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Sample records for proximal signaling domain

  1. Semiconductor detectors with proximity signal readout

    International Nuclear Information System (INIS)

    Asztalos, Stephen J.

    2012-01-01

    Semiconductor-based radiation detectors are routinely used for the detection, imaging, and spectroscopy of x-rays, gamma rays, and charged particles for applications in the areas of nuclear and medical physics, astrophysics, environmental remediation, nuclear nonproliferation, and homeland security. Detectors used for imaging and particle tracking are more complex in that they typically must also measure the location of the radiation interaction in addition to the deposited energy. In such detectors, the position measurement is often achieved by dividing or segmenting the electrodes into many strips or pixels and then reading out the signals from all of the electrode segments. Fine electrode segmentation is problematic for many of the standard semiconductor detector technologies. Clearly there is a need for a semiconductor-based radiation detector technology that can achieve fine position resolution while maintaining the excellent energy resolution intrinsic to semiconductor detectors, can be fabricated through simple processes, does not require complex electrical interconnections to the detector, and can reduce the number of required channels of readout electronics. Proximity electrode signal readout (PESR), in which the electrodes are not in physical contact with the detector surface, satisfies this need

  2. 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.

  3. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

    OpenAIRE

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a ...

  4. Arabidopsis thaliana FLA4 functions as a glycan-stabilized soluble factor via its carboxy-proximal Fasciclin 1 domain.

    Science.gov (United States)

    Xue, Hui; Veit, Christiane; Abas, Lindy; Tryfona, Theodora; Maresch, Daniel; Ricardi, Martiniano M; Estevez, José Manuel; Strasser, Richard; Seifert, Georg J

    2017-08-01

    Fasciclin-like arabinogalactan proteins (FLAs) are involved in numerous important functions in plants but the relevance of their complex structure to physiological function and cellular fate is unresolved. Using a fully functional fluorescent version of Arabidopsis thaliana FLA4 we show that this protein is localized at the plasma membrane as well as in endosomes and soluble in the apoplast. FLA4 is likely to be GPI-anchored, is highly N-glycosylated and carries two O-glycan epitopes previously associated with arabinogalactan proteins. The activity of FLA4 was resistant against deletion of the amino-proximal fasciclin 1 domain and was unaffected by removal of the GPI-modification signal, a highly conserved N-glycan or the deletion of predicted O-glycosylation sites. Nonetheless these structural changes dramatically decreased endoplasmic reticulum (ER)-exit and plasma membrane localization of FLA4, with N-glycosylation acting at the level of ER-exit and O-glycosylation influencing post-secretory fate. We show that FLA4 acts predominantly by molecular interactions involving its carboxy-proximal fasciclin 1 domain and that its amino-proximal fasciclin 1 domain is required for stabilization of plasma membrane localization. FLA4 functions as a soluble glycoprotein via its carboxy-proximal Fas1 domain and its normal cellular trafficking depends on N- and O-glycosylation. © 2017 The Authors. The Plant Journal published by John Wiley & Sons Ltd and Society for Experimental Biology.

  5. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Science.gov (United States)

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  6. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Directory of Open Access Journals (Sweden)

    Ha-Na Na

    Full Text Available Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR, and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1. In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  7. Electromagnetic Signal Feedback Control for Proximity Detection Systems

    Science.gov (United States)

    Smith, Adam K.

    Coal is the most abundant fossil fuel in the United States and remains an essential source of energy. While more than half of coal production comes from surface mining, nearly twice as many workers are employed by underground operations. One of the key pieces of equipment used in underground coal mining is the continuous mining machine. These large and powerful machines are operated in confined spaces by remote control. Since 1984, 40 mine workers in the U. S. have been killed when struck or pinned by a continuous mining machine. It is estimated that a majority of these accidents could have been prevented with the application of proximity detection systems. While proximity detection systems can significantly increase safety around a continuous mining machine, there are some system limitations. Commercially available proximity warning systems for continuous mining machines use magnetic field generators to detect workers and establish safe work areas around the machines. Several environmental factors, however, can influence and distort the magnetic fields. To minimize these effects, a control system has been developed using electromagnetic field strength and generator current to stabilize and control field drift induced by internal and external environmental factors. A laboratory test set-up was built using a ferrite-core magnetic field generator to produce a stable magnetic field. Previous work based on a field-invariant magnetic flux density model, which generically describes the electromagnetic field, is expanded upon. The analytically established transferable shell-based flux density distribution model is used to experimentally validate the control system. By controlling the current input to the ferrite-core generator, a more reliable and consistent magnetic field is produced. Implementation of this technology will improve accuracy and performance of existing commercial proximity detection systems. These research results will help reduce the risk of traumatic

  8. ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

    Directory of Open Access Journals (Sweden)

    Wei Sheng Chia

    Full Text Available p97/Valosin-containing protein (VCP is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD. It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

  9. ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

    Science.gov (United States)

    Chia, Wei Sheng; Chia, Diana Xueqi; Rao, Feng; Bar Nun, Shoshana; Geifman Shochat, Susana

    2012-01-01

    p97/Valosin-containing protein (VCP) is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD). It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

  10. Frequency-domain method for separating signal and noise

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A new method for separation of signal and noise (SSN) is put forward. Frequency is redefined according to the features of signal and its derivative in the sampl ing time interval, thus double orthogonal basis (DOB) is constructed so that a signal can be precisely signified with a linear combination of low-frequency DOB . Under joint consideration in time domain (TD) and frequency domain (FD), a method on SSN with high accuracy is derived and a matched algorithm is designed and analyzed. This method is applicable to SSN in multiple frequency bands, and convenient in applying signal characteristics in TD and FD synthetically with highe raccuracy.

  11. Frequency-domain method for separating signal and noise

    Institute of Scientific and Technical Information of China (English)

    王正明; 段晓君

    2000-01-01

    A new method for separation of signal and noise (SSN) is put forward. Frequency is redefined according to the features of signal and its derivative in the sampling time interval, thus double orthogonal basis (DOB) is constructed so that a signal can be precisely signified with a linear combination of low-frequency DOB. Under joint consideration in time domain (TD) and frequency domain (FD), a method on SSN with high accuracy is derived and a matched algorithm is designed and analyzed. This method is applicable to SSN in multiple frequency bands, and convenient in applying signal characteristics in TD and FD synthetically with higher accuracy.

  12. 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

  13. BAR domain proteins regulate Rho GTPase signaling.

    Science.gov (United States)

    Aspenström, Pontus

    2014-01-01

    BAR proteins comprise a heterogeneous group of multi-domain proteins with diverse biological functions. The common denominator is the Bin-Amphiphysin-Rvs (BAR) domain that not only confers targeting to lipid bilayers, but also provides scaffolding to mold lipid membranes into concave or convex surfaces. This function of BAR proteins is an important determinant in the dynamic reconstruction of membrane vesicles, as well as of the plasma membrane. Several BAR proteins function as linkers between cytoskeletal regulation and membrane dynamics. These links are provided by direct interactions between BAR proteins and actin-nucleation-promoting factors of the Wiskott-Aldrich syndrome protein family and the Diaphanous-related formins. The Rho GTPases are key factors for orchestration of this intricate interplay. This review describes how BAR proteins regulate the activity of Rho GTPases, as well as how Rho GTPases regulate the function of BAR proteins. This mutual collaboration is a central factor in the regulation of vital cellular processes, such as cell migration, cytokinesis, intracellular transport, endocytosis, and exocytosis.

  14. 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.

  15. Higher intramuscular triacylglycerol in women does not impair insulin sensitivity and proximal insulin signaling

    DEFF Research Database (Denmark)

    Høeg, Louise; Roepstorff, Carsten; Thiele, Maja

    2009-01-01

    that despite 47% higher IMTG levels in women in the follicular phase whole body as well as leg insulin sensitivity are higher than in matched men. This was not explained by sex differences in proximal insulin signalling in women. In women it seems that a high capillary density and type 1 muscle fiber...... expression may be important for insulin action. Key words: Muscle Triglycerides, gender, insulin action, sex paradox....

  16. SOIL SPECTRAL IMAGING: MOVING FROM PROXIMAL SENSING TO SPATIAL QUANTITATIVE DOMAIN

    Directory of Open Access Journals (Sweden)

    E. B. Dor

    2012-07-01

    Full Text Available Imaging spectroscopy (IS is a relatively new technique that has attracted the attention of workers in many fields. In the soil sciences, this technology is not well developed and additional research is required – despite the fact that a large number of soil properties in the soil environment have already been studied from a reflectance perspective with much success (e.g. organic matter, cation exchange capacity, carbonate content and specific surface area. Going from proximal sensing to image spectrometry is not only a journey from the micro to macro scales; it is a lengthy one that is fraught with problems, such as dealing with data having a low signal-to-noise level, contamination of the atmosphere, large data sets, the Bidirectional Reflectance Distribution Function (BRDF effect and more. In this paper, provide a brief history of both near infrared spectroscopy (NIRS and IS approaches and attempt to understand why, despite its promise, IS has not yet been well developed for the soil sciences. We assume that research, education, exposure of the technology to end-users and governmental involvement are the major factors that require attention in this venue. Also provide some personal thoughts on the future of IS in soil and conclude that in 5 to 10 years, this application will have matured into one that is ready to use and well-known among soil scientists, end-users and decision-makers.

  17. Pseudo-stochastic signal characterization in wavelet-domain

    International Nuclear Information System (INIS)

    Zaytsev, Kirill I; Zhirnov, Andrei A; Alekhnovich, Valentin I; Yurchenko, Stanislav O

    2015-01-01

    In this paper we present the method for fast and accurate characterization of pseudo-stochastic signals, which contain a large number of similar but randomly-located fragments. This method allows estimating the statistical characteristics of pseudo-stochastic signal, and it is based on digital signal processing in wavelet-domain. Continuous wavelet transform and the criterion for wavelet scale power density are utilized. We are experimentally implementing this method for the purpose of sand granulometry, and we are estimating the statistical parameters of test sand fractions

  18. All-optical signal processing of OTDM and OFDM signals based on time-domain Optical Fourier Transformation

    DEFF Research Database (Denmark)

    Clausen, Anders; Guan, Pengyu; Mulvad, Hans Christian Hansen

    2014-01-01

    All-optical time-domain Optical Fourier Transformation utilised for signal processing of ultra-high-speed OTDM signals and OFDM signals will be presented.......All-optical time-domain Optical Fourier Transformation utilised for signal processing of ultra-high-speed OTDM signals and OFDM signals will be presented....

  19. Inferring Person-to-person Proximity Using WiFi Signals

    DEFF Research Database (Denmark)

    Sapiezynski, Piotr; Stopczynski, Arkadiusz; Wind, David Kofoed

    2017-01-01

    scale is a technical challenge and many commonly used approaches—including RFID badges or Bluetooth scanning—offer only limited scalability. Here we show that it is possible, in a scalable and robust way, to accurately infer person-to-person physical proximity from the lists of WiFi access points...... measured by smartphones carried by the two individuals. Based on a longitudinal dataset of approximately 800 participants with ground-truth interactions collected over a year, we show that our model performs better than the current state-of-the-art. Our results demonstrate the value of WiFi signals...

  20. N-domain angiotensin-I converting enzyme is expressed in immortalized mesangial, proximal tubule and collecting duct cells.

    Science.gov (United States)

    Mei Wang, Pamella Huey; Andrade, Maria Claudina; Quinto, Beata Marie Redublo; Di Marco, Giovana; Mortara, Renato Arruda; Vio, Carlos P; Casarini, Dulce Elena

    2015-01-01

    Somatic ACE (sACE) is found in glomerulus, proximal tubule and excreted in urine. We hypothesized that N-domain ACE can also be found at these sites. ACE profile was analyzed in mesangial (IMC), proximal (LLC-PK1), distal tubule (MDCK) and collecting duct (IMCD) cells. Cell lysate and culture medium were submitted to gel filtration chromatography, which separated two peaks with ACE activity from cells and medium, except from distal tubule. The first had a high molecular weight and the second, a lower one (65 kDa; N-domain ACE). We focused on N-domain ACE purification and characterization from LLC-PK1. Total LLC-PK1 N-domain ACE purification was achieved by ion-exchange chromatography, which presented only one peak with ACE activity, denominated ACE(int2A). ACE(int2A) activity was influenced by pH, NaCl and temperature. The purified enzyme was inhibited by Captopril and hydrolyzed AngI, Ang1-7 and AcSDKP. Its ability to hydrolyze AcSDKP characterized it as an N-domain ACE. ACE(int2A) also presented high amino acid sequence homology with the N-terminal part of sACE from mouse, rat, human and rabbit. The presence of secreted and intracellular N-domain ACE and sACE in IMC, LLC-PK1 and IMCD cells confirmed our studies along the nephron. We identified, purified and characterized N-domain ACE from LLC-PK1. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Assembly of Oligomeric Death Domain Complexes during Toll Receptor Signaling*

    OpenAIRE

    Moncrieffe, Martin C.; Grossmann, J. Günter; Gay, Nicholas J.

    2008-01-01

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show ...

  2. Assembly of Oligomeric Death Domain Complexes during Toll Receptor Signaling*

    Science.gov (United States)

    Moncrieffe, Martin C.; Grossmann, J. Günter; Gay, Nicholas J.

    2008-01-01

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show that both the heterodimeric and heterotrimeric complexes form kidney-shaped structures and that Tube is bivalent and has separate high affinity binding sites for dMyD88 and Pelle. Additionally we found no interaction between the isolated death domains of Pelle and dMyD88. These results indicate that the mode of assembly of the heterotrimeric dMyD88-Tube-Pelle complex downstream of the activated Toll receptor is unique. The measured dissociation constants for the interaction between the death domains of dMyD88 and Tube and of Pelle and a preformed dMyD88-Tube complex are used to propose a model of the early postreceptor events in Drosophila Toll receptor signaling. PMID:18829464

  3. Assembly of oligomeric death domain complexes during Toll receptor signaling.

    Science.gov (United States)

    Moncrieffe, Martin C; Grossmann, J Günter; Gay, Nicholas J

    2008-11-28

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show that both the heterodimeric and heterotrimeric complexes form kidney-shaped structures and that Tube is bivalent and has separate high affinity binding sites for dMyD88 and Pelle. Additionally we found no interaction between the isolated death domains of Pelle and dMyD88. These results indicate that the mode of assembly of the heterotrimeric dMyD88-Tube-Pelle complex downstream of the activated Toll receptor is unique. The measured dissociation constants for the interaction between the death domains of dMyD88 and Tube and of Pelle and a preformed dMyD88-Tube complex are used to propose a model of the early postreceptor events in Drosophila Toll receptor signaling.

  4. Local pH domains regulate NHE3-mediated Na+ reabsorption in the renal proximal tubule

    Science.gov (United States)

    Burford, James L.; McDonough, Alicia A.; Holstein-Rathlou, Niels-Henrik; Peti-Peterdi, Janos

    2014-01-01

    The proximal tubule Na+/H+ exchanger 3 (NHE3), located in the apical dense microvilli (brush border), plays a major role in the reabsorption of NaCl and water in the renal proximal tubule. In response to a rise in blood pressure NHE3 redistributes in the plane of the plasma membrane to the base of the brush border, where NHE3 activity is reduced. This NHE3 redistribution is assumed to provoke pressure natriuresis; however, it is unclear how NHE3 redistribution per se reduces NHE3 activity. To investigate if the distribution of NHE3 in the brush border can change the reabsorption rate, we constructed a spatiotemporal mathematical model of NHE3-mediated Na+ reabsorption across a proximal tubule cell and compared the model results with in vivo experiments in rats. The model predicts that when NHE3 is localized exclusively at the base of the brush border, it creates local pH microdomains that reduce NHE3 activity by >30%. We tested the model's prediction experimentally: the rat kidney cortex was loaded with the pH-sensitive fluorescent dye BCECF, and cells of the proximal tubule were imaged in vivo using confocal fluorescence microscopy before and after an increase of blood pressure by ∼50 mmHg. The experimental results supported the model by demonstrating that a rise of blood pressure induces the development of pH microdomains near the bottom of the brush border. These local changes in pH reduce NHE3 activity, which may explain the pressure natriuresis response to NHE3 redistribution. PMID:25298526

  5. Fluorescent fusion proteins of soluble guanylyl cyclase indicate proximity of the heme nitric oxide domain and catalytic domain.

