular signal transduction immediately downstream of PTKs. Despite pY recognition contributing to roughly half of the binding energy, SH2 domains possess substantial binding specificity, or affinity discrimination between phosphopeptide ligands. This specificity is largely imparted by amino acids (AAs) adjacent to the pY, typically from positions +1 to +4 C-terminal to the pY. Much experimental effort has been undertaken to construct preferred binding motifs for many SH2 domains. However, due to limitations in previous experimental methodologies these motifs do not account for the interplay between AAs. It was therefore not known how AAs within the context of individual peptides function to impart SH2 domain specificity. In this work we identified the critical role context plays in defining SH2 domain specificity for physiological ligands. We also constructed a high quality interactome using 50 SH2 domains and 192 physiological ligands. We next developed a quantitative high-throughput (Q-HTP) peptide microarray platform to assess the affinities four SH2 domains have for 124 physiological ligands. We demonstrated the superior characteristics of our platform relative to preceding approaches and validated our results using established biophysical techniques, literature corroboration, and predictive algorithms. The quantitative information provided by the arrays was leveraged to investigate SH2 domain binding distributions and identify points of binding overlap. Our microarray derived affinity estimates were integrated to produce quantitative interaction motifs capable of predicting interactions. Furthermore, our microarrays proved capable of resolving

Sexual selection on land snail shell ornamentation: a hypothesis that may explain shell diversity

Directory of Open Access Journals (Sweden)

Schilthuizen Menno

2003-06-01

Full Text Available Abstract Background Many groups of land snails show great interspecific diversity in shell ornamentation, which may include spines on the shell and flanges on the aperture. Such structures have been explained as camouflage or defence, but the possibility that they might be under sexual selection has not previously been explored. Presentation of the hypothesis The hypothesis that is presented consists of two parts. First, that shell ornamentation is the result of sexual selection. Second, that such sexual selection has caused the divergence in shell shape in different species. Testing the hypothesis The first part of the hypothesis may be tested by searching for sexual dimorphism in shell ornamentation in gonochoristic snails, by searching for increased variance in shell ornamentation relative to other shell traits, and by mate choice experiments using individuals with experimentally enhanced ornamentation. The second part of the hypothesis may be tested by comparing sister groups and correlating shell diversity with degree of polygamy. Implications of the hypothesis If the hypothesis were true, it would provide an explanation for the many cases of allopatric evolutionary radiation in snails, where shell diversity cannot be related to any niche differentiation or environmental differences.

“Girls are dancin’”: shōjo culture and feminism in contemporary Japanese art

OpenAIRE

Emily Jane Wakeling

2011-01-01

This article explores the gender-transgressive expressions found in shōjo culture in order to highlight the potential for feminist analysis in the prevalence of the shōjo motif in contemporary Japanese art. Shōjo culture is a fascinating cultural space, within contemporary Japanese culture, which fosters creative expressions of gender that negate or make complex hegemonic categories. Departing from stereotypes of Japanese girls, this article will pay particular interest to an emerging wave of...

Height premium for job performance.

Science.gov (United States)

Kim, Tae Hyun; Han, Euna

2017-08-01

This study assessed the relationship of height with wages, using the 1998 and 2012 Korean Labor and Income Panel Study data. The key independent variable was height measured in centimeters, which was included as a series of dummy indicators of height per 5cm span (wages to assess the heterogeneity in the height-wage relationship, across the conditional distribution of monthly wages. We found a non-linear relationship of height with monthly wages. For men, the magnitude of the height wage premium was overall larger at the upper quantile of the conditional distribution of log monthly wages than at the median to low quantile, particularly in professional and semi-professional occupations. The height-wage premium was also larger at the 90th quantile for self-employed women and salaried men. Our findings add a global dimension to the existing evidence on height-wage premium, demonstrating non-linearity in the association between height and wages and heterogeneous changes in the dispersion and direction of the association between height and wages, by wage level. Copyright © 2017 Elsevier B.V. All rights reserved.

Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria.

Science.gov (United States)

Chang, Shih Chieh; Galea, Charles A; Leung, Eleanor W W; Tajhya, Rajeev B; Beeton, Christine; Pennington, Michael W; Norton, Raymond S

2012-10-01

The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which play a crucial role in the activation of human effector memory T-cells (T(EM)). Selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. We have established a recombinant peptide expression system in order to generate isotopically-labelled ShK and various ShK analogues for in-depth biophysical and pharmacological studies. ShK was expressed as a thioredoxin fusion protein in Escherichia coli BL21 (DE3) cells and purified initially by Ni²⁺ iminodiacetic acid affinity chromatography. The fusion protein was cleaved with enterokinase and purified to homogeneity by reverse-phase HPLC. NMR spectra of ¹⁵N-labelled ShK were similar to those reported previously for the unlabelled synthetic peptide, confirming that recombinant ShK was correctly folded. Recombinant ShK blocked Kv1.3 channels with a K(d) of 25 pM and inhibited the proliferation of human and rat T lymphocytes with a preference for T(EM) cells, with similar potency to synthetic ShK in all assays. This expression system also enables the efficient production of ¹⁵N-labelled ShK for NMR studies of peptide dynamics and of the interaction of ShK with Kv1.3 channels. Copyright © 2012 Elsevier Ltd. All rights reserved.

Windows PowerShell 20 Bible

CERN Document Server

Lee, Thomas; Schill, Mark E; Tanasovski, Tome

2011-01-01

Here's the complete guide to Windows PowerShell 2.0 for administrators and developers Windows PowerShell is Microsoft's next-generation scripting and automation language. This comprehensive volume provides the background that IT administrators and developers need in order to start using PowerShell automation in exciting new ways. It explains what PowerShell is, how to use the language, and specific ways to apply PowerShell in various technologies. Windows PowerShell is Microsoft's standard automation tool and something that every Windows administrator will eventually have to understand; this b

A unique set of SH3-SH3 interactions controls IB1 homodimerization

DEFF Research Database (Denmark)

Kristensen, Ole; Guenat, Sylvie; Dar, Imran

2006-01-01

Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components...... reduces IB1-dependent basal JNK activity in 293T cells. Impaired dimerization also results in a reduction in glucose transporter type 2 expression and in glucose-dependent insulin secretion in pancreatic beta-cells. Taken together, these results indicate that IB1 homodimerization through its SH3 domain...

Sleep of reason? The practices of reading shônen manga

OpenAIRE

Gallacher, Lesley-Anne

2011-01-01

In this thesis, I explore the practices of English-speaking readers of shônen manga (Japanese comics written primarily for an audience of teenage boys). I concentrate on three series in particular: Hiromu Arakawa’s Fullmetal Alchemist (2001–2010), Tite Kubo’s Bleach (2001–ongoing), and Masashi Kishimoto’s Naruto (1999–ongoing). I argue that, although it may appear to be inherently imbued with (authorial) meaning, the shônen manga text emerges from a curious ‘alchemy’ through...

Characterization of AKT independent effects of the synthetic AKT inhibitors SH-5 and SH-6 using an integrated approach combining transcriptomic profiling and signaling pathway perturbations

Directory of Open Access Journals (Sweden)

Schäfer Reinhold

2010-06-01

Full Text Available Abstract Background Signal transduction processes mediated by phosphatidyl inositol phosphates affect a broad range of cellular processes such as cell cycle progression, migration and cell survival. The protein kinase AKT is one of the major effectors in this signaling network. Chronic AKT activation contributes to oncogenic transformation and tumor development. Therefore, analogs of phosphatidyl inositol phosphates (PIAs were designed as new small drugs to block AKT activity for cancer treatment. Here we characterize the biological effects of the PIAs SH-5 and SH-6 in colorectal cancer cell lines. Methods Serum-starved or serum-supplemented human colorectal cancer cell lines SW480, HT29 and HCT116 were exposed to SH-5 and SH-6. AKT activation was determined by western blotting. Cell viability was assessed using a colorimetric XTT-based assay, apoptosis and cell cycle changes were monitored by FACS analysis. The dynamics of cell morphology alterations was evaluated by confocal and time-lapse microscopy. Transcriptional changes due to inhibitor treatment were analyzed using Affymetrix HG-U133A microarrays and RT-PCR. Results While the PIAs clearly reduce AKT phosphorylation in serum starved cells, we did not observe a significant reduction under serum supplemented conditions, giving us the opportunity to analyze AKT independent effects of these compounds. Both inhibitors induce broadly the same morphological alterations, in particular changes in cell shape and formation of intracellular vesicles. Moreover, we observed the induction of binucleated cells specifically in the SW480 cell line. Gene expression analysis revealed transcriptional alterations, which are mostly cell line specific. In accordance to the phenotype we found a gene group associated with mitosis and spindle organization down regulated in SW480 cells, but not in the other cell lines. A bioinformatics analysis using the Connectivity Map linked the gene expression pattern of the

Characterization of AKT independent effects of the synthetic AKT inhibitors SH-5 and SH-6 using an integrated approach combining transcriptomic profiling and signaling pathway perturbations

International Nuclear Information System (INIS)

Krech, Till; Thiede, Margarethe; Hilgenberg, Ellen; Schäfer, Reinhold; Jürchott, Karsten

2010-01-01

Signal transduction processes mediated by phosphatidyl inositol phosphates affect a broad range of cellular processes such as cell cycle progression, migration and cell survival. The protein kinase AKT is one of the major effectors in this signaling network. Chronic AKT activation contributes to oncogenic transformation and tumor development. Therefore, analogs of phosphatidyl inositol phosphates (PIAs) were designed as new small drugs to block AKT activity for cancer treatment. Here we characterize the biological effects of the PIAs SH-5 and SH-6 in colorectal cancer cell lines. Serum-starved or serum-supplemented human colorectal cancer cell lines SW480, HT29 and HCT116 were exposed to SH-5 and SH-6. AKT activation was determined by western blotting. Cell viability was assessed using a colorimetric XTT-based assay, apoptosis and cell cycle changes were monitored by FACS analysis. The dynamics of cell morphology alterations was evaluated by confocal and time-lapse microscopy. Transcriptional changes due to inhibitor treatment were analyzed using Affymetrix HG-U133A microarrays and RT-PCR. While the PIAs clearly reduce AKT phosphorylation in serum starved cells, we did not observe a significant reduction under serum supplemented conditions, giving us the opportunity to analyze AKT independent effects of these compounds. Both inhibitors induce broadly the same morphological alterations, in particular changes in cell shape and formation of intracellular vesicles. Moreover, we observed the induction of binucleated cells specifically in the SW480 cell line. Gene expression analysis revealed transcriptional alterations, which are mostly cell line specific. In accordance to the phenotype we found a gene group associated with mitosis and spindle organization down regulated in SW480 cells, but not in the other cell lines. A bioinformatics analysis using the Connectivity Map linked the gene expression pattern of the inhibitor treated SW480 cells to PKC signaling. Using

Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25.

Science.gov (United States)

Ji, Mingfei; Zheng, Guodong; Li, Xiaolong; Zhang, Zhongqin; Jv, Guanqun; Wang, Xiaowei; Wang, Jialin

2017-06-01

The deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein represents an attractive pharmacological target for the treatment of chronic myeloid leukemia (CML). The high affinity of monobody AS25 was designed to target the Src homology 2 (SH2) domain of Bcr-Abl, leading to allosteric inhibition of Bcr-Abl through formation of protein-protein interactions. An I164E mutation in the SH2 domain disrupts AS25 binding to the SH2 domain of Bcr-Abl. The detailed mechanisms, however, remain to be unresolved. Here, molecular dynamics (MD) simulations and binding free energy calculations were performed to explore the conformational and energetic differences between the wild-type (WT) complexes of Bcr-Abl SH2 domain and AS25 (SH2 WT -AS25) as well as the mutated complexes (SH2 I164E -AS25). The results revealed that I164E mutation not only caused an increase in the conformational flexibility of SH2-AS25 complexes, but also weakened the binding affinity of AS25 to SH2. The comparative binding modes of SH2-AS25 complexes between WT and the I164E mutant were comprehensively analyzed to unravel the disruption of hydrophobic and hydrogen bonding interactions in the interface of the SH2-AS25 complex triggered by the I164E mutation. The results obtained may help to design the next generation of higher affinity Bcr-Abl SH2-specific peptide inhibitors.

SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1.

Science.gov (United States)

Anafi, M; Kiefer, F; Gish, G D; Mbamalu, G; Iscove, N N; Pawson, T

1997-10-31

Ste20-related protein kinases have been implicated as regulating a range of cellular responses, including stress-activated protein kinase pathways and the control of cytoskeletal architecture. An important issue involves the identities of the upstream signals and regulators that might control the biological functions of mammalian Ste20-related protein kinases. HPK1 is a protein-serine/threonine kinase that possesses a Ste20-like kinase domain, and in transfected cells activates a protein kinase pathway leading to the stress-activated protein kinase SAPK/JNK. Here we have investigated candidate upstream regulators that might interact with HPK1. HPK1 possesses an N-terminal catalytic domain and an extended C-terminal tail with four proline-rich motifs. The SH3 domains of Grb2 bound in vitro to specific proline-rich motifs in the HPK1 tail and functioned synergistically to direct the stable binding of Grb2 to HPK1 in transfected Cos1 cells. Epidermal growth factor (EGF) stimulation did not affect the binding of Grb2 to HPK1 but induced recruitment of the Grb2.HPK1 complex to the autophosphorylated EGF receptor and to the Shc docking protein. Several activated receptor and cytoplasmic tyrosine kinases, including the EGF receptor, stimulated the tyrosine phosphorylation of the HPK1 serine/threonine kinase. These results suggest that HPK1, a mammalian Ste20-related protein-serine/threonine kinase, can potentially associate with protein-tyrosine kinases through interactions mediated by SH2/SH3 adaptors such as Grb2. Such interaction may provide a possible mechanism for cross-talk between distinct biochemical pathways following the activation of tyrosine kinases.

Use of NLM medical subject headings with the MeSH2010 thesaurus in the PORTAL-DOORS system.

Science.gov (United States)

Taswell, Carl

2010-01-01

The NLM MeSH Thesaurus has been incorporated for use in the PORTAL-DOORS System (PDS) for resource metadata management on the semantic web. All 25588 descriptor records from the NLM 2010 MeSH Thesaurus have been exposed as web accessible resources by the PDS MeSH2010 Thesaurus implemented as a PDS PORTAL Registry operating as a RESTful web service. Examples of records from the PDS MeSH2010 PORTAL are demonstrated along with their use by records in other PDS PORTAL Registries that reference the concepts from the MeSH2010 Thesaurus. Use of this important biomedical terminology will greatly enhance the quality of metadata content of other PDS records thus improving cross-domain searches between different problem oriented domains and amongst different clinical specialty fields.

Deep Sequencing Insights in Therapeutic shRNA Processing and siRNA Target Cleavage Precision.

Science.gov (United States)

Denise, Hubert; Moschos, Sterghios A; Sidders, Benjamin; Burden, Frances; Perkins, Hannah; Carter, Nikki; Stroud, Tim; Kennedy, Michael; Fancy, Sally-Ann; Lapthorn, Cris; Lavender, Helen; Kinloch, Ross; Suhy, David; Corbau, Romu

2014-02-04

TT-034 (PF-05095808) is a recombinant adeno-associated virus serotype 8 (AAV8) agent expressing three short hairpin RNA (shRNA) pro-drugs that target the hepatitis C virus (HCV) RNA genome. The cytosolic enzyme Dicer cleaves each shRNA into multiple, potentially active small interfering RNA (siRNA) drugs. Using next-generation sequencing (NGS) to identify and characterize active shRNAs maturation products, we observed that each TT-034-encoded shRNA could be processed into as many as 95 separate siRNA strands. Few of these appeared active as determined by Sanger 5' RNA Ligase-Mediated Rapid Amplification of cDNA Ends (5-RACE) and through synthetic shRNA and siRNA analogue studies. Moreover, NGS scrutiny applied on 5-RACE products (RACE-seq) suggested that synthetic siRNAs could direct cleavage in not one, but up to five separate positions on targeted RNA, in a sequence-dependent manner. These data support an on-target mechanism of action for TT-034 without cytotoxicity and question the accepted precision of substrate processing by the key RNA interference (RNAi) enzymes Dicer and siRNA-induced silencing complex (siRISC).Molecular Therapy-Nucleic Acids (2014) 3, e145; doi:10.1038/mtna.2013.73; published online 4 February 2014.

Pomegranate inhibits neuroinflammation and amyloidogenesis in IL-1β-stimulated SK-N-SH cells.

Science.gov (United States)

Velagapudi, Ravikanth; Baco, Gina; Khela, Sunjeet; Okorji, Uchechukwu; Olajide, Olumayokun

2016-06-01

Pomegranate fruit, Punica granatum L. (Punicaceae), and its constituents have been shown to inhibit inflammation. In this study, we aimed to assess the effects of freeze-dried pomegranate (PWE) on PGE2 production in IL-1β-stimulated SK-N-SH cells. An enzyme immunoassay (EIA) was used to measure prostaglandin E2 (PGE2) production from supernatants of IL-1β-stimulated SK-N-SH cells. Expression of COX-2, phospho-IκB, and phospho-IKK proteins was evaluated, while NF-κB reporter gene assay was carried out in TNFα-stimulated HEK293 cells to determine the effect of PWE on NF-κB transactivation. Levels of BACE-1 and Aβ in SK-N-SH cells stimulated with IL-1β were measured with an in cell ELISA. PWE (25-200 μg/ml) dose dependently reduced COX-2-dependent PGE2 production in SK-N-SH cells stimulated with IL-1β. Phosphorylation of IκB and IKK was significantly (p pomegranate inhibits inflammation, as well as amyloidogenesis in IL-1β-stimulated SK-N-SH cells. We propose that pomegranate is a potential nutritional strategy in slowing the progression of neurodegenerative disorders such as Alzheimer's disease.

TWO-DIMENSIONAL APPROXIMATION OF EIGENVALUE PROBLEMS IN SHELL THEORY: FLEXURAL SHELLS

Institute of Scientific and Technical Information of China (English)

无

2000-01-01

The eigenvalue problem for a thin linearly elastic shell, of thickness 2e, clamped along its lateral surface is considered. Under the geometric assumption on the middle surface of the shell that the space of inextensional displacements is non-trivial, the authors obtain, as ε→0,the eigenvalue problem for the two-dimensional"flexural shell"model if the dimension of the space is infinite. If the space is finite dimensional, the limits of the eigenvalues could belong to the spectra of both flexural and membrane shells. The method consists of rescaling the variables and studying the problem over a fixed domain. The principal difficulty lies in obtaining suitable a priori estimates for the scaled eigenvalues.

Conventional (CH) vs. stapled hemorrhoidectomy (SH) in surgical treatment of hemorrhoids. Ten years experience.