    Directory of Open Access Journals (Sweden)

    Tobias Haase

    Full Text Available BACKGROUND: To examine the structural organisation of heterodimeric soluble guanylyl cyclase (sGC Förster resonance energy transfer (FRET was measured between fluorescent proteins fused to the amino- and carboxy-terminal ends of the sGC beta1 and alpha subunits. METHODOLOGY/PRINCIPAL FINDINGS: Cyan fluorescent protein (CFP was used as FRET donor and yellow fluorescent protein (YFP as FRET acceptor. After generation of recombinant baculovirus, fluorescent-tagged sGC subunits were co-expressed in Sf9 cells. Fluorescent variants of sGC were analyzed in vitro in cytosolic fractions by sensitized emission FRET. Co-expression of the amino-terminally tagged alpha subunits with the carboxy-terminally tagged beta1 subunit resulted in an enzyme complex that showed a FRET efficiency of 10% similar to fluorescent proteins separated by a helix of only 48 amino acids. Because these findings indicated that the amino-terminus of the alpha subunits is close to the carboxy-terminus of the beta1 subunit we constructed fusion proteins where both subunits are connected by a fluorescent protein. The resulting constructs were not only fluorescent, they also showed preserved enzyme activity and regulation by NO. CONCLUSIONS/SIGNIFICANCE: Based on the ability of an amino-terminal fragment of the beta1 subunit to inhibit activity of an heterodimer consisting only of the catalytic domains (alphacatbetacat, Winger and Marletta (Biochemistry 2005, 44:4083-90 have proposed a direct interaction of the amino-terminal region of beta1 with the catalytic domains. In support of such a concept of "trans" regulation of sGC activity by the H-NOX domains our results indicate that the domains within sGC are organized in a way that allows for direct interaction of the amino-terminal regulatory domains with the carboxy-terminal catalytic region. In addition, we constructed "fluorescent-conjoined" sGC's by fusion of the alpha amino-terminus to the beta1 carboxy-terminus leading to a

  6. Inferring Person-to-person Proximity Using WiFi Signals

    DEFF Research Database (Denmark)

    Sapiezynski, Piotr; Stopczynski, Arkadiusz; Wind, David Kofoed

    2017-01-01

    phone towers, Bluetooth beacons, and WiFi networks as proxies for location. However, while mobility is an important aspect of human behavior, understanding complex social systems requires studying not only the movement of individuals, but also their interactions. Sensing social interactions on a large...... scale is a technical challenge and many commonly used approaches—including RFID badges or Bluetooth scanning—offer only limited scalability. Here we show that it is possible, in a scalable and robust way, to accurately infer person-to-person physical proximity from the lists of WiFi access points...... measured by smartphones carried by the two individuals. Based on a longitudinal dataset of approximately 800 participants with ground-truth interactions collected over a year, we show that our model performs better than the current state-of-the-art. Our results demonstrate the value of WiFi signals...

  7. Acute inhibition of selected membrane-proximal mouse T cell receptor signaling by mitochondrial antagonists.

    Directory of Open Access Journals (Sweden)

    Kwangmi Kim

    2009-11-01

    Full Text Available T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR with cognate peptide/major histocompatibility complex (MHC plus lymphocyte function-associated antigen 1 (LFA-1 with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin, resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s. Thus, activation of Akt and PLC-gamma1 and entry of extracellular Ca(2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function.

  8. The Popeye Domain Containing Genes and cAMP Signaling

    Directory of Open Access Journals (Sweden)

    Thomas Brand

    2014-05-01

    Full Text Available 3'-5'-cyclic adenosine monophosphate (cAMP is a second messenger, which plays an important role in the heart. It is generated in response to activation of G-protein-coupled receptors (GPCRs. Initially, it was thought that protein kinase A (PKA exclusively mediates cAMP-induced cellular responses such as an increase in cardiac contractility, relaxation, and heart rate. With the identification of the exchange factor directly activated by cAMP (EPAC and hyperpolarizing cyclic nucleotide-gated (HCN channels as cAMP effector proteins it became clear that a protein network is involved in cAMP signaling. The Popeye domain containing (Popdc genes encode yet another family of cAMP-binding proteins, which are prominently expressed in the heart. Loss-of-function mutations in mice are associated with cardiac arrhythmia and impaired skeletal muscle regeneration. Interestingly, the cardiac phenotype, which is present in both, Popdc1 and Popdc2 null mutants, is characterized by a stress-induced sinus bradycardia, suggesting that Popdc proteins participate in cAMP signaling in the sinuatrial node. The identification of the two-pore channel TREK-1 and Caveolin 3 as Popdc-interacting proteins represents a first step into understanding the mechanisms of heart rate modulation triggered by Popdc proteins.

  9. 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

  10. 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.

  11. Proximal predictors of depressive symptomatology: perceived losses in self-worth and interpersonal domains and introjective and anaclitic mood states.

    Science.gov (United States)

    Kopala-Sibley, Daniel C; Zuroff, David C

    2010-01-01

    Although much research has demonstrated a relationship between negative life events and depressive symptoms, relatively little research has examined the mechanisms that may mediate this relationship. The theories of Blatt (1974), Bowlby (1980), and Gilbert (1992) each propose proximal predictors of depression. In accordance with these theories, this study examined the relationships among perceived losses in self-worth and interpersonal relationships, anaclitic (dependent) and introjective (self-critical) mood states, and depressive symptoms following a significant negative life event. A sample of 172 undergraduate students completed measures of depressive symptoms and depressive vulnerability factors and retrospectively described the worst period of their lives. They also rated the extent to which the events surrounding this worst period affected their self-worth and their relationships with close others. Structural equation modeling demonstrated that the effect of a perceived loss of self-worth on depressive symptoms was fully mediated by both introjective and anaclitic mood states, whereas the effect of a perceived loss of interpersonal relationships on depressive symptoms was fully mediated by an anaclitic mood state. Additionally, perceived losses of self-worth showed a stronger effect on introjective mood in highly self-critical individuals. Findings highlight the importance of perceived losses in both self-worth and interpersonal domains in response to adverse life events and suggest pathways through which perceived losses may affect depressive symptoms.

  12. Structure of Concatenated HAMP Domains Provides a Mechanism for Signal Transduction

    Energy Technology Data Exchange (ETDEWEB)

    Airola, Michael V.; Watts, Kylie J.; Bilwes, Alexandrine M.; Crane, Brian R. (Cornell); (Lorma Linda U)

    2010-08-23

    HAMP domains are widespread prokaryotic signaling modules found as single domains or poly-HAMP chains in both transmembrane and soluble proteins. The crystal structure of a three-unit poly-HAMP chain from the Pseudomonas aeruginosa soluble receptor Aer2 defines a universal parallel four-helix bundle architecture for diverse HAMP domains. Two contiguous domains integrate to form a concatenated di-HAMP structure. The three HAMP domains display two distinct conformations that differ by changes in helical register, crossing angle, and rotation. These conformations are stabilized by different subsets of conserved residues. Known signals delivered to HAMP would be expected to switch the relative stability of the two conformations and the position of a coiled-coil phase stutter at the junction with downstream helices. We propose that the two conformations represent opposing HAMP signaling states and suggest a signaling mechanism whereby HAMP domains interconvert between the two states, which alternate down a poly-HAMP chain.

  13. Molecular Mechanisms of SH2- and PTB-Domain-Containing Proteins in Receptor Tyrosine Kinase Signaling

    Science.gov (United States)

    Wagner, Melany J.; Stacey, Melissa M.; Liu, Bernard A.; Pawson, Tony

    2013-01-01

    Intracellular signaling is mediated by reversible posttranslational modifications (PTMs) that include phosphorylation, ubiquitination, and acetylation, among others. In response to extracellular stimuli such as growth factors, receptor tyrosine kinases (RTKs) typically dimerize and initiate signaling through phosphorylation of their cytoplasmic tails and downstream scaffolds. Signaling effectors are recruited to these phosphotyrosine (pTyr) sites primarily through Src homology 2 (SH2) domains and pTyr-binding (PTB) domains. This review describes how these conserved domains specifically recognize pTyr residues and play a major role in mediating precise downstream signaling events. PMID:24296166

  14. Molecular mechanisms of SH2- and PTB-domain-containing proteins in receptor tyrosine kinase signaling.

    Science.gov (United States)

    Wagner, Melany J; Stacey, Melissa M; Liu, Bernard A; Pawson, Tony

    2013-12-01

    Intracellular signaling is mediated by reversible posttranslational modifications (PTMs) that include phosphorylation, ubiquitination, and acetylation, among others. In response to extracellular stimuli such as growth factors, receptor tyrosine kinases (RTKs) typically dimerize and initiate signaling through phosphorylation of their cytoplasmic tails and downstream scaffolds. Signaling effectors are recruited to these phosphotyrosine (pTyr) sites primarily through Src homology 2 (SH2) domains and pTyr-binding (PTB) domains. This review describes how these conserved domains specifically recognize pTyr residues and play a major role in mediating precise downstream signaling events.

  15. Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

    Science.gov (United States)

    Endo, Yoko; Suzuki, Masashi; Yamada, Hideomi; Horita, Shoko; Kunimi, Motoei; Yamazaki, Osamu; Shirai, Ayumi; Nakamura, Motonobu; Iso-O, Naoyuki; Li, Yuehong; Hara, Masumi; Tsukamoto, Kazuhisa; Moriyama, Nobuo; Kudo, Akihiko; Kawakami, Hayato; Yamauchi, Toshimasa; Kubota, Naoto; Kadowaki, Takashi; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George; Fujita, Toshiro

    2011-05-04

    Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Domain requirements for the Dock adapter protein in growth- cone signaling

    OpenAIRE

    Rao, Yong; Zipursky, S. Lawrence

    1998-01-01

    Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly speci...

  17. The TIR domain of TIR-NB-LRR resistance proteins is a signaling domain involved in cell death induction.

    Science.gov (United States)

    Swiderski, Michal R; Birker, Doris; Jones, Jonathan D G

    2009-02-01

    In plants, the TIR (toll interleukin 1 receptor) domain is found almost exclusively in nucleotide-binding (NB) leucine-rich repeat resistance proteins and their truncated homologs, and has been proposed to play a signaling role during resistance responses mediated by TIR containing R proteins. Transient expression in Nicotiana benthamiana leaves of "TIR + 80", the RPS4 truncation without the NB-ARC domain, leads to EDS1-, SGT1-, and HSP90-dependent cell death. Transgenic Arabidopsis plants expressing the RPS4 TIR+80 from either dexamethasone or estradiol-inducible promoters display inducer-dependent cell death. Cell death is also elicited by transient expression of similarly truncated constructs from two other R proteins, RPP1A and At4g19530, but is not elicited by similar constructs representing RPP2A and RPP2B proteins. Site-directed mutagenesis of the RPS4 TIR domain identified many loss-of-function mutations but also revealed several gain-of function substitutions. Lack of cell death induction by the E160A substitution suggests that amino acids outside of the TIR domain contribute to cell death signaling in addition to the TIR domain itself. This is consistent with previous observations that the TIR domain itself is insufficient to induce cell death upon transient expression.

  18. Social Signal Processing: Survey of an Emerging Domain

    NARCIS (Netherlands)

    Vinciarelli, Alessandro; Pantic, Maja; Bourlard, Hervé

    2009-01-01

    The ability to understand and manage social signals of a person we are communicating with is the core of social intelligence. Social intelligence is a facet of human intelligence that has been argued to be indispensable and perhaps the most important for success in life. This paper argues that

  19. Windowing of THz time-domain spectroscopy signals: A study based on lactose

    Science.gov (United States)

    Vázquez-Cabo, José; Chamorro-Posada, Pedro; Fraile-Peláez, Francisco Javier; Rubiños-López, Óscar; López-Santos, José María; Martín-Ramos, Pablo

    2016-05-01

    Time-domain spectroscopy has established itself as a reference method for determining material parameters in the terahertz spectral range. This procedure requires the processing of the measured time-domain signals in order to estimate the spectral data. In this work, we present a thorough study of the properties of the signal windowing, a step previous to the parameter extraction algorithm, that permits to improve the accuracy of the results. Lactose has been used as sample material in the study.

  20. Fertility signaling - the proximate mechanism of worker policing in a clonal ant

    DEFF Research Database (Denmark)

    Hartmann, Anne; D'Ettorre, Patrizia; Jones, Graeme R.

    2005-01-01

    In eusocial insects, the ability to regulate reproduction relies on cues that signal the presence of fertile individuals. We investigated the variation of cuticular hydrocarbons (CHCs) with reproductive status in Platythyrea punctata, an ant, in which all workers are capable of producing daughters...... to old reproductives, but not when it was similar to that of nonreproductives. CHCs appear to signal the fertility of individuals and induce policing behavior towards surplus reproductive workers....

  1. Omnidirectional regeneration (ODR) of proximity sensor signals for robust diagnosis of journal bearing systems

    Science.gov (United States)

    Jung, Joon Ha; Jeon, Byung Chul; Youn, Byeng D.; Kim, Myungyon; Kim, Donghwan; Kim, Yeonwhan

    2017-06-01

    Some anomaly states of journal bearing rotor systems are direction-oriented (e.g., rubbing, misalignment). In these situations, vibration signals vary according to the direction of the sensors and the health state. This makes diagnosis difficult with traditional diagnosis methods. This paper proposes an omnidirectional regeneration method to develop a robust diagnosis algorithm for rotor systems. The proposed method can generate vibration signals in arbitrary directions without using extra sensors. In this method, signals are generated around the entire circumference of the rotor to consider all possible directions. Then, the directionality of each state is proved by mathematically and is evaluated using a proposed metric. When a directional state is determined, the classification is carried out on all of the generated signals. When a non-directional state is found, the classification is performed on only one of the generated signals to minimize computational load without sacrificing accuracy. The proposed ODR method was validated using experimental data. The classification results show that the proposed method generally outperforms the conventional classification method. The results support the proposed concept of using ODR signals in diagnosis procedures for journal bearing systems.

  2. Recursive nearest neighbor search in a sparse and multiscale domain for comparing audio signals

    DEFF Research Database (Denmark)

    Sturm, Bob L.; Daudet, Laurent

    2011-01-01

    We investigate recursive nearest neighbor search in a sparse domain at the scale of audio signals. Essentially, to approximate the cosine distance between the signals we make pairwise comparisons between the elements of localized sparse models built from large and redundant multiscale dictionaries...

  3. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins.

    Science.gov (United States)

    Koch, C A; Anderson, D; Moran, M F; Ellis, C; Pawson, T

    1991-05-03

    Src homology (SH) regions 2 and 3 are noncatalytic domains that are conserved among a series of cytoplasmic signaling proteins regulated by receptor protein-tyrosine kinases, including phospholipase C-gamma, Ras GTPase (guanosine triphosphatase)-activating protein, and Src-like tyrosine kinases. The SH2 domains of these signaling proteins bind tyrosine phosphorylated polypeptides, implicated in normal signaling and cellular transformation. Tyrosine phosphorylation acts as a switch to induce the binding of SH2 domains, thereby mediating the formation of heteromeric protein complexes at or near the plasma membrane. The formation of these complexes is likely to control the activation of signal transduction pathways by tyrosine kinases. The SH3 domain is a distinct motif that, together with SH2, may modulate interactions with the cytoskeleton and membrane. Some signaling and transforming proteins contain SH2 and SH3 domains unattached to any known catalytic element. These noncatalytic proteins may serve as adaptors to link tyrosine kinases to specific target proteins. These observations suggest that SH2 and SH3 domains participate in the control of intracellular responses to growth factor stimulation.

  4. Domain requirements for the Dock adapter protein in growth- cone signaling.

    Science.gov (United States)

    Rao, Y; Zipursky, S L

    1998-03-03

    Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons.

  5. Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells

    Directory of Open Access Journals (Sweden)

    Wolff Natascha A

    2010-05-01

    Full Text Available Abstract Background The class 1 carcinogen cadmium (Cd2+ disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis. Results We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC. Cd2+ (25 μM, 3-9 h caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1 were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability. Conclusions Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.

  6. 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.

  7. The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by MacB transporter

    OpenAIRE

    Modali, Sita D.; Zgurskaya, Helen I.

    2011-01-01

    Escherichia coli MacAB-TolC is a tri-partite macrolide efflux transporter driven by hydrolysis of ATP. In this complex, MacA is the periplasmic membrane fusion protein that stimulates the activity of MacB transporter and establishes the link with the outer membrane channel TolC. The molecular mechanism by which MacA stimulates MacB remains unknown. Here, we report that the periplasmic membrane proximal domain of MacA plays a critical role in functional MacA-MacB interactions and stimulation o...

  8. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling

    DEFF Research Database (Denmark)

    Zech, Tobias; Ejsing, Christer S.; Gaus, Katharina

    2009-01-01

    Activating stimuli for T lymphocytes are transmitted through plasma membrane domains that form at T-cell antigen receptor (TCR) signalling foci. Here, we determined the molecular lipid composition of immunoisolated TCR activation domains. We observed that they accumulate cholesterol, sphingomyelin...... and saturated phosphatidylcholine species as compared with control plasma membrane fragments. This provides, for the first time, direct evidence that TCR activation domains comprise a distinct molecular lipid composition reminiscent of liquid-ordered raft phases in model membranes. Interestingly, TCR activation...... domains were also enriched in plasmenyl phosphatidylethanolamine and phosphatidylserine. Modulating the T-cell lipidome with polyunsaturated fatty acids impaired the plasma membrane condensation at TCR signalling foci and resulted in a perturbed molecular lipid composition. These results correlate...

  9. Domain altering SNPs in the human proteome and their impact on signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yichuan Liu

    Full Text Available Single nucleotide polymorphisms (SNPs constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders.

  10. Within a Stone's Throw: Proximal Geolocation of Internet Users via Covert Wireless Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Paul, Nathanael R [ORNL; Shue, Craig [Worcester Polytechnic Institute, Worcester; Taylor, Curtis [Worcester Polytechnic Institute, Worcester

    2013-01-01

    While Internet users may often believe they have anonymity online, a culmination of technologies and recent research may allow an adversary to precisely locate an online user s geophysical location. In many cases, such as peer-to-peer applications, an adversary can easily use a target s IP address to quickly obtain the general geographical location of the target. Recent research has scoped this general area to a 690m (0.43 mile) radius circle. In this work, we show how an adversary can exploit Internet communication for geophysical location by embedding covert signals in communication with a target on a remote wireless local area network. We evaluated the approach in two common real-world settings: a residential neighborhood and an apartment building. In the neighborhood case, we used a single-blind trial in which an observer located a target network to within three houses in less than 40 minutes. Directional antennas may have allowed even more precise geolocation. This approach had only a 0.38% false positive rate, despite 24,000 observed unrelated packets and many unrelated networks. This low rate allowed the observer to exclude false locations and continue searching for the target. Our results enable law enforcement or copyright holders to quickly locate online Internet users without requiring time-consuming subpoenas to Internet Service Providers. Other privacy use cases include rapidly locating individuals based on their online speech or interests. We hope to raise awareness of these issues and to spur discussion on privacy and geolocating techniques.

  11. Photoacoustic signal and noise analysis for Si thin plate: signal correction in frequency domain.

    Science.gov (United States)

    Markushev, D D; Rabasović, M D; Todorović, D M; Galović, S; Bialkowski, S E

    2015-03-01

    Methods for photoacoustic signal measurement, rectification, and analysis for 85 μm thin Si samples in the 20-20 000 Hz modulation frequency range are presented. Methods for frequency-dependent amplitude and phase signal rectification in the presence of coherent and incoherent noise as well as distortion due to microphone characteristics are presented. Signal correction is accomplished using inverse system response functions deduced by comparing real to ideal signals for a sample with well-known bulk parameters and dimensions. The system response is a piece-wise construction, each component being due to a particular effect of the measurement system. Heat transfer and elastic effects are modeled using standard Rosencweig-Gersho and elastic-bending theories. Thermal diffusion, thermoelastic, and plasmaelastic signal components are calculated and compared to measurements. The differences between theory and experiment are used to detect and correct signal distortion and to determine detector and sound-card characteristics. Corrected signal analysis is found to faithfully reflect known sample parameters.

  12. The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by MacB transporter.

    Science.gov (United States)

    Modali, Sita D; Zgurskaya, Helen I

    2011-08-01

    Escherichia coli MacAB-TolC is a tripartite macrolide efflux transporter driven by hydrolysis of ATP. In this complex, MacA is the periplasmic membrane fusion protein that stimulates the activity of MacB transporter and establishes the link with the outer membrane channel TolC. The molecular mechanism by which MacA stimulates MacB remains unknown. Here, we report that the periplasmic membrane proximal domain of MacA plays a critical role in functional MacA-MacB interactions and stimulation of MacB ATPase activity. Binding of MacA to MacB stabilizes the ATP-bound conformation of MacB, whereas interactions with both MacB and TolC affect the conformation of MacA. A single G353A substitution in the C-terminus of MacA inactivates MacAB-TolC function by changing the conformation of the membrane proximal domain of MacA and disrupting the proper assembly of the MacA-MacB complex. We propose that MacA acts in transport by promoting MacB transition into the closed ATP-bound conformation and in this respect, is similar to the periplasmic solute-binding proteins. © 2011 Blackwell Publishing Ltd.

  13. Asymptotically exact localized expansions for signals in the time–frequency domain

    International Nuclear Information System (INIS)

    Muzhikyan, Aramazd H; Avanesyan, Gagik T

    2012-01-01

    Based on a unique waveform with strong exponential localization property, an exact mathematical method for solving problems in signal analysis in the time–frequency domain is presented. An analogue of the Gabor frame exposes the non-commutative geometry of the time–frequency plane. Signals are visualized using the constructed graphical representation. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘Coherent states: mathematical and physical aspects’. (paper)

  14. Extracellular Membrane-proximal Domain of HAb18G/CD147 Binds to Metal Ion-dependent Adhesion Site (MIDAS) Motif of Integrin β1 to Modulate Malignant Properties of Hepatoma Cells*

    Science.gov (United States)

    Li, Yong; Wu, Jiao; Song, Fei; Tang, Juan; Wang, Shi-Jie; Yu, Xiao-Ling; Chen, Zhi-Nan; Jiang, Jian-Li

    2012-01-01

    Several lines of evidence suggest that HAb18G/CD147 interacts with the integrin variants α3β1 and α6β1. However, the mechanism of the interaction remains largely unknown. In this study, mammalian protein-protein interaction trap (MAPPIT), a mammalian two-hybrid method, was used to study the CD147-integrin β1 subunit interaction. CD147 in human hepatocellular carcinoma (HCC) cells was interfered with by small hairpin RNA. Nude mouse xenograft model and metastatic model of HCC were used to detect the role of CD147 in carcinogenesis and metastasis. We found that the extracellular membrane-proximal domain of HAb18G/CD147 (I-type domain) binds at the metal ion-dependent adhesion site in the βA domain of the integrin β1 subunit, and Asp179 in the I-type domain of HAb18G/CD147 plays an important role in the interaction. The levels of the proteins that act downstream of integrin, including focal adhesion kinase (FAK) and phospho-FAK, were decreased, and the cytoskeletal structures of HCC cells were rearranged bearing the HAb18G/CD147 deletion. Simultaneously, the migration and invasion capacities, secretion of matrix metalloproteinases, colony formation rate in vitro, and tumor growth and metastatic potential in vivo were decreased. These results indicate that the interaction of HAb18G/CD147 extracellular I-type domain with the integrin β1 metal ion-dependent adhesion site motif activates the downstream FAK signaling pathway, subsequently enhancing the malignant properties of HCC cells. PMID:22130661

  15. The insulin receptor substrate (IRS)-1 pleckstrin homology domain functions in downstream signaling.

    Science.gov (United States)

    Vainshtein, I; Kovacina, K S; Roth, R A

    2001-03-16

    The pleckstrin homology (PH) domain of the insulin receptor substrate-1 (IRS-1) plays a role in directing this molecule to the insulin receptor, thereby regulating its tyrosine phosphorylation. In this work, the role of the PH domain in subsequent signaling was studied by constructing constitutively active forms of IRS-1 in which the inter-SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase was fused to portions of the IRS-1 molecule. Chimeric molecules containing the PH domain were found to activate the downstream response of stimulating the Ser/Thr kinase Akt. A chimera containing point mutations in the PH domain that abolished the ability of this domain to bind phosphatidylinositol 4,5-bisphosphate prevented these molecules from activating Akt. These mutations also decreased by about 70% the amount of the constructs present in a particulate fraction of the cells. These results indicate that the PH domain of IRS-1, in addition to directing this protein to the receptor for tyrosine phosphorylation, functions in the ability of this molecule to stimulate subsequent responses. Thus, compromising the function of the PH domain, e.g. in insulin-resistant states, could decrease both the ability of IRS-1 to be tyrosine phosphorylated by the insulin receptor and to link to subsequent downstream targets.

  16. Bile acids modulate signaling by functional perturbation of plasma membrane domains.

    Science.gov (United States)

    Zhou, Yong; Maxwell, Kelsey N; Sezgin, Erdinc; Lu, Maryia; Liang, Hong; Hancock, John F; Dial, Elizabeth J; Lichtenberger, Lenard M; Levental, Ilya

    2013-12-13

    Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects.

  17. 1.28 Tbaud Nyquist Signal Transmission using Time-Domain Optical Fourier Transformation based Receiver

    DEFF Research Database (Denmark)

    Hu, Hao; Kong, Deming; Palushani, Evarist

    2013-01-01

    We demonstrate transmission of a 1.28-Tbaud Nyquist-OTDM signal over a record distance of 100 km with detection by time-domain optical Fourier transformation followed by FEC decoding, resulting in error-free performance for all tributaries....

  18. A p130Cas tyrosine phosphorylated substrate domain decoy disrupts v-Crk signaling

    Directory of Open Access Journals (Sweden)

    Hanafusa Hidesaburo

    2002-07-01

    Full Text Available Abstract Background The adaptor protein p130Cas (Cas has been shown to be involved in different cellular processes including cell adhesion, migration and transformation. This protein has a substrate domain with up to 15 tyrosines that are potential kinase substrates, able to serve as docking sites for proteins with SH2 or PTB domains. Cas interacts with focal adhesion plaques and is phosphorylated by the tyrosine kinases FAK and Src. A number of effector molecules have been shown to interact with Cas and play a role in its function, including c-crk and v-crk, two adaptor proteins involved in intracellular signaling. Cas function is dependent on tyrosine phosphorylation of its substrate domain, suggesting that tyrosine phosphorylation of Cas in part regulates its control of adhesion and migration. To determine whether the substrate domain alone when tyrosine phosphorylated could signal, we have constructed a chimeric Cas molecule that is phosphorylated independently of upstream signals. Results We found that a tyrosine phosphorylated Cas substrate domain acts as a dominant negative mutant by blocking Cas-mediated signaling events, including JNK activation by the oncogene v-crk in transient and stable lines and v-crk transformation. This block was the result of competition for binding partners as the chimera competed for binding to endogenous c-crk and exogenously expressed v-crk. Conclusion Our approach suggests a novel method to study adaptor proteins that require phosphorylation, and indicates that mere tyrosine phosphorylation of the substrate domain of Cas is not sufficient for its function.

  19. Laser Capture Microdissection and Multiplex-Tandem PCR Analysis of Proximal Tubular Epithelial Cell Signaling in Human Kidney Disease

    Science.gov (United States)

    Wilkinson, Ray; Wang, Xiangju; Kassianos, Andrew J.; Zuryn, Steven; Roper, Kathrein E.; Osborne, Andrew; Sampangi, Sandeep; Francis, Leo; Raghunath, Vishwas; Healy, Helen

    2014-01-01

    Interstitial fibrosis, a histological process common to many kidney diseases, is the precursor state to end stage kidney disease, a devastating and costly outcome for the patient and the health system. Fibrosis is historically associated with chronic kidney disease (CKD) but emerging evidence is now linking many forms of acute kidney disease (AKD) with the development of CKD. Indeed, we and others have observed at least some degree of fibrosis in up to 50% of clinically defined cases of AKD. Epithelial cells of the proximal tubule (PTEC) are central in the development of kidney interstitial fibrosis. We combine the novel techniques of laser capture microdissection and multiplex-tandem PCR to identify and quantitate “real time” gene transcription profiles of purified PTEC isolated from human kidney biopsies that describe signaling pathways associated with this pathological fibrotic process. Our results: (i) confirm previous in-vitro and animal model studies; kidney injury molecule-1 is up-regulated in patients with acute tubular injury, inflammation, neutrophil infiltration and a range of chronic disease diagnoses, (ii) provide data to inform treatment; complement component 3 expression correlates with inflammation and acute tubular injury, (iii) identify potential new biomarkers; proline 4-hydroxylase transcription is down-regulated and vimentin is up-regulated across kidney diseases, (iv) describe previously unrecognized feedback mechanisms within PTEC; Smad-3 is down-regulated in many kidney diseases suggesting a possible negative feedback loop for TGF-β in the disease state, whilst tight junction protein-1 is up-regulated in many kidney diseases, suggesting feedback interactions with vimentin expression. These data demonstrate that the combined techniques of laser capture microdissection and multiplex-tandem PCR have the power to study molecular signaling within single cell populations derived from clinically sourced tissue. PMID:24475278

  20. Multichannel Signal Enhancement using Non-Causal, Time-Domain Filters

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Christensen, Mads Græsbøll; Benesty, Jacob

    2013-01-01

    In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non-causal. W......In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non......-causal, multichannel filters for enhancement based on an orthogonal decomposition is proposed. The evaluation shows that there is a potential gain in noise reduction and signal distortion by introducing non-causality. Moreover, experiments on real-life speech show that we can improve the perceptual quality....

  1. Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes.

    Science.gov (United States)

    Stone, Matthew B; Shelby, Sarah A; Núñez, Marcos F; Wisser, Kathleen; Veatch, Sarah L

    2017-02-01

    Diverse cellular signaling events, including B cell receptor (BCR) activation, are hypothesized to be facilitated by domains enriched in specific plasma membrane lipids and proteins that resemble liquid-ordered phase-separated domains in model membranes. This concept remains controversial and lacks direct experimental support in intact cells. Here, we visualize ordered and disordered domains in mouse B lymphoma cell membranes using super-resolution fluorescence localization microscopy, demonstrate that clustered BCR resides within ordered phase-like domains capable of sorting key regulators of BCR activation, and present a minimal, predictive model where clustering receptors leads to their collective activation by stabilizing an extended ordered domain. These results provide evidence for the role of membrane domains in BCR signaling and a plausible mechanism of BCR activation via receptor clustering that could be generalized to other signaling pathways. Overall, these studies demonstrate that lipid mediated forces can bias biochemical networks in ways that broadly impact signal transduction.

  2. Domain swapping reveals that the N-terminal domain of the sensor kinase KdpD in Escherichia coli is important for signaling

    Directory of Open Access Journals (Sweden)

    Lippert Marie-Luise

    2009-07-01

    Full Text Available Abstract Background The KdpD/KdpE two-component system of Escherichia coli regulates expression of the kdpFABC operon encoding the high affinity K+ transport system KdpFABC. The input domain of KdpD comprises a domain that belongs to the family of universal stress proteins (Usp. It has been previously demonstrated that UspC binds to this domain, resulting in KdpD/KdpE scaffolding under salt stress. However the mechanistic significance of this domain for signaling remains unclear. Here, we employed a "domain swapping" approach to replace the KdpD-Usp domain with four homologous domains or with the six soluble Usp proteins of E. coli. Results Full response to salt stress was only achieved with a chimera that contains UspC, probably due to unaffected scaffolding of the KdpD/KdpE signaling cascade by soluble UspC. Unexpectedly, chimeras containing either UspF or UspG not only prevented kdpFABC expression under salt stress but also under K+ limiting conditions, although these hybrid proteins exhibited kinase and phosphotransferase activities in vitro. These are the first KdpD derivatives that do not respond to K+ limitation due to alterations in the N-terminal domain. Analysis of the KdpD-Usp tertiary structure revealed that this domain has a net positively charged surface, while UspF and UspG are characterized by net negative surface charges. Conclusion The Usp domain within KdpD not only functions as a binding surface for the scaffold UspC, but it is also important for KdpD signaling. We propose that KdpD sensing/signaling involves alterations of electrostatic interactions between the large N- and C-terminal cytoplasmic domains.

  3. A conserved glutamine plays a central role in LOV domain signal transmission and duration

    Science.gov (United States)

    Nash, Abigail I.; Ko, Wen-Huang; Harper, Shannon M.; Gardner, Kevin H.