Science.gov (United States)

Manfredelli, Simone; Montalto, Gioacchino; Leonetti, Giovanni; Covotta, Marco; Amatucci, Chiara; Covotta, Alfredo; Forte, Angelo

2012-01-01

Interest about hemorrhoids is related to its high incidence and elevated social costs that derive from its treatment. Several comparative studies are reported in Literature to define a standard for ideal treatment of hemorrhoidal disease. Radical surgery is the only therapeutic option in case of III and IV stage haemorrhoids. Hemorrhoids surgical techniques are classified as Open, Closed and Stapled ones. We report our decennial experience on surgical treatment focusing on early, middle and late complications, indications and contraindications, satisfaction level of each surgical procedure for hemorrhoids. Four hundred forty-eight patients have been hospitalized in our department fom 1st January to 31st December 2008. Of these 241 underwent surgery with traditional open or closed technique and 207 with the SH technique according to Longo. This retrospective study includes only patients with symptomatic hemorrhoids at III or IV stage. There were no differences between CH and SH about both pre and post surgery hospitalization and intraoperative length. Pain is the most frequently observed early complication with a statistically significant difference in favour of SH. We obtain good results in CH group using anoderma sparing and perianal anaesthetic infiltration at the end of the surgery. In all cases, pain relief was obtained only with standard analgesic drugs (NSAIDs). We also observed that pain level influences the outcome after surgical treatment. No chronic pain cases were observed in both groups. Bleeding is another relevant early complication in particular after SH: we reported 2 cases of immediate surgical reintenvention and 2 cases treated with blood transfusion. Only in SH group we report also 5 cases of thrombosis of external haemorrhoids and 7 perianal hematoma both solved with medical therapy There were no statistical significant differences between two groups about fever, incontinence to flatus, urinary retention, fecal incontinence, substenosis and anal

Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains.

Science.gov (United States)

Sha, Fern; Gencer, Emel Basak; Georgeon, Sandrine; Koide, Akiko; Yasui, Norihisa; Koide, Shohei; Hantschel, Oliver

2013-09-10

The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in humans and forms a large multiprotein complex that includes the Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is necessary for BCR-ABL-dependent oncogenic transformation, but the precise signaling mechanisms of SHP2 are not well understood. We have developed binding proteins, termed monobodies, for the N- and C-terminal SH2 domains of SHP2. Intracellular expression followed by interactome analysis showed that the monobodies are essentially monospecific to SHP2. Two crystal structures revealed that the monobodies occupy the phosphopeptide-binding sites of the SH2 domains and thus can serve as competitors of SH2-phosphotyrosine interactions. Surprisingly, the segments of both monobodies that bind to the peptide-binding grooves run in the opposite direction to that of canonical phosphotyrosine peptides, which may contribute to their exquisite specificity. When expressed in cells, monobodies targeting the N-SH2 domain disrupted the interaction of SHP2 with its upstream activator, the Grb2-associated binder 2 adaptor protein, suggesting decoupling of SHP2 from the BCR-ABL protein complex. Inhibition of either N-SH2 or C-SH2 was sufficient to inhibit two tyrosine phosphorylation events that are critical for SHP2 catalytic activity and to block ERK activation. In contrast, targeting the N-SH2 or C-SH2 revealed distinct roles of the two SH2 domains in downstream signaling, such as the phosphorylation of paxillin and signal transducer and activator of transcription 5. Our results delineate a hierarchy of function for the SH2 domains of SHP2 and validate monobodies as potent and specific antagonists of protein-protein interactions in cancer cells.

Height-Deterministic Pushdown Automata

DEFF Research Database (Denmark)

Nowotka, Dirk; Srba, Jiri

2007-01-01

We define the notion of height-deterministic pushdown automata, a model where for any given input string the stack heights during any (nondeterministic) computation on the input are a priori fixed. Different subclasses of height-deterministic pushdown automata, strictly containing the class...... of regular languages and still closed under boolean language operations, are considered. Several of such language classes have been described in the literature. Here, we suggest a natural and intuitive model that subsumes all the formalisms proposed so far by employing height-deterministic pushdown automata...

Comparative Genomics and Disorder Prediction Identify Biologically Relevant SH3 Protein Interactions.

Directory of Open Access Journals (Sweden)

2005-08-01

Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

Comparative genomics and disorder prediction identify biologically relevant SH3 protein interactions.

Directory of Open Access Journals (Sweden)

Pedro Beltrao

2005-08-01

Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

Revisiting chameleon gravity: Thin-shell and no-shell fields with appropriate boundary conditions

International Nuclear Information System (INIS)

Tamaki, Takashi; Tsujikawa, Shinji

2008-01-01

We derive analytic solutions of a chameleon scalar field φ that couples to a nonrelativistic matter in the weak gravitational background of a spherically symmetric body, paying particular attention to a field mass m A inside of the body. The standard thin-shell field profile is recovered by taking the limit m A r c →∞, where r c is a radius of the body. We show the existence of ''no-shell'' solutions where the field is nearly frozen in the whole interior of the body, which does not necessarily correspond to the 'zero-shell' limit of thin-shell solutions. In the no-shell case, under the condition m A r c >>1, the effective coupling of φ with matter takes the same asymptotic form as that in the thin-shell case. We study experimental bounds coming from the violation of equivalence principle as well as solar-system tests for a number of models including f(R) gravity and find that the field is in either the thin-shell or the no-shell regime under such constraints, depending on the shape of scalar-field potentials. We also show that, for the consistency with local gravity constraints, the field at the center of the body needs to be extremely close to the value φ A at the extremum of an effective potential induced by the matter coupling.

Transport comparison of multiwall carbon nanotubes by contacting outer shell and all shells.

Science.gov (United States)

Luo, Qiang; Cui, A-Juan; Zhang, Yi-Guang; Lu, Chao; Jin, Ai-Zi; Yang, Hai-Fang; Gu, Chang-Zhi

2010-11-01

Carbon nanotubes, particularly multiwall carbon nanotubes (MWCNTs) can serve as interconnects in nanoelectronic devices and integrated circuits because of their extremely large current-carrying capacity. Many experimental results about the transport properties of individual MWCNTs by contacting outer shell or all shells have been reported. In this work, a compatible method with integrated circuit manufacturing process was presented to compare the transport property of an individual multiwall carbon nanotube (MWCNT) by contacting outer shell only and all shells successively. First of the Ti/Au electrodes contacting outer shell only were fabricated onto the nanotube through the sequence of electron beam lithography (EBL) patterning, metal deposition and lift-off process. After the characterization of its transport property, focused ion beam (FIB) was used to drill holes through the same nanotube at the as-deposited electrodes. Then new contact to the holes and electrodes were made by ion-induced deposition of tungsten from W(CO)6 precursor gas. The transport results indicated that the new contact to all shells can clear up the intershell resistance and the electrical conductance of the tube can be improved about 8 times compared to that of by contacting outer shell only.

AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice.

Science.gov (United States)

Yang, Q; Tang, Y; Imbrogno, K; Lu, A; Proto, J D; Chen, A; Guo, F; Fu, F H; Huard, J; Wang, B

2012-12-01

Chronic inflammation, promoted by an upregulated NF-kappa B (NF-κB) pathway, has a key role in Duchenne muscular dystrophy (DMD) patients' pathogenesis. Blocking the NF-κB pathway has been shown to be a viable approach to diminish chronic inflammation and necrosis in the dystrophin-defective mdx mouse, a murine DMD model. In this study, we used the recombinant adeno-associated virus serotype 9 (AAV9) carrying an short hairpin RNA (shRNA) specifically targeting the messenger RNA of NF-κB/p65 (p65-shRNA), the major subunit of NF-κB associated with chronic inflammation in mdx mice. We examined whether i.m. AAV9-mediated delivery of p65-shRNA could decrease NF-κB activation, allowing for amelioration of muscle pathologies in 1- and 4-month-old mdx mice. At 1 month after treatment, NF-κB/p65 levels were significantly decreased by AAV gene transfer of p65-shRNA in the two ages of treatment groups, with necrosis significantly decreased compared with controls. Quantitative analysis revealed that central nucleation (CN) of the myofibers of p65-shRNA-treated 1-month-old mdx muscles was reduced from 67 to 34%, but the level of CN was not significantly decreased in treated 4-month-old mdx mice. Moreover, delivery of the p65-shRNA enhanced the capacity of myofiber regeneration in old mdx mice treated at 4 months of age when the dystrophic myofibers were most exhausted; however, such p65 silencing diminished the myofiber regeneration in young mdx mice treated at 1 month of age. Taken together, these findings demonstrate that the AAV-mediated delivery of p65-shRNA has the capacity to ameliorate muscle pathologies in mdx mice by selectively reducing NF-κB/p65 activity.

Temporality in Manyōshū

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Yamaguchi Toshiko

2016-12-01

Full Text Available Using the Manyōshū corpus, the paper argues that conceptual metaphor theory imposes limitations on the diversity of linguistic facts, particularly those concerning the speaker or the poet who is communicating. The paper offers explanations of the nature of time by drawing upon the inference operating within “basic sign structure”, specifically, indexicality and iconicity, both of which are at the heart of human semiotic activity.

Solution structure, dynamics and thermodynamics of the three SH3 domains of CD2AP

Energy Technology Data Exchange (ETDEWEB)

Roldan, Jose L. Ortega [Universidad de Granada, Departamento de Quimica Fisica e Instituto de Biotecnologia, Facultad de Ciencias (Spain); Blackledge, Martin [Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, UJF UMR 5075, Protein Dynamics and Flexibility by NMR (France); Nuland, Nico A. J. van, E-mail: nvnuland@vub.ac.be [Vrije Universiteit Brussel, Structural Biology Brussels (Belgium); Azuaga, Ana I. [Universidad de Granada, Departamento de Quimica Fisica e Instituto de Biotecnologia, Facultad de Ciencias (Spain)

2011-06-15

CD2 associated protein (CD2AP) is an adaptor protein that plays an important role in cell to cell union needed for the kidney function. It contains three N-terminal SH3 domains that are able to interact among others with CD2, ALIX, c-Cbl and Ubiquitin. To understand the role of the individual SH3 domains of this adaptor protein we have performed a complete structural, thermodynamic and dynamic characterization of the separate domains using NMR and DSC. The energetic contributions to the stability and the backbone dynamics have been related to the structural features of each domain using the structure-based FoldX algorithm. We have found that the N-terminal SH3 domain of both adaptor proteins CD2AP and CIN85 are the most stable SH3 domains that have been studied until now. This high stability is driven by a more extensive network of intra-molecular interactions. We believe that this increased stabilization of N-terminal SH3 domains in adaptor proteins is crucial to maintain the necessary conformation to establish the proper interactions critical for the recruitment of their natural targets.

Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions.

Science.gov (United States)

Reedijk, M; Liu, X; van der Geer, P; Letwin, K; Waterfield, M D; Hunter, T; Pawson, T

1992-01-01

Efficient binding of active phosphatidylinositol (PI) 3'-kinase to the autophosphorylated macrophage colony stimulating factor receptor (CSF-1R) requires the noncatalytic kinase insert (KI) region of the receptor. To test whether this region could function independently to bind PI 3'-kinase, the isolated CSF-1R KI was expressed in Escherichia coli, and was inducibly phosphorylated on tyrosine. The tyrosine phosphorylated form of the CSF-1R KI bound PI 3'-kinase in vitro, whereas the unphosphorylated form had no binding activity. The p85 alpha subunit of PI 3'-kinase contains two Src homology (SH)2 domains, which are implicated in the interactions of signalling proteins with activated receptors. Bacterially expressed p85 alpha SH2 domains complexed in vitro with the tyrosine phosphorylated CSF-1R KI. Binding of the CSF-1R KI to PI 3'-kinase activity, and to the p85 alpha SH2 domains, required phosphorylation of Tyr721 within the KI domain, but was independent of phosphorylation at Tyr697 and Tyr706. Tyr721 was also critical for the association of activated CSF-1R with PI 3'-kinase in mammalian cells. Complex formation between the CSF-1R and PI 3'-kinase can therefore be reconstructed in vitro in a specific interaction involving the phosphorylated receptor KI and the SH2 domains of p85 alpha. Images PMID:1314163

The SH2 Domain–Containing Proteins in 21 Species Establish the Provenance and Scope of Phosphotyrosine Signaling in Eukaryotes

Science.gov (United States)

Liu, Bernard A.; Shah, Eshana; Jablonowski, Karl; Stergachis, Andrew; Engelmann, Brett; Nash, Piers D.

2014-01-01

The Src homology 2 (SH2) domains are participants in metazoan signal transduction, acting as primary mediators for regulated protein-protein interactions with tyrosine-phosphorylated substrates. Here, we describe the origin and evolution of SH2 domain proteins by means of sequence analysis from 21 eukaryotic organisms from the basal unicellular eukaryotes, where SH2 domains first appeared, through the multicellular animals and increasingly complex metazoans. On the basis of our results, SH2 domains and phosphotyrosine signaling emerged in the early Unikonta, and the numbers of SH2 domains expanded in the choanoflagellate and metazoan lineages with the development of tyrosine kinases, leading to rapid elaboration of phosphotyrosine signaling in early multicellular animals. Our results also indicated that SH2 domains coevolved and the number of the domains expanded alongside protein tyrosine kinases and tyrosine phosphatases, thereby coupling phosphotyrosine signaling to downstream signaling networks. Gene duplication combined with domain gain or loss produced novel SH2-containing proteins that function within phosphotyrosine signaling, which likely have contributed to diversity and complexity in metazoans. We found that intra- and intermolecular interactions within and between SH2 domain proteins increased in prevalence along with organismal complexity and may function to generate more highly connected and robust phosphotyrosine signaling networks. PMID:22155787

Shell report 2001; Les personnes, la planete, les profits. Shell rapport 2001

Energy Technology Data Exchange (ETDEWEB)

NONE

2002-07-01

In 2001, Shell saw mixed results across the social, environmental and economic spectrum. In order to contribute to the sustainable development, the Group is on track towards meeting its target to reduce greenhouse gas emissions to 10 % below 1990 levels by the end of 2002, although there was a significant increase in spill volumes and greenhouse gas emissions rose. Shell has articulated the business case and defined seven principles of sustainable development for use across the Group in business plans and daily operations: generating robust profitability; delivering value to customers; protecting the environment; managing resources; respecting and safeguarding people; benefiting communities; and working with stakeholders. Key points from the Shell Report include: in the framework of Managing, an independent review of the Shell Nigeria Community Development programme and testing of a human rights assessment tool in Shell South Africa and the implementing of a new Diversity and Inclusiveness Standard; in the framework of the economy the cost improvements of 5,1 billion dollars, ahead of target, the second highest earnings ever in difficult market conditions and the election of Shell top brand for fifth year running by motorists; in the framework of the Social, the safety performance, the avoidance of 100 contracts for incompatibility with Shell Business Principles; in the framework of the Environment, the publication of the Fresh water usage report for the first time, the Greenhouse gas emissions, the increase of spills as a result of a small number of incidents including a pipeline rupture in Nigeria and a well blow out in Oman. The economic, environmental and social data of the Shell Report are externally verified. (A.L.B.)

Ultraviolet absorption spectra and kinetics of CH3S and CH2SH radicals

DEFF Research Database (Denmark)

Anastasi, C.; Broomfield, M.; Nielsen, O.J.

1991-01-01

The ultraviolet absorption spectra of CH3S and CH2SH radicals have been measured between 215 and 380 nm using the pulse-radiolysis/kinetic-absorption method. One absorption band between 250 and 300 nm and one around 215 nm have been tentatively assigned to the CH2SH and CH3S radicals, respectively....... This spectrum has been used to measure the self-reaction rates of these radicals. Rate constants of 4 x 10(-11) and 7 x 10(-11) cm3 molecule-1 s-1 have been measured at 298 K for CH3S and CH2SH recombination, respectively. The possible reaction pathways are discussed....

Glutathione transferase-M2-2 secreted from glioblastoma cell protects SH-SY5Y cells from aminochrome neurotoxicity.

Science.gov (United States)

Cuevas, Carlos; Huenchuguala, Sandro; Muñoz, Patricia; Villa, Monica; Paris, Irmgard; Mannervik, Bengt; Segura-Aguilar, Juan

2015-04-01

U373MG cells are able to take up aminochrome that induces glutathione transferase M2-2 (GSTM2) expression in a concentration-dependent manner where 100 µM aminochrome increases GSTM2 expression by 2.1-fold (P protects SH-SY5Y cells incubated with 10 µM aminochrome. The significant protection provided by U373MG-conditioned medium in SH-SY5Y cells incubated with aminochrome was dependent on GSTM2 internalization into SH-SY5Y cells as evidenced by (i) uptake of (14)C-GSTM2 released from U373MG cells into SH-SY5Y cells, a process inhibited by anti-GSTM2 antiserum; (ii) lack of protection of U373MG-conditioned medium in the presence of anti-GSTM2 antiserum on SH-SY5Y cells treated with aminochrome; and (iii) lack of protection of conditioned medium from U373MGsiGST6 that expresses an siRNA directed against GSTM2 on SH-SY5Y cells treated with aminochrome. In conclusion, our results demonstrated that U373MG cells protect SH-SY5Y cells against aminochrome neurotoxicity by releasing GSTM2 into the conditioned medium and subsequent internalization of GSTM2 into SH-SY5Y cells. These results suggest a new mechanism of protection of dopaminergic neurons mediated by astrocytes by releasing GSTM2 into the intersynaptic space and subsequent internalization into dopaminergic neuron in order to protect these cells against aminochrome neurotoxicity.

Hydrophobic interaction between the SH2 domain and the kinase domain is required for the activation of Csk.

Science.gov (United States)

Mikkola, Esa T; Gahmberg, Carl G

2010-06-18

The protein tyrosine kinase C-terminal Src kinase (Csk) is activated by the engagement of its Src homology (SH) 2 domain. However, the molecular mechanism required for this is not completely understood. The crystal structure of the active Csk indicates that Csk could be activated by contact between the SH2 domain and the beta3-alphaC loop in the N-terminal lobe of the kinase domain. To study the importance of this interaction for the SH2-domain-mediated activation of Csk, we mutated the amino acid residues forming the contacts between the SH2 domain and the beta3-alphaC loop. The mutation of the beta3-alphaC loop Ala228 to glycine and of the SH2 domain Tyr116, Tyr133, Leu138, and Leu149 to alanine resulted in the inability of the SH2 domain ligand to activate Csk. Furthermore, the overexpressed Csk mutants A228G, Y133A/Y116A, L138A, and L149A were unable to efficiently inactivate endogenous Src in human embryonic kidney 293 cells. The results suggest that the SH2-domain-mediated activation of Csk is dependent on the binding of the beta3-alphaC loop Ala228 to the hydrophobic pocket formed by the side chains of Tyr116, Tyr133, Leu138, and Leu149 on the surface of the SH2 domain. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Screening for coding variants in FTO and SH2B1 genes in Chinese patients with obesity.