    2009-01-01

    Light is a key stimulus for plant biological functions, several of which are controlled by light-activated kinases known as phototropins, a group of kinases that contain two light-sensing domains (LOV, Light-Oxygen-Voltage domains) and a C-terminal serine/threonine kinase domain. The second sensory domain, LOV2, plays a key role in regulating kinase enzymatic activity via the photochemical formation of a covalent adduct between a LOV2 cysteine residue and an internally-bound flavin mononucleotide (FMN) chromophore. Subsequent conformational changes in LOV2 lead to the unfolding of a peripheral Jα helix, and ultimately, phototropin kinase activation. To date, the mechanism coupling bond formation and helix dissociation has remained unclear. Previous studies found that a conserved glutamine residue (Q513 in the Avena sativa phototropin 1 LOV2 (AsLOV2) domain) switches its hydrogen-bonding pattern with FMN upon light stimulation. Located in the immediate vicinity of the FMN binding site, this Gln residue is provided by the Iβ strand that interacts with the Jα helix, suggesting a route for signal propagation from the core of the LOV domain to its peripheral Jα helix. To test whether Q513 plays a key role in tuning the photochemical and transduction properties of AsLOV2, we designed two point mutations, Q513L and Q513N, and monitored the effects on the chromophore and protein using a combination of UV-visible absorbance and circular dichroism spectroscopy, limited proteolysis, and solution NMR. The results show that these mutations significantly dampen the changes between the dark and lit state AsLOV2 structures, leaving the protein in a pseudo-dark state (Q513L) or a pseudo-lit state (Q513N) conformation. Further, both mutations changed the photochemical properties of this receptor, particularly the lifetime of the photoexcited signaling states. Together, these data establish that this residue plays a central role in both spectral tuning and signal propagation from

  4. Digital signals processing using non-linear orthogonal transformation in frequency domain

    Directory of Open Access Journals (Sweden)

    Ivanichenko E.V.

    2017-12-01

    Full Text Available The rapid progress of computer technology in recent decades led to a wide introduction of methods of digital information processing practically in all fields of scientific research. In this case, among various applications of computing one of the most important places is occupied by digital processing systems signals (DSP that are used in data processing remote solution tasks of navigation of aerospace and marine objects, communications, radiophysics, digital optics and in a number of other applications. Digital Signal Processing (DSP is a dynamically developing an area that covers both technical and software tools. Related areas for digital signal processing are theory information, in particular, the theory of optimal signal reception and theory pattern recognition. In the first case, the main problem is signal extraction against a background of noise and interference of a different physical nature, and in the second - automatic recognition, i.e. classification and signal identification. In the digital processing of signals under a signal, we mean its mathematical description, i.e. a certain real function, containing information on the state or behavior of a physical system under an event that can be defined on a continuous or discrete space of time variation or spatial coordinates. In the broad sense, DSP systems mean a complex algorithmic, hardware and software. As a rule, systems contain specialized technical means of preliminary (or primary signal processing and special technical means for secondary processing of signals. Means of pretreatment are designed to process the original signals observed in general case against a background of random noise and interference of a different physical nature and represented in the form of discrete digital samples, for the purpose of detecting and selection (selection of the useful signal and evaluation characteristics of the detected signal. A new method of digital signal processing in the frequency

  5. Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies.

    Science.gov (United States)

    Bocharov, Eduard V; Lesovoy, Dmitry M; Goncharuk, Sergey A; Goncharuk, Marina V; Hristova, Kalina; Arseniev, Alexander S

    2013-11-05

    Fibroblast growth factor receptor 3 (FGFR3) transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease. Eight different pathogenic mutations, implicated in cancers and growth disorders, have been identified in the FGFR3 transmembrane segment. Here, we describe the dimerization of the FGFR3 transmembrane domain in membrane-mimicking DPC/SDS (9/1) micelles. In the solved NMR structure, the two transmembrane helices pack into a symmetric left-handed dimer, with intermolecular stacking interactions occurring in the dimer central region. Some pathogenic mutations fall within the helix-helix interface, whereas others are located within a putative alternative interface. This implies that although the observed dimer structure is important for FGFR3 signaling, the mechanism of FGFR3-mediated transduction across the membrane is complex. We propose an FGFR3 signaling mechanism that is based on the solved structure, available structures of isolated soluble FGFR domains, and published biochemical and biophysical data. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Optimizing the protein switch: altering nuclear import and export signals, and ligand binding domain

    Science.gov (United States)

    Kakar, Mudit; Davis, James R.; Kern, Steve E.; Lim, Carol S.

    2007-01-01

    Ligand regulated localization controllable protein constructs were optimized in this study. Several constructs were made from a classical nuclear export signal (HIV-rev, MAPKK, or progesterone receptor) in combination with a SV40 T-antigen type nuclear import signal. Different ligand binding domains (LBDs from glucocorticoid receptor or progesterone receptor) were also tested for their ability to impart control over localization of proteins. This study was designed to create constructs which are cytoplasmic in the absence of ligand and nuclear in the presence of ligand, and also to regulate the amount of protein translocating to the nucleus on ligand induction. The balance between the strengths of import and export signals was critical for overall localization of proteins. The amount of protein entering the nucleus was also affected by the dose of ligand (10-100nM). However, the overall import characteristics were determined by the strengths of localization signals and the inherent localization properties of the LBD used. This study established that the amount of protein present in a particular compartment can be regulated by the use of localization signals of various strengths. These optimized localization controllable protein constructs can be used to correct for diseases due to aberrant localization of proteins. PMID:17574289

  7. Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling.

    Science.gov (United States)

    Feener, Edward P; Rosario, Felicia; Dunn, Sarah L; Stancheva, Zlatina; Myers, Martin G

    2004-06-01

    Jak family tyrosine kinases mediate signaling by cytokine receptors to regulate diverse biological processes. Although Jak2 and other Jak kinase family members are phosphorylated on numerous sites during cytokine signaling, the identity and function of most of these sites remains unknown. Using tandem mass spectroscopic analysis of activated Jak2 protein from intact cells, we identified Tyr(221) and Tyr(570) as novel sites of Jak2 phosphorylation. Phosphorylation of both sites was stimulated by cytokine treatment of cultured cells, and this stimulation required Jak2 kinase activity. While we observed no gross alteration of signaling upon mutation of Tyr(221), Tyr(570) lies within the inhibitory JH2 domain of Jak2, and mutation of this site (Jak2(Y570F)) results in constitutive Jak2-dependent signaling in the absence of cytokine stimulation and enhances and prolongs Jak2 activation during cytokine stimulation. Mutation of Tyr(570) does not alter the ability of SOCS3 to bind or inhibit Jak2, however. Thus, the phosphorylation of Tyr(570) in vivo inhibits Jak2-dependent signaling independently of SOCS3-mediated inhibition. This Tyr(570)-dependent mechanism of Jak2 inhibition likely represents an important mechanism by which cytokine function is regulated.

  8. Structural basis for different phosphoinositide specificities of the PX domains of sorting nexins regulating G-protein signaling.

    Science.gov (United States)

    Mas, Caroline; Norwood, Suzanne J; Bugarcic, Andrea; Kinna, Genevieve; Leneva, Natalya; Kovtun, Oleksiy; Ghai, Rajesh; Ona Yanez, Lorena E; Davis, Jasmine L; Teasdale, Rohan D; Collins, Brett M

    2014-10-10

    Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signaling. A subfamily of PX domain proteins possesses two unique PX-associated domains, as well as a regulator of G protein-coupled receptor signaling (RGS) domain that attenuates Gαs-coupled G protein-coupled receptor signaling. Here we delineate the structural organization of these RGS-PX proteins, revealing a protein family with a modular architecture that is conserved in all eukaryotes. The one exception to this is mammalian SNX19, which lacks the typical RGS structure but preserves all other domains. The PX domain is a sensor of membrane phosphoinositide lipids and we find that specific sequence alterations in the PX domains of the mammalian RGS-PX proteins, SNX13, SNX14, SNX19, and SNX25, confer differential phosphoinositide binding preferences. Although SNX13 and SNX19 PX domains bind the early endosomal lipid phosphatidylinositol 3-phosphate, SNX14 shows no membrane binding at all. Crystal structures of the SNX19 and SNX14 PX domains reveal key differences, with alterations in SNX14 leading to closure of the binding pocket to prevent phosphoinositide association. Our findings suggest a role for alternative membrane interactions in spatial control of RGS-PX proteins in cell signaling and trafficking. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.

    Science.gov (United States)

    Durocher, D; Taylor, I A; Sarbassova, D; Haire, L F; Westcott, S L; Jackson, S P; Smerdon, S J; Yaffe, M B

    2000-11-01

    Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes.

  10. Study of time-domain digital pulse shaping algorithms for nuclear signals

    International Nuclear Information System (INIS)

    Zhou Jianbin; Tuo Xianguo; Zhu Xing; Liu Yi; Zhou Wei; Lei Jiarong

    2012-01-01

    With the development on high-speed integrated circuit, fast high resolution sampling ADC and digital signal processors are replacing analog shaping amplifier circuit. This paper firstly presents the numerical analysis and simulation on R-C shaping circuit model and C-R shaping circuit model. Mathematic models are established based on 1 st order digital differential method and Kirchhoff Current Law in time domain, and a simulation and error evaluation experiment on an ideal digital signal are carried out with Excel VBA. A digital shaping test for a semiconductor X-ray detector in real time is also presented. Then a numerical analysis for Sallen-Key(S-K) low-pass filter circuit model is implemented based on the analysis of digital R-C and digital C-R shaping methods. By applying the 2 nd order non-homogeneous differential equation,the authors implement a digital Gaussian filter model for a standard exponential-decaying signal and a nuclear pulse signal. Finally, computer simulations and experimental tests are carried out and the results show the possibility of the digital pulse processing algorithms. (authors)

  11. Recycling domains in plant cell morphogenesis: small GTPase effectors, plasma membrane signalling and the exocyst.

    Science.gov (United States)

    Zárský, Viktor; Potocký, Martin

    2010-04-01

    The Rho/Rop small GTPase regulatory module is central for initiating exocytotically ACDs (active cortical domains) in plant cell cortex, and a growing array of Rop regulators and effectors are being discovered in plants. Structural membrane phospholipids are important constituents of cells as well as signals, and phospholipid-modifying enzymes are well known effectors of small GTPases. We have shown that PLDs (phospholipases D) and their product, PA (phosphatidic acid), belong to the regulators of the secretory pathway in plants. We have also shown that specific NOXs (NADPH oxidases) producing ROS (reactive oxygen species) are involved in cell growth as exemplified by pollen tubes and root hairs. Most plant cells exhibit several distinct plasma membrane domains (ACDs), established and maintained by endocytosis/exocytosis-driven membrane protein recycling. We proposed recently the concept of a 'recycling domain' (RD), uniting the ACD and the connected endosomal recycling compartment (endosome), as a dynamic spatiotemporal entity. We have described a putative GTPase-effector complex exocyst involved in exocytic vesicle tethering in plants. Owing to the multiplicity of its Exo70 subunits, this complex, along with many RabA GTPases (putative recycling endosome organizers), may belong to core regulators of RD organization in plants.

  12. On Time Domain Analysis of Photoplethysmogram Signals for Monitoring Heat Stress

    Directory of Open Access Journals (Sweden)

    Mohamed Elgendi

    2015-09-01

    Full Text Available There are a limited number of studies on heat stress dynamics during exercise using the photoplethysmogram (PPG and its second derivative (APG. However, we investigate the most suitable index from short PPG signal recordings for heat stress assessment. The APG waveform consists of a, b, c and d waves in systole and an e wave in diastole. Our preliminary results indicate that the use of the energy of aa area, derived from PPG signals measured from emergency responders in tropical conditions, is promising in determining the heat stress level using 20-s recordings. After examining 14 time domain features using leave-one-out cross-validation, we found that the aa energy extracted from PPG signals is the most informative feature for classifying heat-stressed subjects, with an overall accuracy of 79%. Moreover, the combination of the aa energy with the traditional heart rate variability index of heat stress (i.e., the square root of the mean of the squares of the successive aa intervals improved the heat stress detection to an overall accuracy of 83%.

  13. The structure and dynamics of tandem WW domains in a negative regulator of notch signaling, Suppressor of deltex.

    Science.gov (United States)

    Fedoroff, Oleg Y; Townson, Sharon A; Golovanov, Alexander P; Baron, Martin; Avis, Johanna M

    2004-08-13

    WW domains mediate protein recognition, usually though binding to proline-rich sequences. In many proteins, WW domains occur in tandem arrays. Whether or how individual domains within such arrays cooperate to recognize biological partners is, as yet, poorly characterized. An important question is whether functional diversity of different WW domain proteins is reflected in the structural organization and ligand interaction mechanisms of their multiple domains. We have determined the solution structure and dynamics of a pair of WW domains (WW3-4) from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a regulator of Notch receptor signaling. We find that the binding of a type 1 PPPY ligand to WW3 stabilizes the structure with effects propagating to the WW4 domain, a domain that is not active for ligand binding. Both WW domains adopt the characteristic triple-stranded beta-sheet structure, and significantly, this is the first example of a WW domain structure to include a domain (WW4) lacking the second conserved Trp (replaced by Phe). The domains are connected by a flexible linker, which allows a hinge-like motion of domains that may be important for the recognition of functionally relevant targets. Our results contrast markedly with those of the only previously determined three-dimensional structure of tandem WW domains, that of the rigidly oriented WW domain pair from the RNA-splicing factor Prp40. Our data illustrate that arrays of WW domains can exhibit a variety of higher order structures and ligand interaction mechanisms.

  14. Gating in time domain as a tool for improving the signal-to-noise ratio of beam transfer function measurements

    CERN Document Server

    Oeftiger, U; Caspers, Fritz

    1992-01-01

    For the measurement of Beam Transfer Functions the signal-to-noise ratio is of great importance. In order to get a reasonable quality of the measured data one may apply averaging and smoothing. In the following another technique called time gating to improve the quality of the measurement will be described. By this technique the measurement data are Fourier transformed and then modified in time domain. Tune gating suppresses signal contributions that are correlated to a time interval when no interesting information is expected. Afterivards an inverse Fourier transform leads to data in frequency domain with an improved signal to noise ratio.

  15. ASIC3 Channels Integrate Agmatine and Multiple Inflammatory Signals through the Nonproton Ligand Sensing Domain

    Directory of Open Access Journals (Sweden)

    Cao Hui

    2010-12-01

    Full Text Available Abstract Background Acid-sensing ion channels (ASICs have long been known to sense extracellular protons and contribute to sensory perception. Peripheral ASIC3 channels represent natural sensors of acidic and inflammatory pain. We recently reported the use of a synthetic compound, 2-guanidine-4-methylquinazoline (GMQ, to identify a novel nonproton sensing domain in the ASIC3 channel, and proposed that, based on its structural similarity with GMQ, the arginine metabolite agmatine (AGM may be an endogenous nonproton ligand for ASIC3 channels. Results Here, we present further evidence for the physiological correlation between AGM and ASIC3. Among arginine metabolites, only AGM and its analog arcaine (ARC activated ASIC3 channels at neutral pH in a sustained manner similar to GMQ. In addition to the homomeric ASIC3 channels, AGM also activated heteromeric ASIC3 plus ASIC1b channels, extending its potential physiological relevance. Importantly, the process of activation by AGM was highly sensitive to mild acidosis, hyperosmolarity, arachidonic acid (AA, lactic acid and reduced extracellular Ca2+. AGM-induced ASIC3 channel activation was not through the chelation of extracellular Ca2+ as occurs with increased lactate, but rather through a direct interaction with the newly identified nonproton ligand sensing domain. Finally, AGM cooperated with the multiple inflammatory signals to cause pain-related behaviors in an ASIC3-dependent manner. Conclusions Nonproton ligand sensing domain might represent a novel mechanism for activation or sensitization of ASIC3 channels underlying inflammatory pain-sensing under in vivo conditions.

  16. Characterization of a baculovirus nuclear localization signal domain in the late expression factor 3 protein

    International Nuclear Information System (INIS)

    Au, Victoria; Yu Mei; Carstens, Eric B.

    2009-01-01

    The baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) single-stranded DNA binding protein LEF-3 is a multi-functional protein that is required to transport the helicase protein P143 into the nucleus of infected cells where they function to replicate viral DNA. The N-terminal 56 amino acid region of LEF-3 is required for nuclear transport. In this report, we analyzed the effect of site-specific mutagenesis of LEF-3 on its intracellular distribution. Fluorescence microscopy of expression plasmid-transfected cells demonstrated that the residues 28 to 32 formed the core nuclear localization signal, but other adjacent positively-charged residues augmented these sequences. Comparison with other group I Alphabaculoviruses suggested that this core region functionally duplicated residues including 18 and 19. This was demonstrated by the loss of nuclear localization when the equivalent residues (18 to 20) in Choristoneura fumiferana nucleopolyhedrovirus (CfMNPV) LEF-3 were mutated. The AcMNPV LEF-3 nuclear localization domain was also shown to drive nuclear transport in mammalian cells indicating that the protein nuclear import systems in insect and mammalian cells are conserved. We also demonstrated by mutagenesis that two conserved cysteine residues located at 82 and 106 were not essential for nuclear localization or for interaction with P143. However, by using a modified construct of P143 that localized on its own to the nucleus, we demonstrated that a functional nuclear localization domain on LEF-3 was required for interaction between LEF-3 and P143

  17. A plasma membrane localization signal in the HIV-1 envelope cytoplasmic domain prevents localization at sites of vesicular stomatitis virus budding and incorporation into VSV virions.

    Science.gov (United States)

    Johnson, J E; Rodgers, W; Rose, J K

    1998-11-25

    Previous studies showed that the HIV-1 envelope (Env) protein was not incorporated into vesicular stomatitis virus (VSV) virions unless its cytoplasmic tail was replaced with that of the VSV glycoprotein (G). To determine whether the G tail provided a positive incorporation signal for Env, or if sequences in the Env tail prevented incorporation, we generated mutants of Env with its 150-amino-acid tail shortened to 29, 10, or 3 amino acids (Envtr mutants). Cells infected with VSV recombinants expressing these proteins or an Env-G tail hybrid showed similar amounts of Env protein at the surface. The Env-G tail hybrid or the Envtr3 mutant were incorporated at the highest levels into budding VSV virions. In contrast, the Envtr29 or Envtr10 mutants were incorporated poorly. These results defined a signal preventing incorporation within the 10 membrane-proximal amino acids of the Env tail. Confocal microscopy revealed that this signal functioned by causing localization of human immunodeficiency virus type 1 Env to plasma membrane domains distinct from the VSV budding sites, where VSV proteins were concentrated. Copyright 1998 Academic Press.

  18. 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.

  19. Regulation of EGF receptor signaling by the MARVEL domain-containing protein CKLFSF8.

    Science.gov (United States)

    Jin, Caining; Ding, Peiguo; Wang, Ying; Ma, Dalong

    2005-11-21

    It is known that chemokine-like factor superfamily 8 (CKLFSF8), a member of the CKLF superfamily, has four putative transmembrane regions and a MARVEL domain. Its structure is similar to TM4SF11 (plasmolipin) and widely distributed in normal tissue. However, its function is not yet known. We show here that CKLFSF8 is associated with the epidermal growth factor receptor (EGFR) and that ectopic expression of CKLFSF8 in several cell lines suppresses EGF-induced cell proliferation, whereas knockdown of CKLFSF8 by siRNA promotes cell proliferation. In cells overexpressing CKLFSF8, the initial activation of EGFR was not affected, but subsequent desensitization of EGF-induced signaling occurred rapidly. This attenuation was correlated with an increased rate of receptor endocytosis. In contrast, knockdown of CKLFSF8 by siCKLFSF8 delayed EGFR endocytosis. These results identify CKLFSF8 as a novel regulator of EGF-induced signaling and indicate that the association of EGFR with four transmembrane proteins is critical for EGFR desensitization.

  20. An integrated domain specific language for post-processing and visualizing electrophysiological signals in Java.

    Science.gov (United States)

    Strasser, T; Peters, T; Jagle, H; Zrenner, E; Wilke, R

    2010-01-01

    Electrophysiology of vision - especially the electroretinogram (ERG) - is used as a non-invasive way for functional testing of the visual system. The ERG is a combined electrical response generated by neural and non-neuronal cells in the retina in response to light stimulation. This response can be recorded and used for diagnosis of numerous disorders. For both clinical practice and clinical trials it is important to process those signals in an accurate and fast way and to provide the results as structured, consistent reports. Therefore, we developed a freely available and open-source framework in Java (http://www.eye.uni-tuebingen.de/project/idsI4sigproc). The framework is focused on an easy integration with existing applications. By leveraging well-established software patterns like pipes-and-filters and fluent interfaces as well as by designing the application programming interfaces (API) as an integrated domain specific language (DSL) the overall framework provides a smooth learning curve. Additionally, it already contains several processing methods and visualization features and can be extended easily by implementing the provided interfaces. In this way, not only can new processing methods be added but the framework can also be adopted for other areas of signal processing. This article describes in detail the structure and implementation of the framework and demonstrate its application through the software package used in clinical practice and clinical trials at the University Eye Hospital Tuebingen one of the largest departments in the field of visual electrophysiology in Europe.

  1. Proximal Humerus

    NARCIS (Netherlands)

    Diercks, Ron L.; Bain, Gregory; Itoi, Eiji; Di Giacomo, Giovanni; Sugaya, Hiroyuki

    2015-01-01

    This chapter describes the bony structures of the proximal humerus. The proximal humerus is often regarded as consisting of four parts, which assists in understanding function and, more specially, describes the essential parts in reconstruction after fracture or in joint replacement. These are the

  2. The adaptor protein NTAL enhances proximal signaling and potentiates corticosteroid-induced apoptosis in T-ALL

    Czech Academy of Sciences Publication Activity Database

    Svojgr, K.; Kalina, T.; Kanderová, V.; Skopcová, Tereza; Brdička, Tomáš; Zuna, J.

    2012-01-01

    Roč. 40, č. 5 (2012), s. 379-385 ISSN 0301-472X R&D Projects: GA MŠk 2B06064 Institutional support: RVO:68378050 Keywords : acute lymphoblastic leukemia * TCR signaling * NTAL * ERK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.907, year: 2012

  3. Cepstral domain modification of audio signals for data embedding: preliminary results

    Science.gov (United States)

    Gopalan, Kaliappan

    2004-06-01

    A method of embedding data in an audio signal using cepstral domain modification is described. Based on successful embedding in the spectral points of perceptually masked regions in each frame of speech, first the technique was extended to embedding in the log spectral domain. This extension resulted at approximately 62 bits /s of embedding with less than 2 percent of bit error rate (BER) for a clean cover speech (from the TIMIT database), and about 2.5 percent for a noisy speech (from an air traffic controller database), when all frames - including silence and transition between voiced and unvoiced segments - were used. Bit error rate increased significantly when the log spectrum in the vicinity of a formant was modified. In the next procedure, embedding by altering the mean cepstral values of two ranges of indices was studied. Tests on both a noisy utterance and a clean utterance indicated barely noticeable perceptual change in speech quality when lower range of cepstral indices - corresponding to vocal tract region - was modified in accordance with data. With an embedding capacity of approximately 62 bits/s - using one bit per each frame regardless of frame energy or type of speech - initial results showed a BER of less than 1.5 percent for a payload capacity of 208 embedded bits using the clean cover speech. BER of less than 1.3 percent resulted for the noisy host with a capacity was 316 bits. When the cepstrum was modified in the region of excitation, BER increased to over 10 percent. With quantization causing no significant problem, the technique warrants further studies with different cepstral ranges and sizes. Pitch-synchronous cepstrum modification, for example, may be more robust to attacks. In addition, cepstrum modification in regions of speech that are perceptually masked - analogous to embedding in frequency masked regions - may yield imperceptible stego audio with low BER.

  4. ProxImaL: efficient image optimization using proximal algorithms

    KAUST Repository

    Heide, Felix; Diamond, Steven; Nieß ner, Matthias; Ragan-Kelley, Jonathan; Heidrich, Wolfgang; Wetzstein, Gordon

    2016-01-01

    domain-specific language and compiler for image optimization problems that makes it easy to experiment with different problem formulations and algorithm choices. The language uses proximal operators as the fundamental building blocks of a variety

  5. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

    Science.gov (United States)

    Mistry, Pragnesh; Laird, Michelle H. W.; Schwarz, Ryan S.; Greene, Shannon; Dyson, Tristan; Snyder, Greg A.; Xiao, Tsan Sam; Chauhan, Jay; Fletcher, Steven; Toshchakov, Vladimir Y.; MacKerell, Alexander D.; Vogel, Stefanie N.

    2015-01-01

    Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein–protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. PMID:25870276

  6. An evolutionary perspective of AMPK-TOR signaling in the three domains of life.

    Science.gov (United States)

    Roustan, Valentin; Jain, Arpit; Teige, Markus; Ebersberger, Ingo; Weckwerth, Wolfram

    2016-06-01

    AMPK and TOR protein kinases are the major control points of energy signaling in eukaryotic cells and organisms. They form the core of a complex regulatory network to co-ordinate metabolic activities in the cytosol with those in the mitochondria and plastids. Despite its relevance, it is still unclear when and how this regulatory pathway was formed during evolution, and to what extent its representations in the major eukaryotic lineages resemble each other. Here we have traced 153 essential proteins forming the human AMPK-TOR pathways across 412 species representing all three domains of life-prokaryotes (bacteria, archaea) and eukaryotes-and reconstructed their evolutionary history. The resulting phylogenetic profiles indicate the presence of primordial core pathways including seven proto-kinases in the last eukaryotic common ancestor. The evolutionary origins of the oldest components of the AMPK pathway, however, extend into the pre-eukaryotic era, and descendants of these ancient proteins can still be found in contemporary prokaryotes. The TOR complex in turn appears as a eukaryotic invention, possibly to aid in retrograde signaling between the mitochondria and the remainder of the cell. Within the eukaryotes, AMPK/TOR showed both a highly conserved core structure and a considerable plasticity. Most notably, KING1, a protein originally assigned as the γ subunit of AMPK in plants, is more closely related to the yeast SDS23 gene family than to the γ subunits in animals or fungi. This suggests its functional difference from a canonical AMPK γ subunit. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  7. Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Jensen, Christine B; Björnholm, Marie

    2004-01-01

    The effect of short- (2 h) and long-term (24 h) low-grade Intralipid infusion on whole-body insulin action, cellular glucose metabolism, and proximal components of the insulin signal transduction cascade was studied in seven obese male glucose intolerant first degree relatives of type 2 diabetic...... h Intralipid infusion (0.4 ml.kg(-1).min(-1)). Insulin-stimulated glucose disposal decreased approximately 25% after short- and long-term fat infusion in both IGT relatives and controls. Glucose oxidation decreased and lipid oxidation increased after both short- and long-term fat infusion in both...... groups. Insulin-stimulated glucose oxidation was higher after long-term as compared with short-term fat infusion in control subjects. Short- or long-term infusion did not affect the absolute values of basal or insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation, tyrosine...

  8. Enhancement of Single-Channel Periodic Signals in the Time-Domain

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

    2012-01-01

    speech. That is, signal-dependent methods based on the signal statistics will introduce undesired distortion for some parts of speech compared to signal-independent methods based on the noise statistics. Since both the signal-independent and signal-dependent approaches to speech enhancement have...

  9. Identifying Functional Neighborhoods within the Cell Nucleus: Proximity Analysis of Early S-Phase Replicating Chromatin Domains to Sites of Transcription, RNA Polymerase II, HP1γ, Matrin 3 and SAF-A

    Science.gov (United States)

    Malyavantham, Kishore S; Bhattacharya, Sambit; Barbeitos, Marcos; Mukherjee, Lopamudra; Xu, Jinhui; Fackelmayer, Frank O; Berezney, Ronald

    2009-01-01

    Higher order chromatin organization in concert with epigenetic regulation is a key process that determines gene expression at the global level. The organization of dynamic chromatin domains and their associated protein factors is intertwined with nuclear function to create higher levels of functional zones within the cell nucleus. As a step towards elucidating the organization and dynamics of these functional zones, we have investigated the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1γ, nascent transcript sites (TS), active DNA replicating sites in early S phase (PCNA) and RNA polymerase II sites. We report close associations among these different sites with proximity values specific for each combination. Analysis of matrin 3 and SAF-A sites demonstrates that these nuclear matrix proteins are highly proximal with the functionally related sites as well as to each other and display closely aligned and overlapping regions following application of the minimal spanning tree (MST) algorithm to visualize higher order network-like patterns. Our findings suggest that multiple factors within the nuclear microenvironment collectively form higher order combinatorial arrays of function. We propose a model for the organization of these functional neighborhoods which takes into account the proximity values of the individual sites and their spatial organization within the nuclear architecture. PMID:18618731

  10. Cyclic phosphopeptides for interference with Grb2 SH2 domain signal transduction prepared by ring-closing metathesis and phosphorylation

    NARCIS (Netherlands)

    Dekker, Frank J; de Mol, Nico J; Fischer, Marcel J E; Kemmink, Johan; Liskamp, Rob M J; Dekker, Frank

    2003-01-01

    Cyclic phosphopeptides were prepared using ring-closing metathesis followed by phosphorylation. These cyclic phosphopeptides were designed to interact with the SH2 domain of Grb2, which is a signal transduction protein of importance as a target for antiproliferative drug development. Binding of

  11. Tacrolimus Modulates TGF-β Signaling to Induce Epithelial-Mesenchymal Transition in Human Renal Proximal Tubule Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Jason Bennett

    2016-04-01

    Full Text Available Epithelial-mesenchymal transition (EMT, a process which describes the trans-differentiation of epithelial cells into motile mesenchymal cells, is pivotal in stem cell behavior, development and wound healing, as well as contributing to disease processes including fibrosis and cancer progression. Maintenance immunosuppression with calcineurin inhibitors (CNIs has become routine management for renal transplant patient, but unfortunately the nephrotoxicity of these drugs has been well documented. HK-2 cells were exposed to Tacrolimus (FK506 and EMT markers were assessed by RT PCR and western blot. FK506 effects on TGF-β mRNA were assessed by RT PCR and TGF-β secretion was measured by ELISA. The impact of increased TGF-β secretion on Smad signaling pathways was investigated. The impact of inhibition of TGF-β signaling on EMT processes was assessed by scratch-wound assay. The results presented in this study suggest that FK506 initiates EMT processes in the HK-2 cell line, with altered expression of epithelial and myofibroblast markers evident. Additionally, the study demonstrates that FK506 activation of the TGF-β/ SMAD pathways is an essential step in the EMT process. Overall the results demonstrate that EMT is heavily involved in renal fibrosis associated with CNI nephrotoxicity.

  12. Lipid induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling

    DEFF Research Database (Denmark)

    Høeg, Louise D; Sjøberg, Kim Anker; Jeppesen, Jacob

    2011-01-01

    than men. We therefore hypothesized that women would be less prone to lipid induced insulin resistance. Research and design methods: Insulin sensitivity of whole body and leg glucose disposal was studied in 16 young well matched healthy men and women infused with intralipid or saline for 7h. Muscle...... ratio was decreased by intralipid. Conclusion: Intralipid infusion causes less insulin resistance of muscle glucose uptake in women than in men. This insulin resistance is not due to decreased canonical insulin signaling, accumulation of lipid intermediates, inflammation or direct inhibition of glucose......AbstractObjective: We have previously shown that overnight fasted women have higher insulin stimulated whole body and leg glucose uptake despite a higher intramyocellular triacylglycerol concentration than men. Women also express higher muscle mRNA levels of proteins related to lipid metabolism...

  13. All-optical signal processing of OTDM and OFDM signals based on time-domain optical fourier transformation

    DEFF Research Database (Denmark)

    Galili, Michael; Guan, Pengyu; Lillieholm, Mads

    2017-01-01

    In the talk, we will review recent work on optical signal processing based on time lenses. Various applications of optical Fourier transformation for optical communications will be discussed.......In the talk, we will review recent work on optical signal processing based on time lenses. Various applications of optical Fourier transformation for optical communications will be discussed....

  14. Effects of the innervation zone on the time and frequency domain parameters of the surface electromyographic signal.

    Science.gov (United States)

    Smith, Cory M; Housh, Terry J; Herda, Trent J; Zuniga, Jorge M; Ryan, Eric D; Camic, Clayton L; Bergstrom, Haley C; Smith, Doug B; Weir, Joseph P; Cramer, Joel T; Hill, Ethan C; Cochrane, Kristen C; Jenkins, Nathaniel D M; Schmidt, Richard J; Johnson, Glen O

    2015-08-01

    The purposes of the present study were to examine the effects of electrode placements over, proximal, and distal to the innervation zone (IZ) on electromyographic (EMG) amplitude (RMS) and frequency (MPF) responses during: (1) a maximal voluntary isometric contraction (MVIC), and; (2) a sustained, submaximal isometric muscle action. A linear array was used to record EMG signals from the vastus lateralis over the IZ, 30mm proximal, and 30mm distal to the IZ during an MVIC and a sustained isometric muscle action of the leg extensors at 50% MVIC. During the MVIC, lower EMG RMS (p>0.05) and greater EMG MPF (ptime relationships over, proximal, and distal to the IZ occurred. Thus, the results of the present study indicated that during an MVIC, EMG RMS and MPF values recorded over the IZ are not comparable to those away from the IZ. However, the rates of fatigue-induced changes in EMG RMS and MPF during sustained, submaximal isometric muscle actions of the leg extensors were the same regardless of the electrode placement locations relative to the IZ. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. A novel signal transduction protein: Combination of solute binding and tandem PAS-like sensor domains in one polypeptide chain.