Directory of Open Access Journals (Sweden)

Zhaojing Zheng

Full Text Available To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity.Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls.A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05. However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05. None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05. One variant (L293R that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups.The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort.

Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells

International Nuclear Information System (INIS)

Park, Jae Hyeon; Lee, Jeong Eun; Shin, In Chul; Koh, Hyun Chul

2013-01-01

Recent studies have shown that up-regulation of autophagy may be a tractable therapeutic intervention for clearing disease-causing proteins, including α-synuclein, ubiquitin, and other misfolded or aggregated proteins in pesticide-induced neurodegeneration. In a previous study, we reported that chlorpyrifos (CPF)-induced mitochondria-dependent apoptosis is mediated through reactive oxygen species in SH-SY5Y cells. In this study, we explored a novel pharmacotherapeutic approach to prevent CPF neurotoxicity involving the regulation of autophagy. We investigated the modulation of CPF-induced apoptosis according to autophagy regulation. We found that CPF induced apoptosis in SH-SY5Y cells, as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, we observed that cells treated with CPF underwent autophagic cell death by monitoring the expression of LC3-II and p62. Pretreatment with the autophagy inducer rapamycin significantly enhanced the cell viability of CPF-exposed cells, and the enhancement of cell viability was partially due to alleviation of CPF-induced apoptosis via a decrease in levels of cleaved caspase-3. Specifically, rapamycin pretreatment decreased Bax and increased Bcl-2 expression in mitochondria. In addition, rapamycin significantly decreased cytochrome c release in from mitochondria into the cytosol. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), remarkably increased CPF toxicity in these cells; this with correlated with increased expression of Bax and decreased expression of Bcl-2 in mitochondria. Our results suggest that CPF-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against CPF-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. - Highlights: ► Chlorpyrifos (CPF) is cytotoxic to SH-SY5Y cells ► CPF-induced cytotoxicity is mediated by

Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells

Energy Technology Data Exchange (ETDEWEB)

Park, Jae Hyeon [Department of Pharmacology, College of Medicine, Hanyang University (Korea, Republic of); Hanyang Biomedical Research Institute, Seoul (Korea, Republic of); Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of); Lee, Jeong Eun [Department of Pharmacology, College of Medicine, Hanyang University (Korea, Republic of); Hanyang Biomedical Research Institute, Seoul (Korea, Republic of); Shin, In Chul [Department of Pharmacology, College of Medicine, Hanyang University (Korea, Republic of); Koh, Hyun Chul, E-mail: hckoh@hanyang.ac.kr [Department of Pharmacology, College of Medicine, Hanyang University (Korea, Republic of); Hanyang Biomedical Research Institute, Seoul (Korea, Republic of); Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of)

2013-04-01

Recent studies have shown that up-regulation of autophagy may be a tractable therapeutic intervention for clearing disease-causing proteins, including α-synuclein, ubiquitin, and other misfolded or aggregated proteins in pesticide-induced neurodegeneration. In a previous study, we reported that chlorpyrifos (CPF)-induced mitochondria-dependent apoptosis is mediated through reactive oxygen species in SH-SY5Y cells. In this study, we explored a novel pharmacotherapeutic approach to prevent CPF neurotoxicity involving the regulation of autophagy. We investigated the modulation of CPF-induced apoptosis according to autophagy regulation. We found that CPF induced apoptosis in SH-SY5Y cells, as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, we observed that cells treated with CPF underwent autophagic cell death by monitoring the expression of LC3-II and p62. Pretreatment with the autophagy inducer rapamycin significantly enhanced the cell viability of CPF-exposed cells, and the enhancement of cell viability was partially due to alleviation of CPF-induced apoptosis via a decrease in levels of cleaved caspase-3. Specifically, rapamycin pretreatment decreased Bax and increased Bcl-2 expression in mitochondria. In addition, rapamycin significantly decreased cytochrome c release in from mitochondria into the cytosol. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), remarkably increased CPF toxicity in these cells; this with correlated with increased expression of Bax and decreased expression of Bcl-2 in mitochondria. Our results suggest that CPF-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against CPF-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. - Highlights: ► Chlorpyrifos (CPF) is cytotoxic to SH-SY5Y cells ► CPF-induced cytotoxicity is mediated by

Combustion of peanut shells in a cone-shaped bubbling fluidized-bed combustor using alumina as the bed material

International Nuclear Information System (INIS)

Arromdee, Porametr; Kuprianov, Vladimir I.

2012-01-01

Highlights: ► We propose burning of peanut shells in a conical fluidized bed using alumina sand. ► We examine hydrodynamic, combustion and emission characteristics of the reactor. ► High, over 99%, combustion efficiency is achievable. ► Emissions of CO and NO from the combustor meet the national emission limits. ► Composition of the bed material undergoes significant changes during the combustion. -- Abstract: This paper reports experimental studies on burning peanut shells in the conical fluidized-bed combustor using alumina sand as the fluidizing agent. Prior to combustion tests, hydrodynamic regimes and characteristics of a conical alumina–biomass bed were investigated under cold-state conditions for variable percentage of peanut shells in the mixture and static bed height. With selected particle sizes (300–500 μm) and static bed height (30 cm), alumina ensured bubbling fluidization regime of the bed at operating conditions specified for firing biomass. Combustion tests were performed at 60 kg/h and 45 kg/h fuel feed rates, while ranging excess air from 20% to 80% at a fixed combustor load. Temperature and gas concentrations (O 2 , CO, C x H y as CH 4 , and NO) were measured along radial and axial directions inside the reactor as well as at stack in order to characterize combustion and emission performance of the combustor for the ranges of operating conditions. For firing 60 kg/h peanut shells, excess air of 40% can be selected as an appropriate value ensuring high, about 99%, combustion efficiency and rather low emissions of CO and NO: 520 ppm and 125 ppm, respectively (both on a dry basis and at 6% O 2 ). With reducing combustor load, the combustion efficiency and emission characteristics were improved to a little extent. No evidence of bed agglomeration was found during 30-h combustion tests on this conical fluidized-bed combustor using alumina sand as the bed material. However, the timescale effect on the composition of the bed material was

Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation.

Science.gov (United States)

Wong, Lilly; Lieser, Scot A; Miyashita, Osamu; Miller, Meghan; Tasken, Kjetil; Onuchic, Josè N; Adams, Joseph A; Woods, Virgil L; Jennings, Patricia A

2005-08-05

The C-terminal Src kinase (Csk) phosphorylates and down-regulates Src family tyrosine kinases. The Csk-binding protein (Cbp) localizes Csk close to its substrates at the plasma membrane, and increases the specific activity of the kinase. To investigate this long-range catalytic effect, the phosphorylation of Src and the conformation of Csk were investigated in the presence of a high-affinity phosphopeptide derived from Cbp. This peptide binds tightly to the SH2 domain and enhances Src recognition (lowers K(m)) by increasing the apparent phosphoryl transfer rate in the Csk active site, a phenomenon detected in rapid quench flow experiments. Previous studies demonstrated that the regulation of Csk activity is linked to conformational changes in the enzyme that can be probed with hydrogen-deuterium exchange methods. We show that the Cbp peptide impacts deuterium incorporation into its binding partner (the SH2 domain), and into the SH2-kinase linker and several sequences in the kinase domain, including the glycine-rich loop in the active site. These findings, along with computational data from normal mode analyses, suggest that the SH2 domain moves in a cantilever fashion with respect to the small lobe of the kinase domain, ordering the active site for catalysis. The binding of a small Cbp-derived peptide to the SH2 domain of Csk modifies these motions, enhancing Src recognition.

Spectral theory of differential operators M. Sh. Birman 80th anniversary collection

CERN Document Server

Suslina, T

2009-01-01

This volume is dedicated to Professor M. Sh. Birman in honor of his eightieth birthday. It contains original articles in spectral and scattering theory of differential operators, in particular, Schrodinger operators, and in homogenization theory. All articles are written by members of M. Sh. Birman's research group who are affiliated with different universities all over the world. A specific feature of the majority of the papers is a combination of traditional methods with new modern ideas.

Construction of lentiviral shRNA expression vector targeting ...

African Journals Online (AJOL)

ajl yemi

2011-10-26

Oct 26, 2011 ... was then selected, while the titer of lentiviral packing PLD2-shRNA was 3.47 × 104 TU/ml and the virus was successfully ... MATERIALS AND METHODS .... such as: transfecting cells not only in mitotic active phase but also in ...

MERTK interactions with SH2-domain proteins in the retinal pigment epithelium.

Science.gov (United States)

Shelby, Shameka J; Colwill, Karen; Dhe-Paganon, Sirano; Pawson, Tony; Thompson, Debra A

2013-01-01

The receptor tyrosine kinase MERTK plays an essential role in the phagocytic uptake of shed photoreceptor membranes by the retinal pigment epithelium (RPE). A fundamental aspect of signal transduction by receptor tyrosine kinases involves autophosphorylation of tyrosine residues that recruit Src-homology 2 (SH2)-domain proteins to the receptor intracellular domain. The goal of the current study was to evaluate the interactions of human MERTK with SH2-domain proteins present in the RPE. The MERTK intracellular domain was expressed as a 6xHis-fusion protein (6xHis-rMERTK(571-999)), purified and phosphorylated. Ni(2+)-NTA pull downs were performed using 6xHis-rMERTK(571-999) in incubations with recombinant phosphotyrosine-recognition sequences expressed as GST-fusion proteins. In addition, pull downs of native SH2-domain proteins were performed using 6xHis-rMERTK(571-999) and protein homogenates from rat RPE/choroid. For both recombinant and native proteins, western analysis detected MERTK interactions with GRB2, PIK3R1 (P85α), VAV3, and SRC. Immunohistochemical analysis localized each protein to mouse RPE. In cultured RPE-J cells incubated with rod outer segments (OS), siRNA knockdown of Grb2 had no effect on OS binding, but significantly reduced OS uptake. Pik3r1 localized to early phagosomes along with Rab5 and Eea1. Phosphorylation and activation of Src was detected downstream of phagocytosis and Mertk activation. These findings suggest that MERTK signaling in the RPE involves a cohort of SH2-domain proteins with the potential to regulate both cytoskeletal rearrangement and membrane movement. Identification of the SH2-domain signaling partners of MERTK is an important step toward further defining the mechanism of RPE phagocytosis that is central to the function and survival of the retina.

MERTK interactions with SH2-domain proteins in the retinal pigment epithelium.

Directory of Open Access Journals (Sweden)

Shameka J Shelby

Full Text Available The receptor tyrosine kinase MERTK plays an essential role in the phagocytic uptake of shed photoreceptor membranes by the retinal pigment epithelium (RPE. A fundamental aspect of signal transduction by receptor tyrosine kinases involves autophosphorylation of tyrosine residues that recruit Src-homology 2 (SH2-domain proteins to the receptor intracellular domain. The goal of the current study was to evaluate the interactions of human MERTK with SH2-domain proteins present in the RPE. The MERTK intracellular domain was expressed as a 6xHis-fusion protein (6xHis-rMERTK(571-999, purified and phosphorylated. Ni(2+-NTA pull downs were performed using 6xHis-rMERTK(571-999 in incubations with recombinant phosphotyrosine-recognition sequences expressed as GST-fusion proteins. In addition, pull downs of native SH2-domain proteins were performed using 6xHis-rMERTK(571-999 and protein homogenates from rat RPE/choroid. For both recombinant and native proteins, western analysis detected MERTK interactions with GRB2, PIK3R1 (P85α, VAV3, and SRC. Immunohistochemical analysis localized each protein to mouse RPE. In cultured RPE-J cells incubated with rod outer segments (OS, siRNA knockdown of Grb2 had no effect on OS binding, but significantly reduced OS uptake. Pik3r1 localized to early phagosomes along with Rab5 and Eea1. Phosphorylation and activation of Src was detected downstream of phagocytosis and Mertk activation. These findings suggest that MERTK signaling in the RPE involves a cohort of SH2-domain proteins with the potential to regulate both cytoskeletal rearrangement and membrane movement. Identification of the SH2-domain signaling partners of MERTK is an important step toward further defining the mechanism of RPE phagocytosis that is central to the function and survival of the retina.

Organizational structures and communications on the SH 130 project.

Science.gov (United States)

2006-03-01

This product summarizes the findings from research analyzing SH 130 organizational structures and communication flows. A set of guidelines pertaining to team organization and communication improvement and the design-build environment is also included...

Emerging medical informatics research trends detection based on MeSH terms.

Science.gov (United States)

Lyu, Peng-Hui; Yao, Qiang; Mao, Jin; Zhang, Shi-Jing

2015-01-01

The aim of this study is to analyze the research trends of medical informatics over the last 12 years. A new method based on MeSH terms was proposed to identify emerging topics and trends of medical informatics research. Informetric methods and visualization technologies were applied to investigate research trends of medical informatics. The metric of perspective factor (PF) embedding MeSH terms was appropriately employed to assess the perspective quality for journals. The emerging MeSH terms have changed dramatically over the last 12 years, identifying two stages of medical informatics: the "medical imaging stage" and the "medical informatics stage". The focus of medical informatics has shifted from acquisition and storage of healthcare data by integrating computational, informational, cognitive and organizational sciences to semantic analysis for problem solving and clinical decision-making. About 30 core journals were determined by Bradford's Law in the last 3 years in this area. These journals, with high PF values, have relative high perspective quality and lead the trend of medical informatics.

Local shell-to-shell energy transfer via nonlocal interactions in fluid ...

Indian Academy of Sciences (India)

However, the shell-to-shell energy transfer rate is found to be local and forward. .... interaction was strong, but the energy exchange occurred predominantly between ..... The wave-number range considered is in the inverse cascade regime.

Unified height systems after GOCE

Science.gov (United States)

Rummel, Reiner; Gruber, Thomas; Sideris, Michael; Rangelova, Elena; Woodworth, Phil; Hughes, Chris; Ihde, Johannes; Liebsch, Gunter; Rülke, Axel; Gerlach, Christian; Haagmans, Roger

2015-04-01

The objectives of global height unification are twofold, (1) the realization of accurate geopotential numbers C together with their standard deviation σ(C) at a selected set of stations (datum points of national height systems, geodetic fundamental stations (IERS), primary tide gauges (PSMSL) and primary reference clocks (IERS)) and (2) the determination of height off-sets between all existing regional/national height systems and one global height reference. In the future the primary method of height determination will be GPS-levelling with very stringent requirements concerning the consistency of the positioning and the gravity potential difference part. Consistency is required in terms of the applied standards (ITRF, zero tide system, geodetic reference system). Geopotential differences will be based on a next generation geopotential model combining GOCE and GRACE and a best possible collection of global terrestrial and altimetric gravity and topographic data. Ultimately, the envisaged accuracy of height unification is about 10 cm2/s2 (or 1cm). At the moment, in well surveyed regions, an accuracy of about 40 to 60 cm2/s2 (or 4 to 6cm) is attainable. Objective One can be realized by straight forward computation of geopotential numbers C, i.e. geopotential differences relative to an adopted height reference. No adjustment is required for this. Objective Two, the unification of existing height systems is achieved by employing a least-squares adjustment based on the GBVP-approach. In order to attain a non-singular solution, this requires for each included datum zone at least one geo-referenced station per zone, i.e. its ellipsoidal height h and, in addition, the corresponding physical height H (geopotential number, normal height, orthometric height, etc.). Changes in geopotential numbers of consecutive realizations reflect (1) temporal changes of station heights, (2) improvements or changes of the applied geopotential (or geoid) model and (3) improvements of the

Global effects of income and income inequality on adult height and sexual dimorphism in height.

Science.gov (United States)

Bogin, Barry; Scheffler, Christiane; Hermanussen, Michael

2017-03-01

Average adult height of a population is considered a biomarker of the quality of the health environment and economic conditions. The causal relationships between height and income inequality are not well understood. We analyze data from 169 countries for national average heights of men and women and national-level economic factors to test two hypotheses: (1) income inequality has a greater association with average adult height than does absolute income; and (2) neither income nor income inequality has an effect on sexual dimorphism in height. Average height data come from the NCD-RisC health risk factor collaboration. Economic indicators are derived from the World Bank data archive and include gross domestic product (GDP), Gross National Income per capita adjusted for personal purchasing power (GNI_PPP), and income equality assessed by the Gini coefficient calculated by the Wagstaff method. Hypothesis 1 is supported. Greater income equality is most predictive of average height for both sexes. GNI_PPP explains a significant, but smaller, amount of the variation. National GDP has no association with height. Hypothesis 2 is rejected. With greater average adult height there is greater sexual dimorphism. Findings support a growing literature on the pernicious effects of inequality on growth in height and, by extension, on health. Gradients in height reflect gradients in social disadvantage. Inequality should be considered a pollutant that disempowers people from the resources needed for their own healthy growth and development and for the health and good growth of their children. © 2017 Wiley Periodicals, Inc.

Two-dimensional Molecular Gas and Ongoing Star Formation around H II Region Sh2-104

Science.gov (United States)

Xu, Jin-Long; Xu, Ye; Yu, Naiping; Zhang, Chuan-peng; Liu, Xiao-Lan; Wang, Jun-Jie; Ning, Chang-chun; Ju, Bing-Gang; Zhang, Guo-Yin

2017-11-01

We performed a multi-wavelength study toward H II region Sh2-104. New maps of 12CO J = 1 - 0 and 13CO J = 1 - 0 were obtained from the Purple Mountain Observatory 13.7 m radio telescope. Sh2-104 displays a double-ring structure. The outer ring with a radius of 4.4 pc is dominated by 12, 500 μm, 12CO J = 1 - 0, and 13CO J = 1 - 0 emission, while the inner ring with a radius of 2.9 pc is dominated by 22 μm and 21 cm emission. We did not detect CO emission inside the outer ring. The north-east portion of the outer ring is blueshifted, while the south-west portion is redshifted. The present observations have provided evidence that the collected outer ring around Sh2-104 is a two-dimensional structure. From the column density map constructed by the Hi-GAL survey data, we extract 21 clumps. About 90% of all the clumps will form low-mass stars. A power-law fit to the clumps yields M=281 {M}⊙ {(r/{pc})}1.31+/- 0.08. The selected YSOs are associated with the collected material on the edge of Sh2-104. The derived dynamical age of Sh2-104 is 1.6× {10}6 yr. Comparing the Sh2-104 dynamical age with the YSO timescale and the fragmentation time of the molecular ring, we further confirm that the collect-and-collapse process operates in this region, indicating positive feedback from a massive star for surrounding gas.

Transferência de fatores genéticos de resistência a Hemileia vastatrix para o cultivar mundo novo Transference of the genes SH2 and SH3 for resistance to Hemileia vastatrix to the mundo novo cultivar of C. arabica

Directory of Open Access Journals (Sweden)

A. Carvalho

1977-01-01

Full Text Available Cafeeiros portadores dos fatores genéticos SH2 ou SH2 e SH3, simultaneamente, que conferem resistência a várias raças de Hemileia vastatrix, foram cruzados com plantas selecionadas do cultivar mundo novo de Coffea arabica a fim de se obter, em F2, recombinações com resistência a esse patógeno e elevada produtividade. Analisaram-se 14 populações F2 segregando apenas para o fator SH2, oito para os fatores SH2 e HS3, e três populações que dão, em sua descendência, plantas do grupo A, resistentes a todas as raças do patógeno até agora conhecidas. De 22.356 cafeeiros originalmente plantados em ensaio, a duas mudas por cova, em parcelas casualizadas, fez-se uma primeira seleção deixando apenas um cafeeiro por cova, reduzindo-se para 11.178 as plantas em estudo. Com base no aspecto vegetativo, na produtividade, na ausência de defeitos nos frutos e na reação de resistência ao agente causal da ferrugem, realizaram-se sucessivas seleções escolhendo-se finalmente, apenas 100 cafeeiros do tipo mundo novo e resistentes a H. vastatrix para derivação das populações F2 e prosseguimento da seleção.Coffee trees homozygous for the alleles SH2 or SH2 and SH3 which confer resistance to several physiological races of Hemileia vastatrix, were crossed to selected plants of Mundo Novo cultivar of Coffea arabica and the F2 generations were studied aiming to develop new high yielding and resistant coffee recombinations. A complete randomized field trial was stablished including 14 F2 populations segregating for SH2, eight populations segregating for SH2 and SH3 genes, and three populations segregating for plants of the A group of reaction to the H. vastatrix attack. A total of 22,356 F2 plants were analysed. Based on the plant vigor, yield capacity, percentage of normal developed seeds and resistance reaction to H. vastatrix, three successive series of selection were undertaken leaving only 100 coffee trees for development of F3 populations

Phosphorylation of the adaptor protein SH2B1β regulates its ability to enhance growth hormone-dependent macrophage motility

OpenAIRE

Su, Hsiao-Wen; Lanning, Nathan J.; Morris, David L.; Argetsinger, Lawrence S.; Lumeng, Carey N.; Carter-Su, Christin

2013-01-01

Previous studies have shown that growth hormone (GH) recruits the adapter protein SH2B1β to the GH-activated, GH receptor-associated tyrosine kinase JAK2, implicating SH2B1β in GH-dependent actin cytoskeleton remodeling, and suggesting that phosphorylation at serines 161 and 165 in SH2B1β releases SH2B1β from the plasma membrane. Here, we examined the role of SH2B1β in GH regulation of macrophage migration. We show that GH stimulates migration of cultured RAW264.7 macrophages, and primary cul...

The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.

Science.gov (United States)

Bae, Jae Hyun; Lew, Erin Denise; Yuzawa, Satoru; Tomé, Francisco; Lax, Irit; Schlessinger, Joseph

2009-08-07

SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated tyrosine kinase domain of FGFR1 in complex with a phospholipase Cgamma fragment. The structural and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cgamma binding and signaling via activated FGFR1 are determined by interactions between a secondary binding site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner. These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate a specific cellular process.

Multi-shelled ZnCo2O4 yolk-shell spheres for high-performance acetone gas sensor

Science.gov (United States)

Xiong, Ya; Zhu, Zongye; Ding, Degong; Lu, Wenbo; Xue, Qingzhong

2018-06-01

In the present study, multi-shelled ZnCo2O4 yolk-shell spheres have been successfully prepared by using carbonaceous microspheres as templates. It is found that the multi-shelled ZnCo2O4 yolk-shell spheres based sensor shows optimal sensing performances (response value of 38.2, response/recovery time of 19 s/71 s) toward 500 ppm acetone at 200 °C. In addition, this sensor exhibits a low detection limit of 0.5 ppm acetone (response value of 1.36) and a good selectivity toward hydrogen, methane, ethanol, ammonia and carbon dioxide. Furthermore, it is demonstrated that acetone gas response of multi-shelled ZnCo2O4 yolk-shell spheres is significantly better than that of ZnCo2O4 nanotubes and ZnCo2O4 nanosheets. High acetone response of the multi-shelled ZnCo2O4 yolk-shell spheres is attributed to the enhanced gas accessibility of the multi-shell morphology caused by the small crystalline size and high specific surface area while the short response/recovery time is mainly related to the rapid gas diffusion determined by the highly porous structure. Our work puts forward an exciting opportunity in designing various yolk-shelled structures for multipurpose applications.

Influence of Shell Thickness on the Colloidal Stability of Magnetic Core-Shell Particle Suspensions.

Science.gov (United States)

Neville, Frances; Moreno-Atanasio, Roberto

2018-01-01

We present a Discrete Element study of the behavior of magnetic core-shell particles in which the properties of the core and the shell are explicitly defined. Particle cores were considered to be made of pure iron and thus possessed ferromagnetic properties, while particle shells were considered to be made of silica. Core sizes ranged between 0.5 and 4.0 μm with the actual particle size of the core-shell particles in the range between 0.6 and 21 μm. The magnetic cores were considered to have a magnetization of one tenth of the saturation magnetization of iron. This study aimed to understand how the thickness of the shell hinders the formation of particle chains. Chain formation was studied with different shell thicknesses and particle sizes in the presence and absence of an electrical double layer force in order to investigate the effect of surface charge density on the magnetic core-shell particle interactions. For core sizes of 0.5 and 4.0 μm the relative shell thicknesses needed to hinder the aggregation process were approximately 0.4 and 0.6 respectively, indicating that larger core sizes are detrimental to be used in applications in which no flocculation is needed. In addition, the presence of an electrical double layer, for values of surface charge density of less than 20 mC/m 2 , could stop the contact between particles without hindering their vertical alignment. Only when the shell thickness was considerably larger, was the electrical double layer able to contribute to the full disruption of the magnetic flocculation process.

Encounter Probability of Individual Wave Height

DEFF Research Database (Denmark)

Liu, Z.; Burcharth, H. F.

1998-01-01

wave height corresponding to a certain exceedence probability within a structure lifetime (encounter probability), based on the statistical analysis of long-term extreme significant wave height. Then the design individual wave height is calculated as the expected maximum individual wave height...... associated with the design significant wave height, with the assumption that the individual wave heights follow the Rayleigh distribution. However, the exceedence probability of such a design individual wave height within the structure lifetime is unknown. The paper presents a method for the determination...... of the design individual wave height corresponding to an exceedence probability within the structure lifetime, given the long-term extreme significant wave height. The method can also be applied for estimation of the number of relatively large waves for fatigue analysis of constructions....

Interelectron correlations in photoionization of outer shells near inner shell thresholds

International Nuclear Information System (INIS)

Amusia, M Ya; Chernysheva, L V; Drukarev, E G

2015-01-01

We have studied the role of virtual excitations of inner shells upon outer shell photoionization. The calculations were performed in the frames of the Random Phase Approximation with Exchange (RPAE) and its generalized version GRPAE that take into account variation of the atomic field due to electron elimination and the inner vacancies decay. We apply both analytic approximation and numeric computations. The results are presented for 3p electrons in Ar and for 4d-electrons in Pd near inner shells thresholds. The effect considered proved to be quite noticeable. (paper)

Strong SH-to-Love wave scattering off the Southern California Continental Borderland

Science.gov (United States)

Yu, Chunquan; Zhan, Zhongwen; Hauksson, Egill; Cochran, Elizabeth S.

2017-01-01

Seismic scattering is commonly observed and results from wave propagation in heterogeneous medium. Yet, deterministic characterization of scatterers associated with lateral heterogeneities remains challenging. In this study, we analyze broadband waveforms recorded by the Southern California Seismic Network and observe strongly scattered Love waves following the arrival of teleseismic SH wave. These scattered Love waves travel approximately in the same (azimuthal) direction as the incident SH wave at a dominant period of ~10 s but at an apparent velocity of ~3.6 km/s as compared to the ~11 km/s for the SH wave. Back-projection suggests that this strong scattering is associated with pronounced bathymetric relief in the Southern California Continental Borderland, in particular the Patton Escarpment. Finite-difference simulations using a simplified 2-D bathymetric and crustal model are able to predict the arrival times and amplitudes of major scatterers. The modeling suggests a relatively low shear wave velocity in the Continental Borderland.

Presence of an SH2 domain in the actin-binding protein tensin.

Science.gov (United States)

Davis, S; Lu, M L; Lo, S H; Lin, S; Butler, J A; Druker, B J; Roberts, T M; An, Q; Chen, L B

1991-05-03

The molecular cloning of the complementary DNA coding for a 90-kilodalton fragment of tensin, an actin-binding component of focal contacts and other submembraneous cytoskeletal structures, is reported. The derived amino acid sequence revealed the presence of a Src homology 2 (SH2) domain. This domain is shared by a number of signal transduction proteins including nonreceptor tyrosine kinases such as Abl, Fps, Src, and Src family members, the transforming protein Crk, phospholipase C-gamma 1, PI-3 (phosphatidylinositol) kinase, and guanosine triphosphatase-activating protein (GAP). Like the SH2 domain found in Src, Crk, and Abl, the SH2 domain of tensin bound specifically to a number of phosphotyrosine-containing proteins from v-src-transformed cells. Tensin was also found to be phosphorylated on tyrosine residues. These findings suggest that by possessing both actin-binding and phosphotyrosine-binding activities and being itself a target for tyrosine kinases, tensin may link signal transduction pathways with the cytoskeleton.

Encounter Probability of Significant Wave Height

DEFF Research Database (Denmark)

Liu, Z.; Burcharth, H. F.

The determination of the design wave height (often given as the significant wave height) is usually based on statistical analysis of long-term extreme wave height measurement or hindcast. The result of such extreme wave height analysis is often given as the design wave height corresponding to a c...

Wrinkling of Pressurized Elastic Shells

KAUST Repository

Vella, Dominic; Ajdari, Amin; Vaziri, Ashkan; Boudaoud, Arezki

2011-01-01

We study the formation of localized structures formed by the point loading of an internally pressurized elastic shell. While unpressurized shells (such as a ping-pong ball) buckle into polygonal structures, we show that pressurized shells

Kinetic investigation of narrow-bore columns packed with prototype sub-2 μm superficially porous particles with various shell thickness.

Science.gov (United States)

Gritti, Fabrice; Omamogho, Jesse; Guiochon, Georges

2011-10-07

The recent successful breakthrough of sub-3 μm shell particles in HPLC has triggered considerable research efforts toward the design of new brands of core-shell particles. We investigated the mass transfer mechanism of a few analytes in narrow-bore columns packed with prototype 1.7 μm shell particles, made of 1.0, 1.2, and 1.4 μm solid nonporous cores surrounded by porous shells 350, 250, and 150 nm thick, respectively. Three probe solutes, uracil, naphthalene, and insulin, were chosen to assess the kinetic performance of these columns. Inverse size exclusion chromatography, peak parking experiments, and the numerical integration of the experimental peak profiles were carried out in order to measure the external, internal, and total column porosities, the true bulk diffusion coefficients of these analytes, the height equivalent to a theoretical plate, the longitudinal diffusion term, and the trans-particle mass transfer resistance term. The residual eddy diffusion term was measured by difference. The results show the existence of important trans-column velocity biases (7%) possibly due to the presence of particle multiplets in the slurry mixture used during the packing process. Our results illustrates some of the difficulties encountered by scientists preparing and packing shell particles into narrow-bore columns. Copyright © 2011 Elsevier B.V. All rights reserved.

SH2-PLA: a sensitive in-solution approach for quantification of modular domain binding by proximity ligation and real-time PCR.

Science.gov (United States)

Thompson, Christopher M; Bloom, Lee R; Ogiue-Ikeda, Mari; Machida, Kazuya

2015-06-26

There is a great interest in studying phosphotyrosine dependent protein-protein interactions in tyrosine kinase pathways that play a critical role in many aspects of cellular function. We previously established SH2 profiling, a phosphoproteomic approach based on membrane binding assays that utilizes purified Src Homology 2 (SH2) domains as a molecular tool to profile the global tyrosine phosphorylation state of cells. However, in order to use this method to investigate SH2 binding sites on a specific target in cell lysate, additional procedures such as pull-down or immunoprecipitation which consume large amounts of sample are required. We have developed PLA-SH2, an alternative in-solution modular domain binding assay that takes advantage of Proximity Ligation Assay and real-time PCR. The SH2-PLA assay utilizes oligonucleotide-conjugated anti-GST and anti-EGFR antibodies recognizing a GST-SH2 probe and cellular EGFR, respectively. If the GST-SH2 and EGFR are in close proximity as a result of SH2-phosphotyrosine interactions, the two oligonucleotides are brought within a suitable distance for ligation to occur, allowing for efficient complex amplification via real-time PCR. The assay detected signal across at least 3 orders of magnitude of lysate input with a linear range spanning 1-2 orders and a low femtomole limit of detection for EGFR phosphotyrosine. SH2 binding kinetics determined by PLA-SH2 showed good agreement with established far-Western analyses for A431 and Cos1 cells stimulated with EGF at various times and doses. Further, we showed that PLA-SH2 can survey lung cancer tissues using 1 μl lysate without requiring phospho-enrichment. We showed for the first time that interactions between SH2 domain probes and EGFR in cell lysate can be determined in a microliter-scale assay using SH2-PLA. The obvious benefit of this method is that the low sample requirement allows detection of SH2 binding in samples which are difficult to analyze using traditional protein

Adsorption of volatile organic compounds by pecan shell- and almond shell-based granular activated carbons.

Science.gov (United States)

Bansode, R R; Losso, J N; Marshall, W E; Rao, R M; Portier, R J

2003-11-01

The objective of this research was to determine the effectiveness of using pecan and almond shell-based granular activated carbons (GACs) in the adsorption of volatile organic compounds (VOCs) of health concern and known toxic compounds (such as bromo-dichloromethane, benzene, carbon tetrachloride, 1,1,1-trichloromethane, chloroform, and 1,1-dichloromethane) compared to the adsorption efficiency of commercially used carbons (such as Filtrasorb 200, Calgon GRC-20, and Waterlinks 206C AW) in simulated test medium. The pecan shell-based GACs were activated using steam, carbon dioxide or phosphoric acid. An almond shell-based GAC was activated with phosphoric acid. Our results indicated that steam- or carbon dioxide-activated pecan shell carbons were superior in total VOC adsorption to phosphoric acid-activated pecan shell or almond shell carbons, inferring that the method of activation selected for the preparation of activated carbons affected the adsorption of VOCs and hence are factors to be considered in any adsorption process. The steam-activated, pecan shell carbon adsorbed more total VOCs than the other experimental carbons and had an adsorption profile similar to the two coconut shell-based commercial carbons, but had greater adsorption than the coal-based commercial carbon. All the carbons studied adsorbed benzene more effectively than the other organics. Pecan shell, steam-activated and acid-activated GACs showed higher adsorption of 1,1,1-trichloroethane than the other carbons studied. Multivariate analysis was conducted to group experimental carbons and commercial carbons based on their physical, chemical, and adsorptive properties. The results of the analysis conclude that steam-activated and acid-activated pecan shell carbons clustered together with coal-based and coconut shell-based commercial carbons, thus inferring that these experimental carbons could potentially be used as alternative sources for VOC adsorption in an aqueous environment.

Instant Windows PowerShell

CERN Document Server

Menon, Vinith

2013-01-01

Get to grips with a new technology, understand what it is and what it can do for you, and then get to work with the most important features and tasks. A practical, hands-on tutorial approach that explores the concepts of PowerShell in a friendly manner, taking an adhoc approach to each topic.If you are an administrator who is new to PowerShell or are looking to get a good grounding in these new features, this book is ideal for you. It's assumed that you will have some experience in PowerShell and Windows Server, as well being familiar with the PowerShell command-line.

Coal option. [Shell Co

Energy Technology Data Exchange (ETDEWEB)

1978-01-01

This paper notes the necessity of developing an international coal trade on a very large scale. The role of Shell in the coal industry is examined; the regions in which Shell companies are most active are Australia, Southern Africa, Indonesia; Europe and North America. Research is being carried out on marketing and transportation, especially via slurry pipelines; coal-oil emulsions; briquets; fluidized-bed combustion; recovery of coal from potential waste material; upgrading of low-rank coals; unconventional forms of mining; coal conversion (the Shell/Koppers high-pressure coal gasification process). Techniques for cleaning flue gas (the Shell Flue Gas Desulfurization process) are being examined.

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility

Science.gov (United States)

Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I.; Hantschel, Oliver

2014-11-01

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

Hiding State in CλaSH Hardware Descriptions

NARCIS (Netherlands)

Gerards, Marco Egbertus Theodorus; Baaij, C.P.R.; Kuper, Jan; Kooijman, Matthijs

Synchronous hardware can be modelled as a mapping from input and state to output and a new state, such mappings are referred to as transition functions. It is natural to use a functional language to implement transition functions. The CaSH compiler is capable of translating transition functions to

Construction of lentiviral shRNA expression vector targeting ...

African Journals Online (AJOL)

DNA oligo was cloned into lentiviral expression vector, and then polymerase chain reaction (PCR) and sequencing analyses were conducted to verify the constructs. The verified vectors were co-transfected into 293FT cells that could produce lentiviral. shRNA lentiviruses from the selected constructs were propagated and ...

MOVPE growth of position-controlled InGaN / GaN core-shell nanorods

Energy Technology Data Exchange (ETDEWEB)

Mandl, Martin [Osram Opto Semiconductors GmbH, Regensburg (Germany); Institut fuer Halbleitertechnik, TU Braunschweig (Germany); Schimpke, Tilman; Binder, Michael; Galler, Bastian; Lugauer, Hans-Juergen; Strassburg, Martin [Osram Opto Semiconductors GmbH, Regensburg (Germany); Wang, Xue; Ledig, Johannes; Ehrenburg, Milena; Wehmann, Hergo-Heinrich; Waag, Andreas [Institut fuer Halbleitertechnik, TU Braunschweig (Germany); Kong, Xiang; Trampert, Achim [Paul-Drude-Institut fuer Festkoerperelektronik, Berlin (Germany)

2013-07-01

Core-shell group III-nitride nano- and microrods (NAMs) enable a significant increase of the active layer area by exploiting the non-polar side facets (m-planes) and thus can potentially contribute to mitigating the so-called efficiency droop in LEDs. GaN NAMs exhibiting high aspect ratios were grown in a production-type MOVPE system. Low V/III ratio, hydrogen-rich carrier gas mixture and surfactants supported the 3D growth of the pencil-shape n-type GaN core. Desired narrow distributions of shape, diameter and height were achieved. The arrangement of the NAMs was controlled by patterns etched into SiO{sub 2} masks deposited on GaN templates. The active layer (InGaN/GaN SQW and MQWs) and the layer for the p-side were deposited with 2D-like conditions wrapped around the core. The crystalline quality of the NAMs, shell growth rates and the Indium distribution were investigated by high resolution transmission electron microscopy. Furthermore, optical emission was studied using density-dependent photoluminescence spectroscopy.

Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling.

OpenAIRE

Rui, L; Mathews, L S; Hotta, K; Gustafson, T A; Carter-Su, C

1997-01-01

Activation of the tyrosine kinase JAK2 is an essential step in cellular signaling by growth hormone (GH) and multiple other hormones and cytokines. Murine JAK2 has a total of 49 tyrosines which, if phosphorylated, could serve as docking sites for Src homology 2 (SH2) or phosphotyrosine binding domain-containing signaling molecules. Using a yeast two-hybrid screen of a rat adipocyte cDNA library, we identified a splicing variant of the SH2 domain-containing protein SH2-B, designated SH2-Bbeta,...

Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

Science.gov (United States)

Gervois, P; Wolfs, E; Dillen, Y; Hilkens, P; Ratajczak, J; Driesen, R B; Vangansewinkel, T; Bronckaers, A; Brône, B; Struys, T; Lambrichts, I

2017-06-01

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na + current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd 2+ -sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca 2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular

Nuclear shell theory

CERN Document Server

de-Shalit, Amos; Massey, H S W

1963-01-01

Nuclear Shell Theory is a comprehensive textbook dealing with modern methods of the nuclear shell model. This book deals with the mathematical theory of a system of Fermions in a central field. It is divided into three parts. Part I discusses the single particle shell model. The second part focuses on the tensor algebra, two-particle systems. The last part covers three or more particle systems. Chapters on wave functions in a central field, tensor fields, and the m-Scheme are also presented. Physicists, graduate students, and teachers of nuclear physics will find the book invaluable.

Novel multiplexed assay for identifying SH2 domain antagonists of STAT family proteins.

Science.gov (United States)

Takakuma, Kazuyuki; Ogo, Naohisa; Uehara, Yutaka; Takahashi, Susumu; Miyoshi, Nao; Asai, Akira

2013-01-01

Some of the signal transducer and activator of transcription (STAT) family members are constitutively activated in a wide variety of human tumors. The activity of STAT depends on their Src homology 2 (SH2) domain-mediated binding to sequences containing phosphorylated tyrosine. Thus, antagonizing this binding is a feasible approach to inhibiting STAT activation. We have developed a novel multiplexed assay for STAT3- and STAT5b-SH2 binding, based on amplified luminescent proximity homogeneous assay (Alpha) technology. AlphaLISA and AlphaScreen beads were combined in a single-well assay, which allowed the binding of STAT3- and STAT5b-SH2 to phosphotyrosine peptides to be simultaneously monitored. Biotin-labeled recombinant human STAT proteins were obtained as N- and C-terminal deletion mutants. The spacer length of the DIG-labeled peptide, the reaction time, and the concentration of sodium chloride were optimized to establish a HTS system with Z' values of greater than 0.6 for both STAT3- and STAT5b-SH2 binding. We performed a HTS campaign for chemical libraries using this multiplexed assay and identified hit compounds. A 2-chloro-1,4-naphthalenedione derivative, Compound 1, preferentially inhibited STAT3-SH2 binding in vitro, and the nuclear translocation of STAT3 in HeLa cells. Initial structure activity relationship (SAR) studies using the multiplexed assay showed the 3-substituent effect on both the activity and selectivity of STAT3 and STAT5b inhibition. Therefore, this multiplexed assay is useful for not only searching for potential lead compounds but also obtaining SAR data for developing new STAT3/STAT5b inhibitors.

Wrinkling of Pressurized Elastic Shells

KAUST Repository

Vella, Dominic

2011-10-01

We study the formation of localized structures formed by the point loading of an internally pressurized elastic shell. While unpressurized shells (such as a ping-pong ball) buckle into polygonal structures, we show that pressurized shells are subject to a wrinkling instability. We study wrinkling in depth, presenting scaling laws for the critical indentation at which wrinkling occurs and the number of wrinkles formed in terms of the internal pressurization and material properties of the shell. These results are validated by numerical simulations. We show that the evolution of the wrinkle length with increasing indentation can be understood for highly pressurized shells from membrane theory. These results suggest that the position and number of wrinkles may be used in combination to give simple methods for the estimation of the mechanical properties of highly pressurized shells. © 2011 American Physical Society.

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3.

Science.gov (United States)

Puchulu-Campanella, Estela; Turrini, Francesco M; Li, Yen-Hsing; Low, Philip S

2016-11-29

Src homology 2 (SH2) domains are composed of weakly conserved sequences of ∼100 aa that bind phosphotyrosines in signaling proteins and thereby mediate intra- and intermolecular protein-protein interactions. In exploring the mechanism whereby tyrosine phosphorylation of the erythrocyte anion transporter, band 3, triggers membrane destabilization, vesiculation, and fragmentation, we discovered a SH2 signature motif positioned between membrane-spanning helices 4 and 5. Evidence that this exposed cytoplasmic sequence contributes to a functional SH2-like domain is provided by observations that: (i) it contains the most conserved sequence of SH2 domains, GSFLVR; (ii) it binds the tyrosine phosphorylated cytoplasmic domain of band 3 (cdb3-PO 4 ) with K d = 14 nM; (iii) binding of cdb3-PO 4 to erythrocyte membranes is inhibited both by antibodies against the SH2 signature sequence and dephosphorylation of cdb3-PO 4 ; (iv) label transfer experiments demonstrate the covalent transfer of photoactivatable biotin from isolated cdb3-PO 4 (but not cdb3) to band 3 in erythrocyte membranes; and (v) phosphorylation-induced binding of cdb3-PO 4 to the membrane-spanning domain of band 3 in intact cells causes global changes in membrane properties, including (i) displacement of a glycolytic enzyme complex from the membrane, (ii) inhibition of anion transport, and (iii) rupture of the band 3-ankyrin bridge connecting the spectrin-based cytoskeleton to the membrane. Because SH2-like motifs are not retrieved by normal homology searches for SH2 domains, but can be found in many tyrosine kinase-regulated transport proteins using modified search programs, we suggest that related cases of membrane transport proteins containing similar motifs are widespread in nature where they participate in regulation of cell properties.

Describing shell shape variations and sexual dimorphism of Golden Apple Snail, Pomacea caniculata (Lamarck, 1822 using geometric morphometric analysis

Directory of Open Access Journals (Sweden)

C.C. Cabuga

2017-09-01

Full Text Available Pomacea caniculata or Golden Apple Snail (GAS existed to be a rice pest in the Philippines and in Asia. Likewise, geographic location also contributes its increasing populations thus making it invasive among freshwater habitats and rice field areas. This study was conducted in order to describe shell shape variations and sexual dimorphism among the populations of P. caniculata. A total of 180 were randomly collected in the three lakes of Esperanza, Agusan del Sur (Lake Dakong Napo, Lake Oro, and Lake Cebulan, of which each lake comprised of 60 samples (30 males and 30 females. To determine the variations and sexual dimorphism in the shell shape of golden apple snail, coordinates was administered to relative warp analysis and the resulting data were subjected to Multivariate Analysis of Variance (MANOVA, Principal Component Analysis (PCA and Canonical Variate Analysis (CVA. The results show statistically significant (P<0.05 from the appended male and female dorsal and ventral/apertural portion. While male and female spire height, body size, and shell shape opening also shows significant variations. These phenotypic distinctions could be associated with geographic isolation, predation and nutrient component of the gastropods. Thus, the importance of using geometric morphometric advances in describing sexual dimorphism in the shell shape of P. caniculata.

SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors.

Science.gov (United States)

McGlade, C J; Ellis, C; Reedijk, M; Anderson, D; Mbamalu, G; Reith, A D; Panayotou, G; End, P; Bernstein, A; Kazlauskas, A

1992-01-01

The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 domains. Both p85 alpha SH2 domains, when expressed individually as fusion proteins in bacteria, bound stably to the activated beta receptor for platelet-derived growth factor (PDGF). Complex formation required PDGF stimulation and was dependent on receptor tyrosine kinase activity. The bacterial p85 alpha SH2 domains recognized activated beta PDGF receptor which had been immobilized on a filter, indicating that SH2 domains contact autophosphorylated receptors directly. Several receptor tyrosine kinases within the PDGF receptor subfamily, including the colony-stimulating factor 1 receptor and the Steel factor receptor (Kit), also associate with PI 3-kinase in vivo. Bacterially expressed SH2 domains derived from the p85 alpha subunit of PI 3-kinase bound in vitro to the activated colony-stimulating factor 1 receptor and to Kit. We infer that the SH2 domains of p85 alpha bind to high-affinity sites on these receptors, whose creation is dependent on receptor autophosphorylation. The SH2 domains of p85 are therefore primarily responsible for the binding of PI 3-kinase to activated growth factor receptors. Images PMID:1372092

Stability of charged thin shells

International Nuclear Information System (INIS)

Eiroa, Ernesto F.; Simeone, Claudio

2011-01-01

In this article we study the mechanical stability of spherically symmetric thin shells with charge, in Einstein-Maxwell and Einstein-Born-Infeld theories. We analyze linearized perturbations preserving the symmetry, for shells around vacuum and shells surrounding noncharged black holes.

Characterization of a novel weak interaction between MUC1 and Src-SH3 using nuclear magnetic resonance spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Gunasekara, Nirosha [Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.21 WCM Health Science Centre, 8440-112th Street, Edmonton, Alberta, Canada T6G 2R7 (Canada); Sykes, Brian, E-mail: brian.sykes@ualberta.ca [Department of Biochemistry, 4-19B Medical Sciences Bldg., University of Alberta Edmonton, Alberta, Canada T6G 2H7 (Canada); Hugh, Judith, E-mail: judithh@ualberta.ca [Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.21 WCM Health Science Centre, 8440-112th Street, Edmonton, Alberta, Canada T6G 2R7 (Canada)

2012-05-18

Highlights: Black-Right-Pointing-Pointer MUC1 binds the Src-SH3 domain potentially triggering Src dependent cell migration. Black-Right-Pointing-Pointer NMR Spectroscopy was used to monitor MUC1-CD and Src SH3 domain titrations. Black-Right-Pointing-Pointer MUC1-CD peptides bind with a low affinity (K{sub d} of 2-3 mM) to a non-canonical site. Black-Right-Pointing-Pointer Weak interactions may mediate dynamic processes like migration. Black-Right-Pointing-Pointer The MUC1-CD and Src-SH3 interaction may be a prime target to inhibit cell migration. -- Abstract: Breast cancer causes death through cancer cell migration and subsequent metastasis to distant organs. In vitro, the MUC1 mucin can mediate breast cancer cell migration by binding to intercellular adhesion molecule-1 (ICAM-1). This migration is dependent on MUC1 cytoplasmic domain (MUC1-CD) activation of the non-receptor tyrosine kinase, Src, possibly through competitive displacement of an inhibitory Src intramolecular SH3 binding. Therefore, we characterized the binding site and affinity of the MUC1-CD for Src-SH3 using multidimensional nuclear magnetic resonance (NMR) spectroscopy to monitor the titration of the {sup 15}N labeled Src-SH3 domain with synthetic native and mutant peptides of MUC1-CD. The results revealed that the dissociation constant (K{sub d}) for the interaction of the native MUC1-CD peptides and Src-SH3 domain was weak with a K{sub d} of 2-3 mM. Notably, the SH3 residues most perturbed upon peptide binding were located outside the usual hydrophobic binding cleft in a previously described alternate binding site on the Src-SH3, suggesting that MUC1-CD binds to a non-canonical site. The binding characteristics outlined here suggest that the interaction between Src-SH3 and MUC1-CD represents a novel weak electrostatic interaction of the type which is increasingly recognized as important in transient and dynamic protein complexes required for cell migration and signal transduction. As such, this

Synthesis and characterization of noble metal–titania core–shell nanostructures with tunable shell thickness

Directory of Open Access Journals (Sweden)

Bartosz Bartosewicz

2017-10-01

Full Text Available Core–shell nanostructures have found applications in many fields, including surface enhanced spectroscopy, catalysis and solar cells. Titania-coated noble metal nanoparticles, which combine the surface plasmon resonance properties of the core and the photoactivity of the shell, have great potential for these applications. However, the controllable synthesis of such nanostructures remains a challenge due to the high reactivity of titania precursors. Hence, a simple titania coating method that would allow better control over the shell formation is desired. A sol–gel based titania coating method, which allows control over the shell thickness, was developed and applied to the synthesis of Ag@TiO2 and Au@TiO2 with various shell thicknesses. The morphology of the synthesized structures was investigated using scanning electron microscopy (SEM. Their sizes and shell thicknesses were determined using tunable resistive pulse sensing (TRPS technique. The optical properties of the synthesized structures were characterized using UV–vis spectroscopy. Ag@TiO2 and Au@TiO2 structures with shell thickness in the range of ≈40–70 nm and 90 nm, for the Ag and Au nanostructures respectively, were prepared using a method we developed and adapted, consisting of a change in the titania precursor concentration. The synthesized nanostructures exhibited significant absorption in the UV–vis range. The TRPS technique was shown to be a very useful tool for the characterization of metal–metal oxide core–shell nanostructures.

Polar Desolvation and Position 226 of Pancreatic and Neutrophil Elastases Are Crucial to their Affinity for the Kunitz-Type Inhibitors ShPI-1 and ShPI-1/K13L.

Science.gov (United States)

Hernández González, Jorge Enrique; García-Fernández, Rossana; Valiente, Pedro Alberto

2015-01-01

The Kunitz-type protease inhibitor ShPI-1 inhibits human neutrophil elastase (HNE, Ki = 2.35·10-8 M) but does not interact with the porcine pancreatic elastase (PPE); whereas its P1 site variant, ShPI-1/K13L, inhibits both HNE and PPE (Ki = 1.3·10-9 M, and Ki = 1.2·10-8 M, respectively). By employing a combination of molecular modeling tools, e.g., structural alignment, molecular dynamics simulations and Molecular Mechanics Generalized-Born/Poisson-Boltzmann Surface Area free energy calculations, we showed that D226 of HNE plays a critical role in the interaction of this enzyme with ShPI-1 through the formation of a strong salt bridge and hydrogen bonds with K13 at the inhibitor's P1 site, which compensate the unfavorable polar-desolvation penalty of the latter residue. Conversely, T226 of PPE is unable to establish strong interactions with K13, thereby precluding the insertion of K13 side-chain into the S1 subsite of this enzyme. An alternative conformation of K13 site-chain placed at the entrance of the S1 subsite of PPE, similar to that observed in the crystal structure of ShPI-1 in complex with chymotrypsin (PDB: 3T62), is also unfavorable due to the lack of stabilizing pair-wise interactions. In addition, our results suggest that the higher affinity of ShPI-1/K13L for both elastases mainly arises from the lower polar-desolvation penalty of L13 compared to that of K13, and not from stronger pair-wise interactions of the former residue with those of each enzyme. These results provide insights into the PPE and HNE inhibition and may contribute to the design of more potent and/or specific inhibitors toward one of these proteases.

Shell supports

DEFF Research Database (Denmark)

Almegaard, Henrik

2004-01-01

A new statical and conceptual model for membrane shell structures - the stringer system - has been found. The principle was first published at the IASS conference in Copenhagen (OHL91), and later the theory has been further developed (ALMO3)(ALMO4). From the analysis of the stringer model it can...... be concluded that all membrane shells can be described by a limited number of basic configurations of which quite a few have free edges....

A relationship between SNR G109.1-1.0 and the molecular cloud of Sh2-152

International Nuclear Information System (INIS)

Heydari-Malayeri, M.; Kahane, C.; Lucas, R.

1981-01-01

The possible association of the supernova remnant SNR G109.1 - 1.0 and the x-ray source GF2259 + 586 with the molecular cloud of Sh2 - 152 has been investigated by observing the molecular line 13 CO (J = 1 → 0) of the complex Sh2 - 147/Sh2 - 153. The present results are compared with those of previous workers. It is shown that although the various estimates of distance for the SNR, the x-ray source, the H II region Sh2 - 152 and the molecular cloud are in relatively good agreement, because of the uncertainties of distance evaluation in the Perseus arm this cannot be regarded as conclusive proof of the association of these objects. (U.K.)

High-Throughput Quantification of SH2 Domain-Phosphopeptide Interactions with Cellulose-Peptide Conjugate Microarrays.

Science.gov (United States)

Engelmann, Brett W

2017-01-01

The Src Homology 2 (SH2) domain family primarily recognizes phosphorylated tyrosine (pY) containing peptide motifs. The relative affinity preferences among competing SH2 domains for phosphopeptide ligands define "specificity space," and underpins many functional pY mediated interactions within signaling networks. The degree of promiscuity exhibited and the dynamic range of affinities supported by individual domains or phosphopeptides is best resolved by a carefully executed and controlled quantitative high-throughput experiment. Here, I describe the fabrication and application of a cellulose-peptide conjugate microarray (CPCMA) platform to the quantitative analysis of SH2 domain specificity space. Included herein are instructions for optimal experimental design with special attention paid to common sources of systematic error, phosphopeptide SPOT synthesis, microarray fabrication, analyte titrations, data capture, and analysis.

Identification of Tyrosine Phosphorylated Proteins by SH2 Domain Affinity Purification and Mass Spectrometry.

Science.gov (United States)

Buhs, Sophia; Gerull, Helwe; Nollau, Peter

2017-01-01

Phosphotyrosine signaling plays a major role in the control of many important biological functions such as cell proliferation and apoptosis. Deciphering of phosphotyrosine-dependent signaling is therefore of great interest paving the way for the understanding of physiological and pathological processes of signal transduction. On the basis of the specific binding of SH2 domains to phosphotyrosine residues, we here present an experimental workflow for affinity purification and subsequent identification of tyrosine phosphorylated proteins by mass spectrometry. In combination with SH2 profiling, a broadly applicable platform for the characterization of phosphotyrosine profiles in cell extracts, our pull down strategy enables researchers by now to identify proteins in signaling cascades which are differentially phosphorylated and selectively recognized by distinct SH2 domains.

The Spectrum of Jupiters Great Red Spot: the Case for Ammonium Hydrosulfide (NH4SH)

Science.gov (United States)

Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

2016-01-01

Here we present new ultraviolet-visible spectra of irradiated ammonium hydrosul?de (NH4SH), a reported Jovian atmospheric cloud component, for a range of temperatures and radiation doses and make assignments to the spectral features. We show that the combination of radiolysis and thermal annealing of NH4SH causes the originally featureless ultraviolet-visible re?ectance spectrum to evolve into one that absorbs in the ultraviolet-visible region. Furthermore, we ?nd that our laboratory spectra resemble HST (Hubble Space Telescope) spectra below 500 nanometers, suggesting that the more stable reaction products of NH4SH radiolysis are likely an important component of the Great Red Spot.

The Spectrum of Jupiter's Great Red Spot: The Case for Ammonium Hydrosulfide (NH4SH)

Science.gov (United States)

Loeffler, Mark J.; Hudson, Reggie L.; Chanover, Nancy J.; Simon, Amy A.