    Science.gov (United States)

    Wu, R; Wilton, R; Cuff, M E; Endres, M; Babnigg, G; Edirisinghe, J N; Henry, C S; Joachimiak, A; Schiffer, M; Pokkuluri, P R

    2017-04-01

    We report the structural and biochemical characterization of a novel periplasmic ligand-binding protein, Dret_0059, from Desulfohalobium retbaense DSM 5692, an organism isolated from Lake Retba, in Senegal. The structure of the protein consists of a unique combination of a periplasmic solute binding protein (SBP) domain at the N-terminal and a tandem PAS-like sensor domain at the C-terminal region. SBP domains are found ubiquitously, and their best known function is in solute transport across membranes. PAS-like sensor domains are commonly found in signal transduction proteins. These domains are widely observed as parts of many protein architectures and complexes but have not been observed previously within the same polypeptide chain. In the structure of Dret_0059, a ketoleucine moiety is bound to the SBP, whereas a cytosine molecule is bound in the distal PAS-like domain of the tandem PAS-like domain. Differential scanning flourimetry support the binding of ligands observed in the crystal structure. There is significant interaction between the SBP and tandem PAS-like domains, and it is possible that the binding of one ligand could have an effect on the binding of the other. We uncovered three other proteins with this structural architecture in the non-redundant sequence data base, and predict that they too bind the same substrates. The genomic context of this protein did not offer any clues for its function. We did not find any biological process in which the two observed ligands are coupled. The protein Dret_0059 could be involved in either signal transduction or solute transport. © 2017 The Protein Society.

  16. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.

    Science.gov (United States)

    Sancho, Rosa M; Law, Bernard M H; Harvey, Kirsten

    2009-10-15

    Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson's disease. The LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an intramolecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3), key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1 DEP domain were necessary and sufficient for LRRK2-DVL1 interaction. Co-expression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2-DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations at residues R1441 and R1728 strengthened LRRK2-DVL1 interactions. Co-expression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-COR domain mutations segregating with Parkinson's disease. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity, and (ii) Roc-COR domain mutations modulating LRRK2-DVL interactions indirectly influence kinase activity. Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new targets for genetic analysis in Parkinson's disease.

  17. Increased signal intensity at the proximal patellar tendon: correlation between MR imaging and histology in eight cadavers and clinical MR imaging studies

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Seong Jong; Jin, Wook; Yoon, So Hee; Park, So Young [Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, Yong-Koo [Kyung Hee University Medical Center, Department of Pathology, Seoul (Korea, Republic of); Kim, Gou Young [Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Department of Pathology, Seoul (Korea, Republic of); Lee, Jung Eun; Park, Ji Seon; Ryu, Kyung Nam [Kyung Hee University Medical Center, Department of Radiology, Seoul (Korea, Republic of)

    2015-10-15

    We set out to investigate the cause of persistently increased signal intensity (SI) in the posterior portion of the proximal patellar tendon (pPT) on T1-weighted images (T1WI). MR imaging was performed in eight cadavers, followed by gross histological examination. In addition, 84 patients without trauma history or anterior knee pain were included to compare the SI of the PTs. The patients were divided according to their age, sex, and Kellgren-Lawrence (KL) grades. The length and thickness of the increased SI portion in the pPT and whole PT (wPT) on T1WI were recorded. Histological specimens demonstrated that the adipose tissue, vessels, and perivascular connective tissue invaginated into the posterior portion of the pPT. This histological anatomy corresponded to the pPT signal change on MR imaging. There was linear and interdigitating increased SI of the pPT in all of the 84 patients (100 %). There were no differences in the lengths and thicknesses of the increased SI portion of pPTs and wPTs according to age, sex, and KL grade (all p > 0.05). The increased SI of the pPT on T1WI and fluid-sensitive MR images results from invaginating fat, vessels, and perivascular connective tissue. It is not pathological, but a normal and common finding. (orig.)

  18. FHA domains as phospho-threonine binding modules in cell signaling.

    Science.gov (United States)

    Hammet, Andrew; Pike, Brietta L; McNees, Carolyn J; Conlan, Lindus A; Tenis, Nora; Heierhorst, Jörg

    2003-01-01

    Forkhead-associated (FHA) domains are present in >200 diverse proteins in all phyla from bacteria to mammals and seem to be particularly prevalent in proteins with cell cycle control functions. Recent work from several laboratories has considerably improved our understanding of the structure and function of these domains that were virtually unknown a few years ago, and the first disease associations of FHA domains have now emerged. FHA domains form 11-stranded beta-sandwiches that contain some 100-180 amino acid residues with a high degree of sequence diversity. FHA domains act as phosphorylation-dependent protein-protein interaction modules that preferentially bind to phospho-threonine residues in their targets. Interestingly, point mutations in the human CHK2 gene that lead to single-residue amino acid substitutions in the FHA domain of this cell cycle checkpoint kinase have been found to cause a subset of cases of the Li-Fraumeni multi-cancer syndrome.

  19. 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.

  20. Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA

    OpenAIRE

    Kim, Jeong Hoon; Yang, Catherine K.; Stallcup, Michael R.

    2006-01-01

    The coiled-coil coactivator (CoCoA) is a transcriptional coactivator for nuclear receptors and enhances nuclear receptor function by the interaction with the bHLH-PAS domain (AD3) of p160 coactivators. The C-terminal activation domain (AD) of CoCoA possesses strong transactivation activity and is required for the coactivator function of CoCoA with nuclear receptors. To understand how CoCoA AD transmits its activating signal to the transcription machinery, we defined specific subregions, amino...

  1. Signaling domain of Sonic Hedgehog as cannibalistic calcium-regulated zinc-peptidase.

    Directory of Open Access Journals (Sweden)

    Rocio Rebollido-Rios

    2014-07-01

    Full Text Available Sonic Hedgehog (Shh is a representative of the evolutionary closely related class of Hedgehog proteins that have essential signaling functions in animal development. The N-terminal domain (ShhN is also assigned to the group of LAS proteins (LAS = Lysostaphin type enzymes, D-Ala-D-Ala metalloproteases, Sonic Hedgehog, of which all members harbor a structurally well-defined Zn2+ center; however, it is remarkable that ShhN so far is the only LAS member without proven peptidase activity. Another unique feature of ShhN in the LAS group is a double-Ca2+ center close to the zinc. We have studied the effect of these calcium ions on ShhN structure, dynamics, and interactions. We find that the presence of calcium has a marked impact on ShhN properties, with the two calcium ions having different effects. The more strongly bound calcium ion significantly stabilizes the overall structure. Surprisingly, the binding of the second calcium ion switches the putative catalytic center from a state similar to LAS enzymes to a state that probably is catalytically inactive. We describe in detail the mechanics of the switch, including the effect on substrate co-ordinating residues and on the putative catalytic water molecule. The properties of the putative substrate binding site suggest that ShhN could degrade other ShhN molecules, e.g. by cleavage at highly conserved glycines in ShhN. To test experimentally the stability of ShhN against autodegradation, we compare two ShhN mutants in vitro: (1 a ShhN mutant unable to bind calcium but with putative catalytic center intact, and thus, according to our hypothesis, a constitutively active peptidase, and (2 a mutant carrying additionally mutation E177A, i.e., with the putative catalytically active residue knocked out. The in vitro results are consistent with ShhN being a cannibalistic zinc-peptidase. These experiments also reveal that the peptidase activity depends on pH.

  2. Compartmentalized cAMP Signaling Associated With Lipid Raft and Non-raft Membrane Domains in Adult Ventricular Myocytes.

    Science.gov (United States)

    Agarwal, Shailesh R; Gratwohl, Jackson; Cozad, Mia; Yang, Pei-Chi; Clancy, Colleen E; Harvey, Robert D

    2018-01-01

    Aim: Confining cAMP production to discrete subcellular locations makes it possible for this ubiquitous second messenger to elicit unique functional responses. Yet, factors that determine how and where the production of this diffusible signaling molecule occurs are incompletely understood. The fluid mosaic model originally proposed that signal transduction occurs through random interactions between proteins diffusing freely throughout the plasma membrane. However, it is now known that the movement of membrane proteins is restricted, suggesting that the plasma membrane is segregated into distinct microdomains where different signaling proteins can be concentrated. In this study, we examined what role lipid raft and non-raft membrane domains play in compartmentation of cAMP signaling in adult ventricular myocytes. Methods and Results: The freely diffusible fluorescence resonance energy transfer-based biosensor Epac2-camps was used to measure global cytosolic cAMP responses, while versions of the probe targeted to lipid raft (Epac2-MyrPalm) and non-raft (Epac2-CAAX) domains were used to monitor local cAMP production near the plasma membrane. We found that β-adrenergic receptors, which are expressed in lipid raft and non-raft domains, produce cAMP responses near the plasma membrane that are distinctly different from those produced by E-type prostaglandin receptors, which are expressed exclusively in non-raft domains. We also found that there are differences in basal cAMP levels associated with lipid raft and non-raft domains, and that this can be explained by differences in basal adenylyl cyclase activity associated with each of these membrane environments. In addition, we found evidence that phosphodiesterases 2, 3, and 4 work together in regulating cAMP activity associated with both lipid raft and non-raft domains, while phosphodiesterase 3 plays a more prominent role in the bulk cytoplasmic compartment. Conclusion: These results suggest that different membrane

  3. Are Distal and Proximal Visual Cues Equally Important during Spatial Learning in Mice? A Pilot Study of Overshadowing in the Spatial Domain

    Directory of Open Access Journals (Sweden)

    Marie Hébert

    2017-06-01

    Full Text Available Animals use distal and proximal visual cues to accurately navigate in their environment, with the possibility of the occurrence of associative mechanisms such as cue competition as previously reported in honey-bees, rats, birds and humans. In this pilot study, we investigated one of the most common forms of cue competition, namely the overshadowing effect, between visual landmarks during spatial learning in mice. To this end, C57BL/6J × Sv129 mice were given a two-trial place recognition task in a T-maze, based on a novelty free-choice exploration paradigm previously developed to study spatial memory in rodents. As this procedure implies the use of different aspects of the environment to navigate (i.e., mice can perceive from each arm of the maze, we manipulated the distal and proximal visual landmarks during both the acquisition and retrieval phases. Our prospective findings provide a first set of clues in favor of the occurrence of an overshadowing between visual cues during a spatial learning task in mice when both types of cues are of the same modality but at varying distances from the goal. In addition, the observed overshadowing seems to be non-reciprocal, as distal visual cues tend to overshadow the proximal ones when competition occurs, but not vice versa. The results of the present study offer a first insight about the occurrence of associative mechanisms during spatial learning in mice, and may open the way to promising new investigations in this area of research. Furthermore, the methodology used in this study brings a new, useful and easy-to-use tool for the investigation of perceptive, cognitive and/or attentional deficits in rodents.

  4. GUM2DFT—a software tool for uncertainty evaluation of transient signals in the frequency domain

    International Nuclear Information System (INIS)

    Eichstädt, S; Wilkens, V

    2016-01-01

    The Fourier transform and its counterpart for discrete time signals, the discrete Fourier transform (DFT), are common tools in measurement science and application. Although almost every scientific software package offers ready-to-use implementations of the DFT, the propagation of uncertainties in line with the guide to the expression of uncertainty in measurement (GUM) is typically neglected. This is of particular importance in dynamic metrology, when input estimation is carried out by deconvolution in the frequency domain. To this end, we present the new open-source software tool GUM2DFT, which utilizes closed formulas for the efficient propagation of uncertainties for the application of the DFT, inverse DFT and input estimation in the frequency domain. It handles different frequency domain representations, accounts for autocorrelation and takes advantage of the symmetry inherent in the DFT result for real-valued time domain signals. All tools are presented in terms of examples which form part of the software package. GUM2DFT will foster GUM-compliant evaluation of uncertainty in a DFT-based analysis and enable metrologists to include uncertainty evaluations in their routine work. (paper)

  5. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-κB signaling.

    Science.gov (United States)

    Askarian, Fatemeh; van Sorge, Nina M; Sangvik, Maria; Beasley, Federico C; Henriksen, Jørn R; Sollid, Johanna U E; van Strijp, Jos A G; Nizet, Victor; Johannessen, Mona

    2014-01-01

    Signaling through Toll-like receptors (TLRs), crucial molecules in the induction of host defense responses, requires adaptor proteins that contain a Toll/interleukin-1 receptor (TIR) domain. The pathogen Staphylococcus aureus produces several innate immune-evasion molecules that interfere with the host's innate immune response. A database search analysis suggested the presence of a gene encoding a homologue of the human TIR domain in S. aureus MSSA476 which was named staphylococcal TIR domain protein (TirS). Ectopic expression of TirS in human embryonic kidney, macrophage and keratinocyte cell lines interfered with signaling through TLR2, including MyD88 and TIRAP, NF-κB and/or mitogen-activated protein kinase pathways. Moreover, the presence of TirS reduced the levels of cytokines MCP-1 and G-CSF secreted in response to S. aureus. The effects on NF-κB pathway were confirmed using S. aureus MSSA476 wild type, an isogenic mutant MSSA476ΔtirS, and complemented MSSA476ΔtirS +pTirS in a Transwell system where bacteria and host cells were physically separated. Finally, in a systematic mouse infection model, TirS promoted bacterial accumulation in several organs 4 days postinfection. The results of this study reveal a new S. aureus virulence factor that can interfere with PAMP-induced innate immune signaling in vitro and bacterial survival in vivo. © 2014 S. Karger AG, Basel.

  6. Functional Independence and Interdependence of the Src Homology Domains of Phospholipase C-γ1 in B-Cell Receptor Signal Transduction

    Science.gov (United States)

    DeBell, Karen E.; Stoica, Bogdan A.; Verí, Maria-Concetta; Di Baldassarre, Angela; Miscia, Sebastiano; Graham, Laurie J.; Rellahan, Barbara L.; Ishiai, Masamichi; Kurosaki, Tomohiro; Bonvini, Ezio

    1999-01-01

    B-cell receptor (BCR)-induced activation of phospholipase C-γ1 (PLCγ1) and PLCγ2 is crucial for B-cell function. While several signaling molecules have been implicated in PLCγ activation, the mechanism coupling PLCγ to the BCR remains undefined. The role of PLCγ1 SH2 and SH3 domains at different steps of BCR-induced PLCγ1 activation was examined by reconstitution in a PLCγ-negative B-cell line. PLCγ1 membrane translocation required a functional SH2 N-terminal [SH2(N)] domain, was decreased by mutation of the SH3 domain, but was unaffected by mutation of the SH2(C) domain. Tyrosine phosphorylation did not require the SH2(C) or SH3 domains but depended exclusively on a functional SH2(N) domain, which mediated the association of PLCγ1 with the adapter protein, BLNK. Forcing PLCγ1 to the membrane via a myristoylation signal did not bypass the SH2(N) domain requirement for phosphorylation, indicating that the phosphorylation mediated by this domain is not due to membrane anchoring alone. Mutation of the SH2(N) or the SH2(C) domain abrogated BCR-stimulated phosphoinositide hydrolysis and signaling events, while mutation of the SH3 domain partially decreased signaling. PLCγ1 SH domains, therefore, have interrelated but distinct roles in BCR-induced PLCγ1 activation. PMID:10523627

  7. Regulation of abiotic stress signalling by Arabidopsis C-terminal domain phosphatase-like 1 requires interaction with a k-homology domain-containing protein.

    Directory of Open Access Journals (Sweden)

    In Sil Jeong

    Full Text Available Arabidopsis thaliana CARBOXYL-TERMINAL DOMAIN (CTD PHOSPHATASE-LIKE 1 (CPL1 regulates plant transcriptional responses to diverse stress signals. Unlike typical CTD phosphatases, CPL1 contains two double-stranded (ds RNA binding motifs (dsRBMs at its C-terminus. Some dsRBMs can bind to dsRNA and/or other proteins, but the function of the CPL1 dsRBMs has remained obscure. Here, we report identification of REGULATOR OF CBF GENE EXPRESSION 3 (RCF3 as a CPL1-interacting protein. RCF3 co-purified with tandem-affinity-tagged CPL1 from cultured Arabidopsis cells and contains multiple K-homology (KH domains, which were predicted to be important for binding to single-stranded DNA/RNA. Yeast two-hybrid, luciferase complementation imaging, and bimolecular fluorescence complementation analyses established that CPL1 and RCF3 strongly associate in vivo, an interaction mediated by the dsRBM1 of CPL1 and the KH3/KH4 domains of RCF3. Mapping of functional regions of CPL1 indicated that CPL1 in vivo function requires the dsRBM1, catalytic activity, and nuclear targeting of CPL1. Gene expression profiles of rcf3 and cpl1 mutants were similar during iron deficiency, but were distinct during the cold response. These results suggest that tethering CPL1 to RCF3 via dsRBM1 is part of the mechanism that confers specificity to CPL1-mediated transcriptional regulation.