2016-01-01

Here we present new ultraviolet-visible spectra of irradiated ammonium hydrosul?de (NH4SH), a reported Jovian atmospheric cloud component, for a range of temperatures and radiation doses and make assignments to the spectral features. We show that the combination of radiolysis and thermal annealing of NH4SH causes the originally featureless ultraviolet-visible re?ectance spectrum to evolve into one that absorbs in the ultraviolet-visible region. Furthermore, we ?nd that our laboratory spectra resemble HST (Hubble Space Telescope) spectra below 500 nanometers, suggesting that the more stable reaction products of NH4SH radiolysis are likely an important component of the Great Red Spot.

A refined element-based Lagrangian shell element for geometrically nonlinear analysis of shell structures

Directory of Open Access Journals (Sweden)

Woo-Young Jung

2015-04-01

Full Text Available For the solution of geometrically nonlinear analysis of plates and shells, the formulation of a nonlinear nine-node refined first-order shear deformable element-based Lagrangian shell element is presented. Natural co-ordinate-based higher order transverse shear strains are used in present shell element. Using the assumed natural strain method with proper interpolation functions, the present shell element generates neither membrane nor shear locking behavior even when full integration is used in the formulation. Furthermore, a refined first-order shear deformation theory for thin and thick shells, which results in parabolic through-thickness distribution of the transverse shear strains from the formulation based on the third-order shear deformation theory, is proposed. This formulation eliminates the need for shear correction factors in the first-order theory. To avoid difficulties resulting from large increments of the rotations, a scheme of attached reference system is used for the expression of rotations of shell normal. Numerical examples demonstrate that the present element behaves reasonably satisfactorily either for the linear or for geometrically nonlinear analysis of thin and thick plates and shells with large displacement but small strain. Especially, the nonlinear results of slit annular plates with various loads provided the benchmark to test the accuracy of related numerical solutions.

Statistical Mechanics of Thin Spherical Shells

Directory of Open Access Journals (Sweden)

Andrej Košmrlj

2017-01-01

Full Text Available We explore how thermal fluctuations affect the mechanics of thin amorphous spherical shells. In flat membranes with a shear modulus, thermal fluctuations increase the bending rigidity and reduce the in-plane elastic moduli in a scale-dependent fashion. This is still true for spherical shells. However, the additional coupling between the shell curvature, the local in-plane stretching modes, and the local out-of-plane undulations leads to novel phenomena. In spherical shells, thermal fluctuations produce a radius-dependent negative effective surface tension, equivalent to applying an inward external pressure. By adapting renormalization group calculations to allow for a spherical background curvature, we show that while small spherical shells are stable, sufficiently large shells are crushed by this thermally generated “pressure.” Such shells can be stabilized by an outward osmotic pressure, but the effective shell size grows nonlinearly with increasing outward pressure, with the same universal power-law exponent that characterizes the response of fluctuating flat membranes to a uniform tension.

Genomic analysis of the aconidial and high-performance protein producer, industrially relevant Aspergillus niger SH2 strain.

Science.gov (United States)

Yin, Chao; Wang, Bin; He, Pan; Lin, Ying; Pan, Li

2014-05-15

Aspergillus niger is usually regarded as a beneficial species widely used in biotechnological industry. Obtaining the genome sequence of the widely used aconidial A. niger SH2 strain is of great importance to understand its unusual production capability. In this study we assembled a high-quality genome sequence of A. niger SH2 with approximately 11,517 ORFs. Relatively high proportion of genes enriched for protein expression related FunCat items verify its efficient capacity in protein production. Furthermore, genome-wide comparative analysis between A. niger SH2 and CBS513.88 reveals insights into unique properties of A. niger SH2. A. niger SH2 lacks the gene related with the initiation of asexual sporulation (PrpA), leading to its distinct aconidial phenotype. Frame shift mutations and non-synonymous SNPs in genes of cell wall integrity signaling, β-1,3-glucan synthesis and chitin synthesis influence its cell wall development which is important for its hyphal fragmentation during industrial high-efficiency protein production. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimization of a Finned Shell and Tube Heat Exchanger Using a Multi-Objective Optimization Genetic Algorithm

Directory of Open Access Journals (Sweden)

Heidar Sadeghzadeh

2015-08-01

Full Text Available Heat transfer rate and cost significantly affect designs of shell and tube heat exchangers. From the viewpoint of engineering, an optimum design is obtained via maximum heat transfer rate and minimum cost. Here, an analysis of a radial, finned, shell and tube heat exchanger is carried out, considering nine design parameters: tube arrangement, tube diameter, tube pitch, tube length, number of tubes, fin height, fin thickness, baffle spacing ratio and number of fins per unit length of tube. The “Delaware modified” technique is used to determine heat transfer coefficients and the shell-side pressure drop. In this technique, the baffle cut is 20 percent and the baffle ratio limits range from 0.2 to 0.4. The optimization of the objective functions (maximum heat transfer rate and minimum total cost is performed using a non-dominated sorting genetic algorithm (NSGA-II, and compared against a one-objective algorithm, to find the best solutions. The results are depicted as a set of solutions on a Pareto front, and show that the heat transfer rate ranges from 3517 to 7075 kW. Also, the minimum and maximum objective functions are specified, allowing the designer to select the best points among these solutions based on requirements. Additionally, variations of shell-side pressure drop with total cost are depicted, and indicate that the pressure drop ranges from 3.8 to 46.7 kPa.

SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase.

OpenAIRE

Kotani, K; Wilden, P; Pillay, T S

1998-01-01

We identified SH2-Balpha as an insulin-receptor-binding protein based on interaction screening in yeast hybrid systems and co-precipitation in cells. SH2-Balpha contains pleckstrin-homology ('PH') and Src homology 2 (SH2) domains and is closely related to APS (adapter protein with a PH domain and an SH2 domain) and lnk, adapter proteins first identified in lymphocytes. SH2-Balpha is ubiquitously expressed and is present in rat epididymal adipose tissue, liver and skeletal muscle, physiologica...

Estrogen Receptor Folding Modulates cSrc Kinase SH2 Interaction via a Helical Binding Mode.

Science.gov (United States)

Nieto, Lidia; Tharun, Inga M; Balk, Mark; Wienk, Hans; Boelens, Rolf; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, Luc

2015-11-20

The estrogen receptors (ERs) feature, next to their transcriptional role, important nongenomic signaling actions, with emerging clinical relevance. The Src Homology 2 (SH2) domain mediated interaction between cSrc kinase and ER plays a key role in this; however the molecular determinants of this interaction have not been elucidated. Here, we used phosphorylated ER peptide and semisynthetic protein constructs in a combined biochemical and structural study to, for the first time, provide a quantitative and structural characterization of the cSrc SH2-ER interaction. Fluorescence polarization experiments delineated the SH2 binding motif in the ER sequence. Chemical shift perturbation analysis by nuclear magnetic resonance (NMR) together with molecular dynamics (MD) simulations allowed us to put forward a 3D model of the ER-SH2 interaction. The structural basis of this protein-protein interaction has been compared with that of the high affinity SH2 binding sequence GpYEEI. The ER features a different binding mode from that of the "two-pronged plug two-hole socket" model in the so-called specificity determining region. This alternative binding mode is modulated via the folding of ER helix 12, a structural element directly C-terminal of the key phosphorylated tyrosine. The present findings provide novel molecular entries for understanding nongenomic ER signaling and targeting the corresponding disease states.

Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker.

Science.gov (United States)

Yan, Qingrong; Barros, Tiago; Visperas, Patrick R; Deindl, Sebastian; Kadlecek, Theresa A; Weiss, Arthur; Kuriyan, John

2013-06-01

Serial activation of the tyrosine kinases Lck and ZAP-70 initiates signaling downstream of the T cell receptor. We previously reported the structure of an autoinhibited ZAP-70 variant in which two regulatory tyrosine residues (315 and 319) in the SH2-kinase linker were replaced by phenylalanine. We now present a crystal structure of ZAP-70 in which Tyr 315 and Tyr 319 are not mutated, leading to the recognition of a five-residue sequence register error in the SH2-kinase linker of the original crystallographic model. The revised model identifies distinct roles for these two tyrosines. As seen in a recently reported structure of the related tyrosine kinase Syk, Tyr 315 of ZAP-70 is part of a hydrophobic interface between the regulatory apparatus and the kinase domain, and the integrity of this interface would be lost upon engagement of doubly phosphorylated peptides by the SH2 domains. Tyr 319 is not necessarily dislodged by SH2 engagement, which activates ZAP-70 only ∼5-fold in vitro. In contrast, phosphorylation by Lck activates ZAP-70 ∼100-fold. This difference is due to the ability of Tyr 319 to suppress ZAP-70 activity even when the SH2 domains are dislodged from the kinase domain, providing stringent control of ZAP-70 activity downstream of Lck.

Expression, refolding and crystallizations of the Grb2-like (GADS) C-terminal SH3 domain complexed with a SLP-76 motif peptide

International Nuclear Information System (INIS)

Faravelli, Alessandro; Dimasi, Nazzareno

2005-01-01

Several crystals of the Grb2-like C-terminal SH3 domain in complex with a motif peptide from the SLP-76 protein were obtained and characterized. The Grb2-like adaptor protein GADS is composed of an N-terminal SH3 domain, an SH2 domain, a proline-rich region and a C-terminal SH3 domain. GADS interacts through its C-terminal SH3 domain with the adaptor protein SLP-76, thus recruiting this protein and other associated molecules to the linker for activation of T-cell (LAT) protein. The DNA encoding the C-terminal SH3 domain of GADS (GADS-cSH3) was assembled synthetically using a recursive PCR technique and the protein was overexpressed in Escherichia coli, refolded and purified. Several crystals of this domain in complex with the SLP-76 peptide were obtained and characterized

Temporal structures in shell models

DEFF Research Database (Denmark)

Okkels, F.

2001-01-01

The intermittent dynamics of the turbulent Gledzer, Ohkitani, and Yamada shell-model is completely characterized by a single type of burstlike structure, which moves through the shells like a front. This temporal structure is described by the dynamics of the instantaneous configuration of the shell...

Expert system development (ESD) shell

International Nuclear Information System (INIS)

Padmini, S.; Diwakar, M.P.; Rathode, N.C.; Bairi, B.R.

1991-01-01

An Expert System Development (ESD) Shell design implementation is desribed in detail. The shell provides high-level generic facilities for Knowledge Representation (KR) and inferencing and tools for developing user interfaces. Powerful set of tools in the shell relieves much of the programming burden in the ES development. The shell is written in PROLOG under IBM PC/AT. KR facilities are based on two very powerful formalisms namely, frames and rules. Inference Engine (IE) draws most of its power from unification and backward reasoning strategy in PROLOG. This basic mechanism is enhanced further by incorporating both forward and backward chaining of rules and frame-based inferencing. Overall programming style integrates multiple paradigms including logic, object oriented, access-oriented and imperative programming. This permits ES designer a lot of flexibility in organizing inference control. Creation and maintainance of knowledge base is a major activity. The shell, therefore, provides number of facilities to simplify these tasks. Shell design also takes note of the fact that final success of any system depends on end-user satisfaction and hence provides features to build use-friendly interfaces. The shell also provides a set of interfacing predicates so that it can be embedded within any PROLOG program to incorporate functionalilty of the shell in the user program. (author). 10 refs., 8 figs

A novel disulfide bond in the SH2 Domain of the C-terminal Src kinase controls catalytic activity.

Science.gov (United States)

Mills, Jamie E; Whitford, Paul C; Shaffer, Jennifer; Onuchic, Jose N; Adams, Joseph A; Jennings, Patricia A

2007-02-02

The SH2 domain of the C-terminal Src kinase [Csk] contains a unique disulfide bond that is not present in other known SH2 domains. To investigate whether this unusual disulfide bond serves a novel function, the effects of disulfide bond formation on catalytic activity of the full-length protein and on the structure of the SH2 domain were investigated. The kinase activity of full-length Csk decreases by an order of magnitude upon formation of the disulfide bond in the distal SH2 domain. NMR spectra of the fully oxidized and fully reduced SH2 domains exhibit similar chemical shift patterns and are indicative of similar, well-defined tertiary structures. The solvent-accessible disulfide bond in the isolated SH2 domain is highly stable and far from the small lobe of the kinase domain. However, reduction of this bond results in chemical shift changes of resonances that map to a cluster of residues that extend from the disulfide bond across the molecule to a surface that is in direct contact with the small lobe of the kinase domain in the intact molecule. Normal mode analyses and molecular dynamics calculations suggest that disulfide bond formation has large effects on residues within the kinase domain, most notably within the active-site cleft. Overall, the data indicate that reversible cross-linking of two cysteine residues in the SH2 domain greatly impacts catalytic function and interdomain communication in Csk.

On the Performance of Medical Information Retrieval using MeSH Terms – A Survey

Directory of Open Access Journals (Sweden)

Swetha S

2014-09-01

Full Text Available Internet users have increased everywhere. Searching and retrieving documents is a common thing nowadays. Retrieving related documents from the search engines are difficult task. To retrieve correct documents, knowledge about the search topic is essential. Even though separate search engines are there to retrieve medical documents the users are not familiar with MeSH terms (Medical Subject Heading. So, both the search browser and the MeSH terms have to be integrated to make the search effective and efficient. To implement this integration, SimpleMed and MeSHMed were introduced. The MeSH terms have to be ranked to know how frequently it has been used and to know the importance of the MeSH terms. To rank it a semi – automated tool called MeSHy was developed. The terms were extracted, filtered, ranked and displayed to the user. Classifiers have to be constructed to label the documents as health and non – health. Three strategies were used to classify them. The errors that are commonly done by the users have to be found out. It was calculated based on the queries presented by the user to the search browser.

Design aids for stiffened composite shells with cutouts

CERN Document Server

Sahoo, Sarmila

2017-01-01

This book focuses on the free vibrations of graphite-epoxy laminated composite stiffened shells with cutout both in terms of the natural frequencies and mode shapes. The dynamic analysis of shell structures, which may have complex geometry and arbitrary loading and boundary conditions, is solved efficiently by the finite element method, even including cutouts in shells. The results may be readily used by practicing engineers dealing with stiffened composite shells with cutouts. Several shell forms viz. cylindrical shell, hypar shell, conoidal shell, spherical shell, saddle shell, hyperbolic paraboloidal shell and elliptic paraboloidal shell are considered in the book. The dynamic characteristics of stiffened composite shells with cutout are described in terms of the natural frequency and mode shapes. The size of the cutouts and their positions with respect to the shell centre are varied for different edge constraints of cross-ply and angle-ply laminated composite shells. The effects of these parametric variat...

Activated carbons prepared from hazelnut shells, walnut shells and peanut shells for high CO2 adsorption

Directory of Open Access Journals (Sweden)

Lewicka Katarzyna

2017-06-01

Full Text Available Research treats about producing activated carbons for CO2 capture from hazelnut shells (HN, walnut shells (WN and peanut shells (PN. Saturated solution of KOH was used as an activating agent in ratio 1:1. Samples were carbonized in the furnace in the range of temperatures 600°C–900°C. Properties of carbons were tested by N2 adsorption method, using BET equation, DFT method and volumetric CO2 adsorption method. With the increase of carbonization temperature specific surface area of studied samples increased. The largest surface area was calculated for samples carbonized at 900°C and the highest values of CO2 adsorption had samples: PN900 at 0°C (5.5 mmol/g and WN900 at 25°C (4.34 mmol/g. All of the samples had a well-developed microporous structure.

Physiological pattern of lumbar disc height

International Nuclear Information System (INIS)

Biggemann, M.; Frobin, W.; Brinckmann, P.

1997-01-01

Purpose of this study is to present a new method of quantifying objectively the height of all discs in lateral radiographs of the lumbar spine and of analysing the normal craniocaudal sequence pattern of lumbar disc heights. Methods: The new parameter is the ventrally measured disc height corrected for the dependence on the angle of lordosis by normalisation to mean angles observed in the erect posture of healthy persons. To eliminate radiographic magnification, the corrected ventral height is related to the mean depth of the cranially adjoining vertebra. In this manner lumbar disc heights were objectively measured in young, mature and healthy persons (146 males and 65 females). The craniocaudal sequence pattern was analysed by mean values from all persons and by height differences of adjoining discs in each individual lumbar spine. Results: Mean normative values demonstrated an increase in disc height between L1/L2 and L4/L5 and a constant or decreasing disc height between L4/L5 and L5/S1. However, this 'physiological sequence of disc height in the statistical mean' was observed in only 36% of normal males and 55% of normal females. Conclusion: The radiological pattern of the 'physiological sequence of lumbar disc height' leads to a relevant portion of false positive pathological results especially at L4/L5. An increase of disc height from L4/L5 to L5/S1 may be normal. The recognition of decreased disc height should be based on an abrupt change in the heights of adjoining discs and not on a deviation from a craniocaudal sequence pattern. (orig.) [de

Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

Science.gov (United States)

Ding, J; Takano, T; Hermann, P; Gao, S; Han, W; Noda, C; Yanagi, S; Yamamura, H

2000-05-01

Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.

Adult height, nutrition, and population health

Science.gov (United States)

Perkins, Jessica M.; Subramanian, S.V.; Davey Smith, George

2016-01-01

In this review, the potential causes and consequences of adult height, a measure of cumulative net nutrition, in modern populations are summarized. The mechanisms linking adult height and health are examined, with a focus on the role of potential confounders. Evidence across studies indicates that short adult height (reflecting growth retardation) in low- and middle-income countries is driven by environmental conditions, especially net nutrition during early years. Some of the associations of height with health and social outcomes potentially reflect the association between these environmental factors and such outcomes. These conditions are manifested in the substantial differences in adult height that exist between and within countries and over time. This review suggests that adult height is a useful marker of variation in cumulative net nutrition, biological deprivation, and standard of living between and within populations and should be routinely measured. Linkages between adult height and health, within and across generations, suggest that adult height may be a potential tool for monitoring health conditions and that programs focused on offspring outcomes may consider maternal height as a potentially important influence. PMID:26928678

SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson's disease.