  8. Chasing probabilities — Signaling negative and positive prediction errors across domains

    DEFF Research Database (Denmark)

    Meder, David; Madsen, Kristoffer H; Hulme, Oliver

    2016-01-01

    of the two. We acquired functional MRI data while volunteers performed four probabilistic reversal learning tasks which differed in terms of outcome valence (reward-seeking versus punishment-avoidance) and domain (abstract symbols versus facial expressions) of outcomes. We found that ventral striatum...

  9. A novel time-domain signal processing algorithm for real time ventricular fibrillation detection

    International Nuclear Information System (INIS)

    Monte, G E; Scarone, N C; Liscovsky, P O; Rotter, P

    2011-01-01

    This paper presents an application of a novel algorithm for real time detection of ECG pathologies, especially ventricular fibrillation. It is based on segmentation and labeling process of an oversampled signal. After this treatment, analyzing sequence of segments, global signal behaviours are obtained in the same way like a human being does. The entire process can be seen as a morphological filtering after a smart data sampling. The algorithm does not require any ECG digital signal pre-processing, and the computational cost is low, so it can be embedded into the sensors for wearable and permanent applications. The proposed algorithms could be the input signal description to expert systems or to artificial intelligence software in order to detect other pathologies.

  10. A novel time-domain signal processing algorithm for real time ventricular fibrillation detection

    Science.gov (United States)

    Monte, G. E.; Scarone, N. C.; Liscovsky, P. O.; Rotter S/N, P.

    2011-12-01

    This paper presents an application of a novel algorithm for real time detection of ECG pathologies, especially ventricular fibrillation. It is based on segmentation and labeling process of an oversampled signal. After this treatment, analyzing sequence of segments, global signal behaviours are obtained in the same way like a human being does. The entire process can be seen as a morphological filtering after a smart data sampling. The algorithm does not require any ECG digital signal pre-processing, and the computational cost is low, so it can be embedded into the sensors for wearable and permanent applications. The proposed algorithms could be the input signal description to expert systems or to artificial intelligence software in order to detect other pathologies.

  11. Complexity of EEG-signal in Time Domain - Possible Biomedical Application

    Science.gov (United States)

    Klonowski, Wlodzimierz; Olejarczyk, Elzbieta; Stepien, Robert

    2002-07-01

    Human brain is a highly complex nonlinear system. So it is not surprising that in analysis of EEG-signal, which represents overall activity of the brain, the methods of Nonlinear Dynamics (or Chaos Theory as it is commonly called) can be used. Even if the signal is not chaotic these methods are a motivating tool to explore changes in brain activity due to different functional activation states, e.g. different sleep stages, or to applied therapy, e.g. exposure to chemical agents (drugs) and physical factors (light, magnetic field). The methods supplied by Nonlinear Dynamics reveal signal characteristics that are not revealed by linear methods like FFT. Better understanding of principles that govern dynamics and complexity of EEG-signal can help to find `the signatures' of different physiological and pathological states of human brain, quantitative characteristics that may find applications in medical diagnostics.

  12. Tyrosine Phosphorylation of Jak2 in the JH2 Domain Inhibits Cytokine Signaling

    OpenAIRE

    Feener, Edward P.; Rosario, Felicia; Dunn, Sarah L.; Stancheva, Zlatina; Myers, Martin G.

    2004-01-01

    Jak family tyrosine kinases mediate signaling by cytokine receptors to regulate diverse biological processes. Although Jak2 and other Jak kinase family members are phosphorylated on numerous sites during cytokine signaling, the identity and function of most of these sites remains unknown. Using tandem mass spectroscopic analysis of activated Jak2 protein from intact cells, we identified Tyr221 and Tyr570 as novel sites of Jak2 phosphorylation. Phosphorylation of both sites was stimulated by c...

  13. Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.

    Science.gov (United States)

    Vilches, Silvia; Vergara, Cristina; Nicolás, Oriol; Mata, Ágata; Del Río, José A; Gavín, Rosalina

    2016-09-01

    The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N-terminal deleted forms were properly processed through the secretory pathway. However, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.

  14. 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.

  15. Porcine bocavirus NP1 negatively regulates interferon signaling pathway by targeting the DNA-binding domain of IRF9

    International Nuclear Information System (INIS)

    Zhang, Ruoxi; Fang, Liurong; Wang, Dang; Cai, Kaimei; Zhang, Huan; Xie, Lilan; Li, Yi; Chen, Huanchun; Xiao, Shaobo

    2015-01-01

    To subvert host antiviral immune responses, many viruses have evolved countermeasures to inhibit IFN signaling pathway. Porcine bocavirus (PBoV), a newly identified porcine parvovirus, has received attention because it shows clinically high co-infection prevalence with other pathogens in post-weaning multisystemic wasting syndrome (PWMS) and diarrheic piglets. In this study, we screened the structural and non-structural proteins encoded by PBoV and found that the non-structural protein NP1 significantly suppressed IFN-stimulated response element (ISRE) activity and subsequent IFN-stimulated gene (ISG) expression. However, NP1 affected neither the activation and translocation of STAT1/STAT2, nor the formation of the heterotrimeric transcription factor complex ISGF3 (STAT1/STAT2/IRF9). Detailed analysis demonstrated that PBoV NP1 blocked the ISGF3 DNA-binding activity by combining with the DNA-binding domain (DBD) of IRF9. In summary, these results indicate that PBoV NP1 interferes with type I IFN signaling pathway by blocking DNA binding of ISGF3 to attenuate innate immune responses. - Highlights: • Porcine bocavirus (PBoV) NP1 interferes with the IFN α/β signaling pathway. • PBoV NP1 does not prevent STAT1/STAT2 phosphorylation and nuclear translocation. • PBoV NP1 inhibits the DNA-binding activity of ISGF3. • PBoV NP1 interacts with the DNA-binding domain of IRF9.

  16. Porcine bocavirus NP1 negatively regulates interferon signaling pathway by targeting the DNA-binding domain of IRF9

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ruoxi [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China); Fang, Liurong, E-mail: fanglr@mail.hzau.edu.cn [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China); Wang, Dang; Cai, Kaimei; Zhang, Huan [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China); Xie, Lilan; Li, Yi [College of Life Science and Technology, Wuhan Institute of Bioengineering, Wuhan 430415 (China); Chen, Huanchun; Xiao, Shaobo [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China)

    2015-11-15

    To subvert host antiviral immune responses, many viruses have evolved countermeasures to inhibit IFN signaling pathway. Porcine bocavirus (PBoV), a newly identified porcine parvovirus, has received attention because it shows clinically high co-infection prevalence with other pathogens in post-weaning multisystemic wasting syndrome (PWMS) and diarrheic piglets. In this study, we screened the structural and non-structural proteins encoded by PBoV and found that the non-structural protein NP1 significantly suppressed IFN-stimulated response element (ISRE) activity and subsequent IFN-stimulated gene (ISG) expression. However, NP1 affected neither the activation and translocation of STAT1/STAT2, nor the formation of the heterotrimeric transcription factor complex ISGF3 (STAT1/STAT2/IRF9). Detailed analysis demonstrated that PBoV NP1 blocked the ISGF3 DNA-binding activity by combining with the DNA-binding domain (DBD) of IRF9. In summary, these results indicate that PBoV NP1 interferes with type I IFN signaling pathway by blocking DNA binding of ISGF3 to attenuate innate immune responses. - Highlights: • Porcine bocavirus (PBoV) NP1 interferes with the IFN α/β signaling pathway. • PBoV NP1 does not prevent STAT1/STAT2 phosphorylation and nuclear translocation. • PBoV NP1 inhibits the DNA-binding activity of ISGF3. • PBoV NP1 interacts with the DNA-binding domain of IRF9.

  17. Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Bukhari, Hassan; Glotzbach, Annika; Kolbe, Katharina; Leonhardt, Gregor; Loosse, Christina; Müller, Thorsten

    2017-09-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease with tens of millions of people affected worldwide. The pathogenesis is still poorly understood and various therapeutical approaches targeting the amyloid β (Aβ) peptide, a product of the amyloidogenic cleavage of the amyloid precursor protein (APP), failed. Moreover, a couple of studies critically questioned the relevance of Aβ in the pathogenesis of AD. Thus, new ideas need to be studied and one highly interesting hypothesis is the APP mediated signal transduction to the nucleus. As a consequence nuclear -potentially toxic- structures emerge, which were recently found to a high extent in human AD tissue and thus, may contribute to neurodegeneration. Relevant for the signaling machinery are modifications at the very C-terminal end of the precursor protein, the APP intracellular domain (AICD). In this review we update the knowledge on mechanisms on AICD referring to our 2008 article: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-Relevance for Alzheimer's disease (T. Muller, et al., 2008). We summarize how AICD is generated and degraded, we describe its intramolecular motifs, translational modifications, and how those as well as APP dimerization influence AICD generation and function. Moreover, we resume the AICD interactome and elucidate AICDs involvement in nuclear signaling, transcriptional regulation, cell death, DNA repair and cell cycle re-entry and we give insights in its physiological function. Results are summarized in the comprehensive poster "The world of AICD". Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Inter-domain tagging implicates caveolin-1 in insulin receptor trafficking and Erk signaling bias in pancreatic beta-cells

    Directory of Open Access Journals (Sweden)

    Tobias Boothe

    2016-05-01

    Full Text Available Objective: The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. Methods: We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies. Results: Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact. Conclusions: We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation. Author Video: Author Video Watch what authors say about their articles Keywords: Insulin receptor internalization, Insulin resistance, Pancreatic islet beta-cells, Autocrine insulin signaling

  19. Evaluation of different time domain peak models using extreme learning machine-based peak detection for EEG signal.

    Science.gov (United States)

    Adam, Asrul; Ibrahim, Zuwairie; Mokhtar, Norrima; Shapiai, Mohd Ibrahim; Cumming, Paul; Mubin, Marizan

    2016-01-01

    Various peak models have been introduced to detect and analyze peaks in the time domain analysis of electroencephalogram (EEG) signals. In general, peak model in the time domain analysis consists of a set of signal parameters, such as amplitude, width, and slope. Models including those proposed by Dumpala, Acir, Liu, and Dingle are routinely used to detect peaks in EEG signals acquired in clinical studies of epilepsy or eye blink. The optimal peak model is the most reliable peak detection performance in a particular application. A fair measure of performance of different models requires a common and unbiased platform. In this study, we evaluate the performance of the four different peak models using the extreme learning machine (ELM)-based peak detection algorithm. We found that the Dingle model gave the best performance, with 72 % accuracy in the analysis of real EEG data. Statistical analysis conferred that the Dingle model afforded significantly better mean testing accuracy than did the Acir and Liu models, which were in the range 37-52 %. Meanwhile, the Dingle model has no significant difference compared to Dumpala model.

  20. A reaction time advantage for calculating beliefs over public representations signals domain specificity for 'theory of mind'.

    Science.gov (United States)

    Cohen, Adam S; German, Tamsin C

    2010-06-01

    In a task where participants' overt task was to track the location of an object across a sequence of events, reaction times to unpredictable probes requiring an inference about a social agent's beliefs about the location of that object were obtained. Reaction times to false belief situations were faster than responses about the (false) contents of a map showing the location of the object (Experiment 1) and about the (false) direction of an arrow signaling the location of the object (Experiment 2). These results are consistent with developmental, neuro-imaging and neuropsychological evidence that there exist domain specific mechanisms within human cognition for encoding and reasoning about mental states. Specialization of these mechanisms may arise from either core cognitive architecture or via the accumulation of expertise in the social domain.

  1. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Ching Chang, E-mail: ccjwo@yahoo.com.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Chou, Ruey Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models—the S100A5-RAGE V domain and S100A5-Pentamidine complex—and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.

  2. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling

    DEFF Research Database (Denmark)

    Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija

    2011-01-01

    Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased...... JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling....... Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized...

  3. The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo

    Czech Academy of Sciences Publication Activity Database

    Bryja, Vítězslav; Andersson, E.R.; Schambony, A.; Esner, M.; Bryjová, Lenka; Biris, K.K.; Hall, A.C.; Kraft, B.; Čajánek, L.; Yamaguchi, T.P.; Buckingham, M.; Arenas, E.

    2009-01-01

    Roč. 20, č. 3 (2009), s. 924-936 ISSN 1059-1524 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : non-canonical Wnt signaling * Lrp5/6 * mouse Subject RIV: BO - Biophysics Impact factor: 5.979, year: 2009

  4. Social Signal Processing: State-of-the-Art and Future Perspectives of an Emerging Domain

    NARCIS (Netherlands)

    Vinciarelli, Alessandro; Pantic, Maja; Bourlard, Hervé; Pentland, Alex

    2008-01-01

    The ability to understand and manage social signals of a person we are communicating with is the core of social intelligence. Social intelligence is a facet of human intelligence that has been argued to be indispensable and perhaps the most important for success in life. This paper argues that

  5. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Qiang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); The First Affiliated Hospital of Xiamen University, Xiamen (China); Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); Yu, Chundong, E-mail: cdyu@xmu.edu.cn [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China)

    2011-06-17

    Highlights: {yields} Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. {yields} FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. {yields} FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. {yields} FGFR4-ECD reduced tetracycline-induced fatty liver in mice. {yields} FGFR4-ECD partially restored tetracycline-repressed PPAR{alpha} expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  6. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Chen, Qiang; Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang; Yu, Chundong

    2011-01-01

    Highlights: → Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. → FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. → FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. → FGFR4-ECD reduced tetracycline-induced fatty liver in mice. → FGFR4-ECD partially restored tetracycline-repressed PPARα expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor α (PPARα), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  7. Robust classification of motor imagery EEG signals using statistical time–domain features

    International Nuclear Information System (INIS)

    Khorshidtalab, A; Salami, M J E; Hamedi, M

    2013-01-01

    The tradeoff between computational complexity and speed, in addition to growing demands for real-time BMI (brain–machine interface) systems, expose the necessity of applying methods with least possible complexity. Willison amplitude (WAMP) and slope sign change (SSC) are two promising time–domain features only if the right threshold value is defined for them. To overcome the drawback of going through trial and error for the determination of a suitable threshold value, modified WAMP and modified SSC are proposed in this paper. Besides, a comprehensive assessment of statistical time–domain features in which their effectiveness is evaluated with a support vector machine (SVM) is presented. To ensure the accuracy of the results obtained by the SVM, the performance of each feature is reassessed with supervised fuzzy C-means. The general assessment shows that every subject had at least one of his performances near or greater than 80%. The obtained results prove that for BMI applications, in which a few errors can be tolerated, these combinations of feature–classifier are suitable. Moreover, features that could perform satisfactorily were selected for feature combination. Combinations of the selected features are evaluated with the SVM, and they could significantly improve the results, in some cases, up to full accuracy. (paper)

  8. Improvement of range spatial resolution of medical ultrasound imaging by element-domain signal processing

    Science.gov (United States)

    Hasegawa, Hideyuki

    2017-07-01

    The range spatial resolution is an important factor determining the image quality in ultrasonic imaging. The range spatial resolution in ultrasonic imaging depends on the ultrasonic pulse length, which is determined by the mechanical response of the piezoelectric element in an ultrasonic probe. To improve the range spatial resolution without replacing the transducer element, in the present study, methods based on maximum likelihood (ML) estimation and multiple signal classification (MUSIC) were proposed. The proposed methods were applied to echo signals received by individual transducer elements in an ultrasonic probe. The basic experimental results showed that the axial half maximum of the echo from a string phantom was improved from 0.21 mm (conventional method) to 0.086 mm (ML) and 0.094 mm (MUSIC).