Science.gov (United States)

Xie, Hong-rong; Hu, Lin-sen; Li, Guo-yi

2010-04-20

To evaluate the human neuroblastoma SH-SY5Y cell line as an in vitro model of dopaminergic (DAergic) neurons for Parkinson's disease (PD) research and to determine the effect of differentiation on this cell model. The data of this review were selected from the original reports and reviews related to SH-SY5Y cells published in Chinese and foreign journals (Pubmed 1973 to 2009). After searching the literature, 60 articles were selected to address this review. The SH-SY5Y cell line has become a popular cell model for PD research because this cell line posses many characteristics of DAergic neurons. For example, these cells express tyrosine hydroxylase and dopamine-beta-hydroxylase, as well as the dopamine transporter. Moreover, this cell line can be differentiated into a functionally mature neuronal phenotype in the presence of various agents. Upon differentiation, SH-SY5Y cells stop proliferating and a constant cell number is subsequently maintained. However, different differentiating agents induce different neuronal phenotypes and biochemical changes. For example, retinoic acid induces differentiation toward a cholinergic neuronal phenotype and increases the susceptibility of SH-SY5Y cells to neurotoxins and neuroprotective agents, whereas treatment with retinoic acid followed by phorbol ester 12-O-tetradecanoylphorbol-13-acetate results in a DAergic neuronal phenotype and decreases the susceptibility of cells to neurotoxins and neuroprotective agents. Some differentiating agents also alter kinetics of 1-methyl-4-phenyl-pyridinium (MPP(+)) uptake, making SH-SY5Y cells more similar to primary mesencephalic neurons. Differentiated and undifferentiated SH-SY5Y cells have been widely used as a cell model of DAergic neurons for PD research. Some differentiating agents afford SH-SY5Y cells with more potential for studying neurotoxicity and neuroprotection and are thus more relevant to experimental PD research.

The globular cluster system of NGC 1316. II. The extraordinary object SH2

Science.gov (United States)

Richtler, T.; Kumar, B.; Bassino, L. P.; Dirsch, B.; Romanowsky, A. J.

2012-07-01

Context. SH2 has been described as an isolated HII-region, located about 6.5' south of the nucleus of NGC 1316 (Fornax A), a merger remnant in the the outskirts of the Fornax cluster of galaxies. Aims: We give a first, preliminary description of the stellar content and environment of this remarkable object. Methods: We used photometric data in the Washington system and HST photometry from the Hubble Legacy Archive for a morphological description and preliminary aperture photometry. Low-resolution spectroscopy provides radial velocities of the brightest star cluster in SH2 and a nearby intermediate-age cluster. Results: SH2 is not a normal HII-region, ionized by very young stars. It contains a multitude of star clusters with ages of approximately 108 yr. A ring-like morphology is striking. SH2 seems to be connected to an intermediate-age massive globular cluster with a similar radial velocity, which itself is the main object of a group of fainter clusters. Metallicity estimates from emission lines remain ambiguous. Conclusions: The present data do not yet allow firm conclusions about the nature or origin of SH2. It might be a dwarf galaxy that has experienced a burst of extremely clustered star formation. We may witness how globular clusters are donated to a parent galaxy. Based on observations taken at the European Southern Observatory, Cerro Paranal, Chile, under the programmes 082.B-0680, on observations taken at the Interamerican Observatory, Cerro Tololo, Chile. Furthermore based on observations made with the NASA/ESA Hubble Space Telescope (HST, PI: A. Sandage, Prop.ID: 7504), and obtained from the Hubble Legacy Archive, which is a collaboration between the Space Telescope Science Institute (STScI/NASA), the Space Telescope European Coordinating Facility (ST-ECF/ESA) and the Canadian Astronomy Data Centre (CADC/NRC/CSA).

Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration.

Science.gov (United States)

Wu, Jui-Chung; Chen, Yu-Chen; Kuo, Chih-Ting; Wenshin Yu, Helen; Chen, Yin-Quan; Chiou, Arthur; Kuo, Jean-Cheng

2015-12-18

Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration.

In defense of the classical height system

Science.gov (United States)

Foroughi, Ismael; Vaníček, Petr; Sheng, Michael; Kingdon, Robert William; Santos, Marcelo C.

2017-11-01

In many European countries, normal heights referred to the quasi-geoid as introduced by Molodenskij in the mid-20th century are preferred to the classical height system that consists of orthometric heights and the geoid as a reference surface for these heights. The rationale for this choice is supposed to be that in the classical height system, neither the geoid, nor the orthometric height can be ever known with centimetre level accuracy because one would need to know the topographical mass density to a level that can never be achieved. The aim of this paper is to question the validity of this rationale. The common way of assessing the congruency of a local geoid model and the orthometric heights is to compare the geoid heights with the difference between orthometric heights provided by leveling and geodetic heights provided by GNSS. On the other hand, testing the congruency of a quasi-geoidal model with normal height a similar procedure is used, except that instead of orthometric heights, normal heights are employed. For the area of Auvergne, France, which is now a more or less standard choice for precise geoid or quasi-geoid testing, only the normal heights are supplied by the Institute Geographic National, the provider of the data. This is clearly the consequence of the European preference for the Molodenskij system. The quality of the height system is to be judged by the congruency of the difference of the geoid/quasi-geoid heights subtracted from the geodetic heights and orthometric/normal heights. To assess the congruency of the classical height system, the Helmert approximation of orthometric heights is typically used as the transformation between normal and Helmert's heights is easily done. However, the evaluation of the differences between Helmert's and the rigorous orthometric heights is somewhat more involved as will be seen from the review in this paper. For the area of interest, the differences between normal and Helmert's heights at the control

Bed agglomeration characteristics of palm shell and corncob combustion in fluidized bed

International Nuclear Information System (INIS)

Chaivatamaset, Pawin; Sricharoon, Panchan; Tia, Suvit

2011-01-01

Bed particle agglomeration was studied experimentally in an atmospheric laboratory scale fluidized bed combustor using quartz sand as bed material. Palm shell and corncob were tested. The objectives of the study were (i) to describe the contributions of the biomass ash properties and the operating conditions on the bed agglomeration tendency in term of the bed defluidization time (t def ) and the extent of potassium accumulation in the bed (K/Bed) and (ii) to further elucidate the ash inorganic behaviors and the governing bed agglomeration mechanisms. Defluidization caused by the bed agglomeration was experienced in all experiments during combustion of these biomasses, as a consequence of the presence of potassium in biomass. The experimental results indicated that biomass ash characteristics were the significant influence on the bed agglomeration. The increasing bed temperature, bed particle size and static bed height and the decreasing fluidizing air velocity enhanced the bed agglomeration tendency. The SEM/EDS analyses on the agglomerates confirmed that the agglomeration was attributed to the formation of potassium silicate liquid enriched on the surface of quartz sand particles in conjunction with the high surface temperature of the burning biomass char particles. Thermodynamic examination based on the phase diagram analysis confirmed that the molten phase formation was responsible for the agglomeration. In this study, the high molten ash fraction resulting from the high potassium content in biomass promoted the agglomeration and thus defluidization. - Highlights: → Palm shell and corncob of Thailand are tested their bed agglomeration behaviors during fluidized bed combustion. → The increase of bed temperature, bed particle size and static bed height and the decrease of air velocity enhance bed agglomeration. → The formation of ash derived potassium silicate melts enriched on sand surface is the key process. → The collision between char and sand

Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms.

Science.gov (United States)

Lu, Yin; Figler, Bryan; Huang, Hong; Tu, Yi-Cheng; Wang, Ju; Cheng, Feng

2017-01-01

Identifying drug-drug interaction (DDI) is an important topic for the development of safe pharmaceutical drugs and for the optimization of multidrug regimens for complex diseases such as cancer and HIV. There have been about 150,000 publications on DDIs in PubMed, which is a great resource for DDI studies. In this paper, we introduced an automatic computational method for the systematic analysis of the mechanism of DDIs using MeSH (Medical Subject Headings) terms from PubMed literature. MeSH term is a controlled vocabulary thesaurus developed by the National Library of Medicine for indexing and annotating articles. Our method can effectively identify DDI-relevant MeSH terms such as drugs, proteins and phenomena with high accuracy. The connections among these MeSH terms were investigated by using co-occurrence heatmaps and social network analysis. Our approach can be used to visualize relationships of DDI terms, which has the potential to help users better understand DDIs. As the volume of PubMed records increases, our method for automatic analysis of DDIs from the PubMed database will become more accurate.

Al-Shāṭibīs sufismekritik:

DEFF Research Database (Denmark)

Riexinger, Martin Thomas

2016-01-01

The faqīh (Islamic legal scholar) al-Shāṭibī (d. 1388) from Granada is primarily known for his innovative approach within the field of legal theory (uṣūl al-fiqh). However, he dedicated much attention to the criticism of sufism. But like other Islamic scholars who opposed Sufism he did...

Dyson shells: a retrospective

Science.gov (United States)

Bradbury, Robert J.

2001-08-01

More than 40 years have passed since Freeman Dyson suggested that advanced technological civilizations are likely to dismantle planets in their solar systems to harvest all of the energy their stars wastefully radiate into space. Clearly this was an idea that was ahead of its time. Since that time, dozens of SETI searches have been conducted and almost all of them have focused their attention on stars which by definition cannot be the advanced civilizations that Dyson envisioned. I will review the data that created the confusion between Dyson spheres and Dyson shells. The sources that disprove Dyson spheres while still allowing Dyson shells will be discussed. The use of outmoded ideas that have biased the few searches for Dyson Shells that have occurred will be pointed out. An update of the concept of Dyson shells to include our current knowledge of biotechnology, nanotechnology and computer science will be explored. Finally, an approach to setting limits on the abundance of Dyson shells in our galaxy using existing optical astronomical data and future optical satellites will be proposed.

On the Extreme Wave Height Analysis

DEFF Research Database (Denmark)

Burcharth, H. F.; Liu, Zhou

1994-01-01

The determination of the design wave height is usually based on the statistical analysis of long-term extreme wave height measurements. After an introduction to the procedure of the extreme wave height analysis, the paper presents new development concerning various aspects of the extreme wave...... height analysis. Finally, the paper gives a practical example based on a data set of the hindcasted wave heights for a deep water location in the Mediterranean Sea....

The role of SH3BP2 in the pathophysiology of cherubism

Directory of Open Access Journals (Sweden)

Reichenberger Ernst J

2012-05-01

Full Text Available Abstract Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.

CH+ and SH+ in the diffuse interstellar medium: Tracers of turbulent dissipation

International Nuclear Information System (INIS)

Edith, Falgarone; Maryvonne, Gerin; Massimo, De Luca; Benjamin, Godard

2015-01-01

Absorption spectroscopy performed with Herschel/HIFI against the dust continuum emission of bright galactic star-forming regions has allowed the detection of the ground-state transitions of several hydride cations, CH + , OH + , H 2 O + , and SH + in the intervening diffuse medium. These hydrides, that need H 2 to form but are also destroyed by H 2 , appear to be most sensitive tracers of a poorly known component of the interstellar medium (ISM): molecular gas weakly shielded from UV radiation. Among them, because their formation routes are so highly endoenergic, the CH + and SH + cations are proposed to be specific tracers of turbulent dissipation occurring in diffuse gas. Their elusive origin in the diffuse ISM is therefore much more than a chemical riddle: it is rooted in the physics of the diffuse ISM, its turbulent dissipation rate and connects with the far broader issue of galaxy evolution. The Herschel/HIFI observations of CH + and SH + are compared with the predictions of chemical models that include the non-equilibrium effects of turbulent dissipation

Mussel Shell Impaction in the Esophagus

Directory of Open Access Journals (Sweden)

Sunmin Kim

2013-03-01

Full Text Available Mussels are commonly used in cooking around the world. The mussel shell breaks more easily than other shells, and the edge of the broken mussel shell is sharp. Impaction can ultimately cause erosion, perforation and fistula. Aside from these complications, the pain can be very intense. Therefore, it is essential to verify and remove the shell as soon as possible. In this report we describe the process of diagnosing and treating mussel shell impaction in the esophagus. Physicians can overlook this unusual foreign body impaction due to lack of experience. When physicians encounter a patient with severe chest pain after a meal with mussels, mussel shell impaction should be considered when diagnosing and treating the patient.

Plate shell structures of glass

DEFF Research Database (Denmark)

Bagger, Anne

to their curved shape. A plate shell structure maintains a high stiffness-to-weight ratio, while facilitating the use of plane structural elements. The study focuses on using laminated glass panes for the load bearing facets. Various methods of generating a plate shell geometry are suggested. Together with Ghent......, such as facet size, imperfections, and connection characteristics. The critical load is compared to that of a similar, but smoothly curved, shell structure. Based on the investigations throughout the study, a set of guidelines for the structural design of plate shells of glass is proposed....

FiSH: put fault data in a seismic hazard basket

Science.gov (United States)

Pace, Bruno; Visini, Francesco; Peruzza, Laura

2016-04-01

The practice of using fault sources in seismic hazard studies is growing in popularity, including in regions with moderate seismic activity, such as the European countries. In these areas, fault identification may be affected by similarly large uncertainties in the historical and instrumental seismic histories of more active areas that have not been inhabited for long periods of time. Certain studies have effectively applied a time-dependent perspective to combine historical and instrumental seismic data with geological and paleoseismological information, partially compensating for a lack of information. We present a package of Matlab® tools (called FiSH), in publication on Seismological Research Letters, designed to help seismic hazard modellers analyse fault data. These tools enable the derivation of expected earthquake rates given common fault data, and allow you to test the consistency between the magnitude frequency distributions assigned to a fault and some available observations. The basic assumption of FiSH is that the geometric and kinematic features of a fault are the expression of its seismogenic potential. Three tools have been designed to integrate the variable levels of information available: (a) the first tool allows users to convert fault geometry and slip rates into a global budget of the seismic moment released in a given time frame, taking uncertainties into account; (b) the second tool computes the recurrence parameters and associated uncertainties from historical and/or paleoseismological data; 
(c) the third tool outputs time-independent or time-dependent earthquake rates for different magnitude frequency distribution models. We present moreover a test case to illustrate the capabilities of FiSH, on the Paganica normal fault in Central Italy that ruptured during the L'Aquila 2009 earthquake sequence (mainshock Mw 6.3). FiSH is available at http://fish-code.com, and the source codes are open. We encourage users to handle the scripts

Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target.

Science.gov (United States)

Watson, Gabrielle M; Lucas, William A H; Gunzburg, Menachem J; Wilce, Jacqueline A

2017-01-01

Growth factor receptor bound protein 7 (Grb7) is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine), however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors.

Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target

Directory of Open Access Journals (Sweden)

Gabrielle M. Watson

2017-09-01

Full Text Available Growth factor receptor bound protein 7 (Grb7 is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine, however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors.

Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target

Science.gov (United States)

Watson, Gabrielle M.; Lucas, William A. H.; Gunzburg, Menachem J.; Wilce, Jacqueline A.

2017-01-01

Growth factor receptor bound protein 7 (Grb7) is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine), however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors. PMID:29018805

Piezo-phototronic Effect Enhanced UV/Visible Photodetector Based on Fully Wide Band Gap Type-II ZnO/ZnS Core/Shell Nanowire Array.

Science.gov (United States)

Rai, Satish C; Wang, Kai; Ding, Yong; Marmon, Jason K; Bhatt, Manish; Zhang, Yong; Zhou, Weilie; Wang, Zhong Lin

2015-06-23

A high-performance broad band UV/visible photodetector has been successfully fabricated on a fully wide bandgap ZnO/ZnS type-II heterojunction core/shell nanowire array. The device can detect photons with energies significantly smaller (2.2 eV) than the band gap of ZnO (3.2 eV) and ZnS (3.7 eV), which is mainly attributed to spatially indirect type-II transition facilitated by the abrupt interface between the ZnO core and ZnS shell. The performance of the device was further enhanced through the piezo-phototronic effect induced lowering of the barrier height to allow charge carrier transport across the ZnO/ZnS interface, resulting in three orders of relative responsivity change measured at three different excitation wavelengths (385, 465, and 520 nm). This work demonstrates a prototype UV/visible photodetector based on the truly wide band gap semiconducting 3D core/shell nanowire array with enhanced performance through the piezo-phototronic effect.

Optimised photocatalytic hydrogen production using core–shell AuPd promoters with controlled shell thickness

DEFF Research Database (Denmark)

Jones, Wilm; Su, Ren; Wells, Peter

2014-01-01

of these materials towards the reforming of alcohols for hydrogen production. The core–shell structured Au–Pd bimetallic nanoparticle supported on TiO2 has being of interest as it exhibited extremely high quantum efficiencies for hydrogen production. However, the effect of shell composition and thickness...... of the nanoparticles by a combination of X-ray absorption fine structure and X-ray photoelectron spectroscopy. Photocatalytic ethanol reforming showed that the core–shell structured Au–Pd promoters supported on TiO2 exhibit enhanced activity compared to that of monometallic Au and Pd as promoters, whilst the core......–shell Au–Pd promoters containing one ML equivalent Pd provide the optimum reactivity....

Nanostructued core–shell Sn nanowires @ CNTs with controllable thickness of CNT shells for lithium ion battery

Energy Technology Data Exchange (ETDEWEB)

Zhong, Yu; Li, Xifei; Zhang, Yong; Li, Ruying [Department of Mechanical and Materials Engineering, University of Western Ontario, London, Ontario N6A 5B9 (Canada); Cai, Mei [General Motors Research and Development Center, Warren, MI 48090-9055 (United States); Sun, Xueliang, E-mail: xsun@eng.uwo.ca [Department of Mechanical and Materials Engineering, University of Western Ontario, London, Ontario N6A 5B9 (Canada)

2015-03-30

Graphical abstract: - Highlights: • Sn nanowires encapsulated in CNTs directly grew on current collectors. • The thickness of CNTs were controlled via growth time, gas flow rate and synthesis temperature. • Thick CNTs contributed to a better capacity retention while thin CNTs led to a higher capacity. • The core–shell structures formed in one-step CVD process. - Abstract: Core–shell structure of Sn nanowires encapsulated in amorphous carbon nanotubes (Sn@CNTs) with controlled thickness of CNT shells was in situ prepared via chemical vapor deposition (CVD) method. The thickness of CNT shells was accurately controlled from 4 to 99 nm by using different growth time, flow rate of hydrocarbon gas (C{sub 2}H{sub 4}) and synthesis temperature. The microstructure and composition of the coaxial Sn@CNTs were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and high resolution transmission electron microscopy (HRTEM) techniques. Moreover, the Sn@CNTs were studied as anode materials for Li-ion batteries and showed excellent cycle performance. The capacity was affected by the thickness of outer CNT shells: thick CNT shells contributed to a better retention while thin CNT shells led to a higher capacity. The thin CNT shell of 6 nm presented the highest capacity around 630 mAh g{sup −1}.

Nanostructued core–shell Sn nanowires @ CNTs with controllable thickness of CNT shells for lithium ion battery

International Nuclear Information System (INIS)

Zhong, Yu; Li, Xifei; Zhang, Yong; Li, Ruying; Cai, Mei; Sun, Xueliang

2015-01-01

Graphical abstract: - Highlights: • Sn nanowires encapsulated in CNTs directly grew on current collectors. • The thickness of CNTs were controlled via growth time, gas flow rate and synthesis temperature. • Thick CNTs contributed to a better capacity retention while thin CNTs led to a higher capacity. • The core–shell structures formed in one-step CVD process. - Abstract: Core–shell structure of Sn nanowires encapsulated in amorphous carbon nanotubes (Sn@CNTs) with controlled thickness of CNT shells was in situ prepared via chemical vapor deposition (CVD) method. The thickness of CNT shells was accurately controlled from 4 to 99 nm by using different growth time, flow rate of hydrocarbon gas (C 2 H 4 ) and synthesis temperature. The microstructure and composition of the coaxial Sn@CNTs were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and high resolution transmission electron microscopy (HRTEM) techniques. Moreover, the Sn@CNTs were studied as anode materials for Li-ion batteries and showed excellent cycle performance. The capacity was affected by the thickness of outer CNT shells: thick CNT shells contributed to a better retention while thin CNT shells led to a higher capacity. The thin CNT shell of 6 nm presented the highest capacity around 630 mAh g −1

Extensions to a nonlinear finite element axisymmetric shell model based on Reissner's shell theory

International Nuclear Information System (INIS)

Cook, W.A.