  9. Time Domain Feature Extraction Technique for earth's electric field signal prior to the Earthquake

    International Nuclear Information System (INIS)

    Astuti, W; Sediono, W; Akmeliawati, R; Salami, M J E

    2013-01-01

    Earthquake is one of the most destructive of natural disasters that killed many people and destroyed a lot of properties. By considering these catastrophic effects, it is highly important of knowing ahead of earthquakes in order to reduce the number of victims and material losses. Earth's electric field is one of the features that can be used to predict earthquakes (EQs), since it has significant changes in the amplitude of the signal prior to the earthquake. This paper presents a detailed analysis of the earth's electric field due to earthquakes which occurred in Greece, between January 1, 2008 and June 30, 2008. In that period of time, 13 earthquakes had occurred. 6 of them were recorded with magnitudes greater than Ms=5R (5R), while 7 of them were recorded with magnitudes greater than Ms=6R (6R). Time domain feature extraction technique is applied to analyze the 1st significant changes in the earth's electric field prior to the earthquake. Two different time domain feature extraction techniques are applied in this work, namely Simple Square Integral (SSI) and Root Mean Square (RMS). The 1st significant change of the earth's electric field signal in each of monitoring sites is extracted using those two techniques. The feature extraction result can be used as input parameter for an earthquake prediction system

  10. Towards a time-domain modeling framework for small-signal analysis of unbalanced microgrids

    OpenAIRE

    Ojo, Y; Schiffer, JF

    2017-01-01

    Small-signal analysis is one of the most frequently used techniques to assess the operating conditions of power systems. Typically, this analysis is conducted by employing a phasor-based model of the power network derived under the assumption of balanced operating conditions. However, distribution networks and, amongst these, microgrids are often unbalanced. Hence, their analysis requires the development of tools and methods valid under such conditions. Motivated by this, we propose a modelin...

  11. OsBRI1 Activates BR Signaling by Preventing Binding between the TPR and Kinase Domains of OsBSK3 via Phosphorylation.

    Science.gov (United States)

    Zhang, Baowen; Wang, Xiaolong; Zhao, Zhiying; Wang, Ruiju; Huang, Xiahe; Zhu, Yali; Yuan, Li; Wang, Yingchun; Xu, Xiaodong; Burlingame, Alma L; Gao, Yingjie; Sun, Yu; Tang, Wenqiang

    2016-02-01

    Many plant receptor kinases transduce signals through receptor-like cytoplasmic kinases (RLCKs); however, the molecular mechanisms that create an effective on-off switch are unknown. The receptor kinase BR INSENSITIVE1 (BRI1) transduces brassinosteroid (BR) signal by phosphorylating members of the BR-signaling kinase (BSK) family of RLCKs, which contain a kinase domain and a C-terminal tetratricopeptide repeat (TPR) domain. Here, we show that the BR signaling function of BSKs is conserved in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) and that the TPR domain of BSKs functions as a "phospho-switchable" autoregulatory domain to control BSKs' activity. Genetic studies revealed that OsBSK3 is a positive regulator of BR signaling in rice, while in vivo and in vitro assays demonstrated that OsBRI1 interacts directly with and phosphorylates OsBSK3. The TPR domain of OsBSK3, which interacts directly with the protein's kinase domain, serves as an autoinhibitory domain to prevent OsBSK3 from interacting with bri1-SUPPRESSOR1 (BSU1). Phosphorylation of OsBSK3 by OsBRI1 disrupts the interaction between its TPR and kinase domains, thereby increasing the binding between OsBSK3's kinase domain and BSU1. Our results not only demonstrate that OsBSK3 plays a conserved role in regulating BR signaling in rice, but also provide insight into the molecular mechanism by which BSK family proteins are inhibited under basal conditions but switched on by the upstream receptor kinase BRI1. © 2016 American Society of Plant Biologists. All Rights Reserved.

  12. Time domain acoustic contrast control implementation of sound zones for low-frequency input signals

    DEFF Research Database (Denmark)

    Schellekens, Daan H. M.; Møller, Martin Bo; Olsen, Martin

    2016-01-01

    Sound zones are two or more regions within a listening space where listeners are provided with personal audio. Acoustic contrast control (ACC) is a sound zoning method that maximizes the average squared sound pressure in one zone constrained to constant pressure in other zones. State......-of-the-art time domain broadband acoustic contrast control (BACC) methods are designed for anechoic environments. These methods are not able to realize a flat frequency response in a limited frequency range within a reverberant environment. Sound field control in a limited frequency range is a requirement...... to accommodate the effective working range of the loudspeakers. In this paper, a new BACC method is proposed which results in an implementation realizing a flat frequency response in the target zone. This method is applied in a bandlimited low-frequency scenario where the loudspeaker layout surrounds two...

  13. Machine learning approaches to evaluate correlation patterns in allosteric signaling: A case study of the PDZ2 domain

    Science.gov (United States)

    Botlani, Mohsen; Siddiqui, Ahnaf; Varma, Sameer

    2018-06-01

    Many proteins are regulated by dynamic allostery wherein regulator-induced changes in structure are comparable with thermal fluctuations. Consequently, understanding their mechanisms requires assessment of relationships between and within conformational ensembles of different states. Here we show how machine learning based approaches can be used to simplify this high-dimensional data mining task and also obtain mechanistic insight. In particular, we use these approaches to investigate two fundamental questions in dynamic allostery. First, how do regulators modify inter-site correlations in conformational fluctuations (Cij)? Second, how are regulator-induced shifts in conformational ensembles at two different sites in a protein related to each other? We address these questions in the context of the human protein tyrosine phosphatase 1E's PDZ2 domain, which is a model protein for studying dynamic allostery. We use molecular dynamics to generate conformational ensembles of the PDZ2 domain in both the regulator-bound and regulator-free states. The employed protocol reproduces methyl deuterium order parameters from NMR. Results from unsupervised clustering of Cij combined with flow analyses of weighted graphs of Cij show that regulator binding significantly alters the global signaling network in the protein; however, not by altering the spatial arrangement of strongly interacting amino acid clusters but by modifying the connectivity between clusters. Additionally, we find that regulator-induced shifts in conformational ensembles, which we evaluate by repartitioning ensembles using supervised learning, are, in fact, correlated. This correlation Δij is less extensive compared to Cij, but in contrast to Cij, Δij depends inversely on the distance from the regulator binding site. Assuming that Δij is an indicator of the transduction of the regulatory signal leads to the conclusion that the regulatory signal weakens with distance from the regulatory site. Overall, this

  14. Low power laser generated ultrasound: Signal processing for time domain data acquisition

    International Nuclear Information System (INIS)

    Cleary, A; Thursby, G; McKee, C; Armstrong, I; Culshaw, B; Veres, I; Pierce, S G

    2011-01-01

    The use of low power modulated laser diode systems has previously been established as a suitable method for non-destructive laser generation of ultrasound. Using a quasi-continuous optical excitation amplified by an erbium-doped fibre amplifier (EDFA) allows flexible generation of ultrasonic waves, offering control of further parameters such as the frequency content or signal shape. In addition, pseudo-random binary sequences (PRBS) can be used to improve the detected impulse response. Here we compare two sequences, the m-sequence and the Golay code, and discuss the advantages and practical limits of their application with laser diode based optical excitation of ultrasound.

  15. Some considerations for different time-domain signal processing of pulse compression radar

    Directory of Open Access Journals (Sweden)

    Maria Graciela Molina

    2010-06-01

    Full Text Available Radar technology has for a long time used various systems that allow detection under high-resolution conditions, while emitting at the same time low peak power. Among these systems, transmitted pulse encoding by means of biphasic codes has been used for the advanced ionospheric sounder that was developed by the AIS-INGV ionosonde. In the receiving process, suitable decoding of the signal must be accomplished. This can be achieved in both the time and the frequency domains. Focusing on the time domain, different approaches are possible. In this study, two of these approaches have been compared, using data acquired by the AIS-INGV and processed by means of software tools (mainly Mathcad©. The analysis reveals the differences under both noiseless and noisy conditions, although this does not allow the conclusive establishment as to which method is better, as each of them has benefits and drawbacks.

  1. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.

    Science.gov (United States)

    Tanaka, I; Osada, H; Fujii, M; Fukatsu, A; Hida, T; Horio, Y; Kondo, Y; Sato, A; Hasegawa, Y; Tsujimura, T; Sekido, Y

    2015-01-02

    Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

  2. Processing grounded-wire TEM signal in time-frequency-pseudo-seismic domain: A new paradigm

    Science.gov (United States)

    Khan, M. Y.; Xue, G. Q.; Chen, W.; Huasen, Z.

    2017-12-01

    Grounded-wire TEM has received great attention in mineral, hydrocarbon and hydrogeological investigations for the last several years. Conventionally, TEM soundings have been presented as apparent resistivity curves as function of time. With development of sophisticated computational algorithms, it became possible to extract more realistic geoelectric information by applying inversion programs to 1-D & 3-D problems. Here, we analyze grounded-wire TEM data by carrying out analysis in time, frequency and pseudo-seismic domain supported by borehole information. At first, H, K, A & Q type geoelectric models are processed using a proven inversion program (1-D Occam inversion). Second, time-to-frequency transformation is conducted from TEM ρa(t) curves to magneto telluric MT ρa(f) curves for the same models based on all-time apparent resistivity curves. Third, 1-D Bostick's algorithm was applied to the transformed resistivity. Finally, EM diffusion field is transformed into propagating wave field obeying the standard wave equation using wavelet transformation technique and constructed pseudo-seismic section. The transformed seismic-like wave indicates that some reflection and refraction phenomena appear when the EM wave field interacts with geoelectric interface at different depth intervals due to contrast in resistivity. The resolution of the transformed TEM data is significantly improved in comparison to apparent resistivity plots. A case study illustrates the successful hydrogeophysical application of proposed approach in recovering water-filled mined-out area in a coal field located in Ye county, Henan province, China. The results support the introduction of pseudo-seismic imaging technology in short-offset version of TEM which can also be an useful aid if integrated with seismic reflection technique to explore possibilities for high resolution EM imaging in future.

  3. Role of the ERC motif in the proximal part of the second intracellular loop and the C-terminal domain of the human prostaglandin F2alpha receptor (hFP-R) in G-protein coupling control.

    Science.gov (United States)

    Pathe-Neuschäfer-Rube, Andrea; Neuschäfer-Rube, Frank; Püschel, Gerhard P

    2005-05-15

    The human FP-R (F2alpha prostaglandin receptor) is a Gq-coupled heptahelical ectoreceptor, which is of significant medical interest, since it is a potential target for the treatment of glaucoma and preterm labour. On agonist exposure, it mediates an increase in intracellular inositol phosphate formation. Little is known about the structures that govern the agonist-dependent receptor activation. In other prostanoid receptors, the C-terminal domain has been inferred in the control of agonist-dependent receptor activation. A DRY motif at the beginning of the second intracellular loop is highly conserved throughout the G-protein-coupled receptor family and appears to be crucial for controlling agonist-dependent receptor activation. It is replaced by an ERC motif in the FP-R and no evidence for the relevance of this motif in ligand-dependent activation of prostanoid receptors has been provided so far. The aim of the present study was to elucidate the potential role of the C-terminal domain and the ERC motif in agonist-controlled intracellular signalling in FP-R mutants generated by site-directed mutagenesis. It was found that substitution of the acidic Glu(132) in the ERC motif by a threonine residue led to full constitutive activation, whereas truncation of the receptor's C-terminal domain led to partial constitutive activation of all three intracellular signal pathways that had previously been shown to be activated by the FP-R, i.e. inositol trisphosphate formation, focal adhesion kinase activation and T-cell factor signalling. Inositol trisphosphate formation and focal adhesion kinase phosphorylation were further enhanced by ligand binding in cells expressing the truncation mutant but not the E132T (Glu132-->Thr) mutant. Thus C-terminal truncation appeared to result in a receptor with partial constitutive activation, whereas substitution of Glu132 by threonine apparently resulted in a receptor with full constitutive activity.

  4. The ShcA SH2 domain engages a 14-3-3/PI3'K signaling complex and promotes breast cancer cell survival.

    Science.gov (United States)

    Ursini-Siegel, J; Hardy, W R; Zheng, Y; Ling, C; Zuo, D; Zhang, C; Podmore, L; Pawson, T; Muller, W J

    2012-11-29

    The ShcA adapter protein transmits activating signals downstream of receptor and cytoplasmic tyrosine kinases through the establishment of phosphotyrosine-dependent complexes. In this regard, ShcA possesses both a phosphotyrosine-binding domain (PTB) and Src homology 2 domain (SH2), which bind phosphotyrosine residues in a sequence-specific manner. Although the majority of receptor tyrosine kinases expressed in breast cancer cells bind the PTB domain, very little is known regarding the biological importance of SH2-driven ShcA signaling during mammary tumorigenesis. To address this, we employed transgenic mice expressing a mutant ShcA allele harboring a non-functional SH2 domain (ShcR397K) under the transcriptional control of the endogenous ShcA promoter. Using transplantation approaches, we demonstrate that SH2-dependent ShcA signaling within the mammary epithelial compartment is essential for breast tumor outgrowth, survival and the development of lung metastases. We further show that the ShcA SH2 domain activates the AKT pathway, potentially through a novel SH2-mediated complex between ShcA, 14-3-3ζ and the p85 regulatory subunit of phosphatidylinositol 3 (PI3') kinase. This study is the first to demonstrate that the SH2 domain of ShcA is critical for tumor survival during mammary tumorigenesis.

  5. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zong-Sian, E-mail: gary810426@hotmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Liu, Che Fu, E-mail: s9823002@m98.nthu.edu.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Fu, Brian, E-mail: brianfu9@gmail.com [Northwood High School, Irvine, CA (United States); Chou, Ruey-Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Department of Biotechnology, Asia University, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

    2016-09-02

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  6. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    International Nuclear Information System (INIS)

    Wu, Zong-Sian; Liu, Che Fu; Fu, Brian; Chou, Ruey-Hwang; Yu, Chin

    2016-01-01

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by "1H-"1"5N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  7. SH3 domain-mediated binding of the Drk protein to Dos is an important step in signaling of Drosophila receptor tyrosine kinases.

    Science.gov (United States)

    Feller, Stephan M; Wecklein, Heike; Lewitzky, Marc; Kibler, Eike; Raabe, Thomas

    2002-08-01

    Activation of the Sevenless (Sev) receptor tyrosine kinase (RTK) in the developing Drosophila eye is required for the specification of the R7 photoreceptor cell fate. Daughter of Sevenless (Dos), a putative multi-site adaptor protein, is a substrate of the Sev kinase and is known to associate with the tyrosine phosphatase Corkscrew (Csw). Binding of Csw to Dos depends on the Csw Src homology 2 (SH2) domains and is an essential step for signaling by the Sev RTK. Dos, however, lacks a recognizable phosphotyrosine interaction domain and it was previously unclear how it is recruited to the Sev receptor. Here it is shown that the SH2/SH3 domain adaptor protein Drk can provide this link. Drk binds with its SH2 domain to the autophosphorylated Sev receptor while the C-terminal SH3 domain is able to associate with Dos. The Drk SH3 domain binding motifs on Dos were mapped to two sites which do not conform the known Drk SH3 domain binding motif (PxxPxR) but instead have the consensus PxxxRxxKP. Mutational analysis in vitro and in vivo provided evidence that both Drk binding sites fulfil an important function in the context of Sev and Drosophila epidermal growth factor receptor mediated signaling processes.

  8. Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor.

    Science.gov (United States)

    Schiffmann, D A; White, J H; Cooper, A; Nutley, M A; Harding, S E; Jumel, K; Solari, R; Ray, K P; Gay, N J

    1999-09-07

    In Drosophila, the Toll receptor signaling pathway is required for embryonic dorso-ventral patterning and at later developmental stages for innate immune responses. It is thought that dimerization of the receptor by binding of the ligand spätzle causes the formation of a postreceptor activation complex at the cytoplasmic surface of the membrane. Two components of this complex are the adaptor tube and protein kinase pelle. These proteins both have "death domains", protein interaction motifs found in a number of signaling pathways, particularly those involved in apoptotic cell death. It is thought that pelle is bound by tube during formation of the activation complexes, and that this interaction is mediated by the death domains. In this paper, we show using the yeast two-hybrid system that the wild-type tube and pelle death domains bind together. Mutant tube proteins which do not support signaling in the embryo are also unable to bind pelle in the 2-hybrid assay. We have purified proteins corresponding to the death domains of tube and pelle and show that these form corresponding heterodimeric complexes in vitro. Partial proteolysis reveals a smaller core consisting of the minimal death domain sequences. We have studied the tube/pelle interaction with the techniques of surface plasmon resonance, analytical ultracentrifugation and isothermal titration calorimetry. These measurements produce a value of K(d