1981-01-01

A finite element shell-of-revolution model has been developed to analyze shipping containers under severe impact conditions. To establish the limits for this shell model, I studied the basic assumptions used in its development; these are listed in this paper. Several extensions were evident from the study of these limits: a thick shell, a plastic hinge, and a linear normal stress. (orig./HP)

A YOUNG ECLIPSING BINARY AND ITS LUMINOUS NEIGHBORS IN THE EMBEDDED STAR CLUSTER Sh 2-252E

Energy Technology Data Exchange (ETDEWEB)

Lester, Kathryn V.; Gies, Douglas R.; Guo, Zhao, E-mail: lester@chara.gsu.edu, E-mail: gies@chara.gsu.edu, E-mail: guo@chara.gsu.edu [Center for High Angular Resolution Astronomy and Department of Physics and Astronomy, Georgia State University, P.O. Box 5060, Atlanta, GA 30302-5060 (United States)

2016-12-01

We present a photometric and light curve analysis of an eccentric eclipsing binary in the K2 Campaign 0 field, which resides in Sh 2-252E, a young star cluster embedded in an H ii region. We describe a spectroscopic investigation of the three brightest stars in the crowded aperture to identify which is the binary system. We find that none of these stars are components of the eclipsing binary system, which must be one of the fainter nearby stars. These bright cluster members all have remarkable spectra: Sh 2-252a (EPIC 202062176) is a B0.5 V star with razor sharp absorption lines, Sh 2-252b is a Herbig A0 star with disk-like emission lines, and Sh 2-252c is a pre-main-sequence star with very red color.

Protein flexibility and ligand rigidity : a thermodynamic and kinetic study of ITAM-based ligand binding to Syk tandem SH2

NARCIS (Netherlands)

de Mol, Nico J; Catalina, M Isabel; Dekker, Frank J; Fischer, Marcel J E; Heck, Albert J R; Liskamp, Rob M J; Dekker, Frank

2005-01-01

The Syk tandem Src homology 2 domain (Syk tSH2) constitutes a flexible protein module involved in the regulation of Syk kinase activity. The Syk tSH2 domain is assumed to function by adapting the distance between its two SH2 domains upon bivalent binding to diphosphotyrosine ligands. A thermodynamic

MEDLINE MeSH Indexing: Lessons Learned from Machine Learning and Future Directions

DEFF Research Database (Denmark)

Jimeno-Yepes, Antonio; Mork, James G.; Wilkowski, Bartlomiej

2012-01-01

and analyzed the issues when using standard machine learning algorithms. We show that in some cases machine learning can improve the annotations already recommended by MTI, that machine learning based on low variance methods achieves better performance and that each MeSH heading presents a different behavior......Map and a k-NN approach called PubMed Related Citations (PRC). Our motivation is to improve the quality of MTI based on machine learning. Typical machine learning approaches fit this indexing task into text categorization. In this work, we have studied some Medical Subject Headings (MeSH) recommended by MTI...

Technology development and production of elongated shell for reactor vessel active zone of WWER-TOI project from steel 15Cr2NiMoVN class 1

International Nuclear Information System (INIS)

Shklyaev, S.Eh.; Titova, T.I.; Ratushev, D.V.; Shul'gan, N.A.; Eroshkin, S.B.; Durynin, V.A.; Efimov, S.V.; Dub, V.S.; Kulikov, A.P.; Romashkin, A.N.

2015-01-01

Production process for the elongated shell blank of the active zone of the reactor pressure vessel made from steel 15Cr2NiMoVN Class 1 with finished sizes Dext=4.655 mm, Dint=4.240 mm, H=4.910 mm (height for heat treatment – 5.750 mm) is presented. For the first time in Russia in production site of OMZ-Special steel LLC a unique elongated shell blank of the reactor vessel active zone was made from ingot 420.0 t for WWER-TOI project fully meeting the specified requirements in terms of metallurgical quality and set of service properties [ru

Core-Shell-Corona Micelles with a Responsive Shell.

Science.gov (United States)

Gohy, Jean-François; Willet, Nicolas; Varshney, Sunil; Zhang, Jian-Xin; Jérôme, Robert

2001-09-03

A reactor for the synthesis of gold nanoparticles is one of the uses of a poly(styrene)-block-poly(2-vinylpyridine)-block-poly(ethylene oxide) triblock copolymer (PS-b-P2VP-b-PEO) which forms core-shell-corona micelles in water. Very low polydispersity spherical micelles are observed that consist of a PS core surrounded by a pH-sensitive P2VP shell and a corona of PEO chains end-capped by a hydroxyl group. The corona can act as a site for attaching responsive or sensing molecules. © 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

Biomineral repair of abalone shell apertures.

Science.gov (United States)

Cusack, Maggie; Guo, Dujiao; Chung, Peter; Kamenos, Nicholas A

2013-08-01

The shell of the gastropod mollusc, abalone, is comprised of nacre with an outer prismatic layer that is composed of either calcite or aragonite or both, depending on the species. A striking characteristic of the abalone shell is the row of apertures along the dorsal margin. As the organism and shell grow, new apertures are formed and the preceding ones are filled in. Detailed investigations, using electron backscatter diffraction, of the infill in three species of abalone: Haliotis asinina, Haliotis gigantea and Haliotis rufescens reveals that, like the shell, the infill is composed mainly of nacre with an outer prismatic layer. The infill prismatic layer has identical mineralogy as the original shell prismatic layer. In H. asinina and H. gigantea, the prismatic layer of the shell and infill are made of aragonite while in H. rufescens both are composed of calcite. Abalone builds the infill material with the same high level of biological control, replicating the structure, mineralogy and crystallographic orientation as for the shell. The infill of abalone apertures presents us with insight into what is, effectively, shell repair. Copyright © 2013 Elsevier Inc. All rights reserved.

Process Optimization for Ethyl Ester Production in Fixed Bed Reactor Using Calcium Oxide Impregnated Palm Shell Activated Carbon (CaO/PSAC

Directory of Open Access Journals (Sweden)

A Buasri

2012-11-01

Full Text Available : The continuous production of ethyl ester was studied by using a steady-state fixed bed reactor (FBR. Transesterification of palm stearin (PS and waste cooking palm oil (WCPO with ethanol in the presence of calcium oxide impregnated palm shell activated carbon (CaO/PSAC solid catalyst was investigated. This work was determined the optimum conditions for the production of ethyl ester from PS and WCPO in order to obtain fatty acid ethyl ester (FAEE with the highest yield. The effects of reaction variables such as residence time, ethanol/oil molar ratio, reaction temperature, catalyst bed height and reusability of catalyst in a reactor system on the yield of biodiesel were considered. The optimum conditions were the residence time 2-3 h, ethanol/oil molar ratio 16-20, reaction temperature at 800C, and catalyst bed height 300 mm which yielded 89.46% and 83.32% of the PS and WCPO conversion, respectively. CaO/PSAC could be used repeatedly for 4 times without any activation treatment and no obvious activity loss was observed. It has potential for industrial application in the transesterification of triglyceride (TG. The fuel properties of biodiesel were determined. Keywords: biodiesel, calcium oxide, ethyl ester, fixed bed reactor, palm shell activated carbon

Calibration of the SH134-20 Standard Gain Horn

DEFF Research Database (Denmark)

Pivnenko, Sergey; Breinbjerg, Olav

This report documents the measurement of the linearly polarized SH134-20 Standard Gain Horn. The measurement comprises on-axis gain, on-axis polarization characteristics, and reflection coefficient at 111 frequencies in the frequency range from 22-33 GHz. The measurement was carried out at the DTU...

Loss of Sh3gl2/Endophilin A1 Is a Common Event in Urothelial Carcinoma that Promotes Malignant Behavior

Directory of Open Access Journals (Sweden)

Shyama Majumdar

2013-07-01

Full Text Available Urothelial carcinoma (UC causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1 as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1 enhanced proliferation and colony formation in vitro, 2 inhibited EGF-induced EGFR internalization and increased EGFR activation, 3 stimulated phosphorylation of Src family kinases and STAT3, and 4 promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

NH4SH and cloud cover in the atmospheres of the giant planets

Science.gov (United States)

Ibragimov, K. Iu.; Solodovnik, A. A.

1991-02-01

The probability of the formation of NH4SH and (NH4)2S is examined on the basis of the Le Chatelier principle. It is shown that it is very doubtful if NH4SH can be created in the atmospheres of the giant planets in quantities sufficient for cloud formation. Thus (NH4)2S is considered as a more likely candidate for cloud formation in the atmospheres of these planets, inasmuch as the conditions for its production there are more favorable.

Hydrogen Peroxide Toxicity Induces Ras Signaling in Human Neuroblastoma SH-SY5Y Cultured Cells

Directory of Open Access Journals (Sweden)

Jirapa Chetsawang

2010-01-01

Full Text Available It has been reported that overproduction of reactive oxygen species occurs after brain injury and mediates neuronal cells degeneration. In the present study, we examined the role of Ras signaling on hydrogen peroxide-induced neuronal cells degeneration in dopaminergic neuroblastoma SH-SY5Y cells. Hydrogen peroxide significantly reduced cell viability in SH-SY5Y cultured cells. An inhibitor of the enzyme that catalyzes the farnesylation of Ras proteins, FTI-277, and a competitive inhibitor of GTP-binding proteins, GDP-beta-S significantly decreased hydrogen peroxide-induced reduction in cell viability in SH-SY5Y cultured cells. The results of this study might indicate that a Ras-dependent signaling pathway plays a role in hydrogen peroxide-induced toxicity in neuronal cells.

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface*

Science.gov (United States)

Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

2016-01-01

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. PMID:26912659

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface.

Science.gov (United States)

Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

2016-04-15

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

High resolution crystal structure of the Grb2 SH2 domain with a phosphopeptide derived from CD28.

Directory of Open Access Journals (Sweden)

Kunitake Higo

Full Text Available Src homology 2 (SH2 domains play a critical role in cellular signal transduction. They bind to peptides containing phosphotyrosine (pY with various specificities that depend on the flanking amino-acid residues. The SH2 domain of growth-factor receptor-bound protein 2 (Grb2 specifically recognizes pY-X-N-X, whereas the SH2 domains in phosphatidylinositol 3-kinase (PI3K recognize pY-X-X-M. Binding of the pY site in CD28 (pY-M-N-M by PI3K and Grb2 through their SH2 domains is a key step that triggers the CD28 signal transduction for T cell activation and differentiation. In this study, we determined the crystal structure of the Grb2 SH2 domain in complex with a pY-containing peptide derived from CD28 at 1.35 Å resolution. The peptide was found to adopt a twisted U-type conformation, similar to, but distinct from type-I β-turn. In all previously reported crystal structures, the peptide bound to the Grb2 SH2 domains adopts a type-I β-turn conformation, except those with a proline residue at the pY+3 position. Molecular modeling also suggests that the same peptide bound to PI3K might adopt a very different conformation.

High resolution crystal structure of the Grb2 SH2 domain with a phosphopeptide derived from CD28.

Science.gov (United States)

Higo, Kunitake; Ikura, Teikichi; Oda, Masayuki; Morii, Hisayuki; Takahashi, Jun; Abe, Ryo; Ito, Nobutoshi

2013-01-01

Src homology 2 (SH2) domains play a critical role in cellular signal transduction. They bind to peptides containing phosphotyrosine (pY) with various specificities that depend on the flanking amino-acid residues. The SH2 domain of growth-factor receptor-bound protein 2 (Grb2) specifically recognizes pY-X-N-X, whereas the SH2 domains in phosphatidylinositol 3-kinase (PI3K) recognize pY-X-X-M. Binding of the pY site in CD28 (pY-M-N-M) by PI3K and Grb2 through their SH2 domains is a key step that triggers the CD28 signal transduction for T cell activation and differentiation. In this study, we determined the crystal structure of the Grb2 SH2 domain in complex with a pY-containing peptide derived from CD28 at 1.35 Å resolution. The peptide was found to adopt a twisted U-type conformation, similar to, but distinct from type-I β-turn. In all previously reported crystal structures, the peptide bound to the Grb2 SH2 domains adopts a type-I β-turn conformation, except those with a proline residue at the pY+3 position. Molecular modeling also suggests that the same peptide bound to PI3K might adopt a very different conformation.

Porous Core-Shell Nanostructures for Catalytic Applications

Science.gov (United States)

Ewers, Trevor David

Porous core-shell nanostructures have recently received much attention for their enhanced thermal stability. They show great potential in the field of catalysis, as reactant gases can diffuse in and out of the porous shell while the core particle is protected from sintering, a process in which particles coalesce to form larger particles. Sintering is a large problem in industry and is the primary cause of irreversible deactivation. Despite the obvious advantages of high thermal stability, porous core-shell nanoparticles can be developed to have additional interactive properties from the combination of the core and shell together, rather than just the core particle alone. This dissertation focuses on developing new porous core-shell systems in which both the core and shell take part in catalysis. Two types of systems are explored; (1) yolk-shell nanostructures with reducible oxide shells formed using the Kirkendall effect and (2) ceramic-based porous oxide shells formed using sol-gel chemistry. Of the Kirkendall-based systems, Au FexOy and Cu CoO were synthesized and studied for catalytic applications. Additionally, ZnO was explored as a potential shelling material. Sol-gel work focused on optimizing synthetic methods to allow for coating of small gold particles, which remains a challenge today. Mixed metal oxides were explored as a shelling material to make dual catalysts in which the product of a reaction on the core particle becomes a reactant within the shell.

More practical critical height sampling.

Science.gov (United States)

Thomas B. Lynch; Jeffrey H. Gove

2015-01-01

Critical Height Sampling (CHS) (Kitamura 1964) can be used to predict cubic volumes per acre without using volume tables or equations. The critical height is defined as the height at which the tree stem appears to be in borderline condition using the point-sampling angle gauge (e.g. prism). An estimate of cubic volume per acre can be obtained from multiplication of the...

Ge/Si core/shell quantum dots in alumina: tuning the optical absorption by the core and shell size

Directory of Open Access Journals (Sweden)

Nekić Nikolina

2017-03-01

Full Text Available Ge/Si core/shell quantum dots (QDs recently received extensive attention due to their specific properties induced by the confinement effects of the core and shell structure. They have a type II confinement resulting in spatially separated charge carriers, the electronic structure strongly dependent on the core and shell size. Herein, the experimental realization of Ge/Si core/shell QDs with strongly tunable optical properties is demonstrated. QDs embedded in an amorphous alumina glass matrix are produced by simple magnetron sputtering deposition. In addition, they are regularly arranged within the matrix due to their self-assembled growth regime. QDs with different Ge core and Si shell sizes are made. These core/shell structures have a significantly stronger absorption compared to pure Ge QDs and a highly tunable absorption peak dependent on the size of the core and shell. The optical properties are in agreement with recent theoretical predictions showing the dramatic influence of the shell size on optical gap, resulting in 0.7 eV blue shift for only 0.4 nm decrease at the shell thickness. Therefore, these materials are very promising for light-harvesting applications.

Imagery and fear influence height perception.

Science.gov (United States)

Clerkin, Elise M; Cody, Meghan W; Stefanucci, Jeanine K; Proffitt, Dennis R; Teachman, Bethany A

2009-04-01

The current study tested whether height overestimation is related to height fear and influenced by images of falling. To assess perceptual biases, participants high (n=65) versus low (n=64) in height fear estimated the vertical extents of two balconies using a visual matching task. On one of the balconies, participants engaged in an imagery exercise designed to enhance the subjective sense that they were acting in a dangerous environment by picturing themselves falling. As expected, we found that individuals overestimated the balcony's height more after they imagined themselves falling, particularly if they were already afraid of heights. These findings suggest that height fear may serve as a vulnerability factor that leads to perceptual biases when triggered by a stressor (in this case, images of falling).

A recombined fusion protein PTD-Grb2-SH2 inhibits the proliferation of breast cancer cells in vitro.

Science.gov (United States)

Yin, Jikai; Cai, Zhongliang; Zhang, Li; Zhang, Jian; He, Xianli; Du, Xilin; Wang, Qing; Lu, Jianguo

2013-03-01

The growth factor receptor bound protein 2 (Grb2) is one of the affirmative targets for cancer therapy, especially for breast cancer. In this study, we hypothesized the Src-homology 2 (SH2) domain in Grb2 may serve as a competitive protein-binding agent to interfere with the proliferation of breast cancer cells in vitro. We designed, constructed, expressed and purified a novel fusion protein containing the protein transduction domain (PTD) and Grb2-SH2 domain (we named it after PTD-Grb2-SH2). An immunofluorescence assay was used to investigate the location of PTD-Grb2-SH2 in cells. MTT assay and EdU experiments were applied to detect the proliferation of breast cancer cells. The ultra-structure was observed using transmission electron microscopy. Flow cytometry was used to determine the cytotoxicity of PTD-Grb2-SH2 on cell proliferation. We successfully obtained the PTD-Grb2-SH2 fusion protein in soluble form using a prokaryotic expression system. The new fusion protein successfully passed through both the cellular and nuclear membranes of breast cancer cells. The MTT assay showed that PTD-Grb2-SH2 exhibited significant toxicity to breast cancer cells in a dose- and time-dependent manner in vitro. EdU identified the decreased proliferation rates in treated MDA-MB-231 and SK-BR-3 cells. Observation by transmission electron microscopy and flow cytometry further confirmed the cytotoxicity as apoptosis. Our results show that the HIV1-TAT domain is a useful tool for transporting a low molecular weight protein across the cell membrane in vitro. The PTD-Grb2-SH2 may be a novel agent for breast cancer therapy.

Studies of dust shells around stars

International Nuclear Information System (INIS)

Bedijn, P.J.

1977-01-01

This thesis deals with some aspects of circumstellar dust shells. This dust shell, emitting infrared radiation, is described by way of its absorptive and emissive properties as well as by the transfer of radiation through the dust shell itself. Model calculations are compared to experimental results and agree reasonably well. The author also discusses the dynamics of the extended shells of gas and dust around newly formed stars

Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol

OpenAIRE

Teppola, Heidi; Sarkanen, Jertta-Riina; Jalonen, Tuula O.; Linne, Marja-Leena

2015-01-01

Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all-trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was...

Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol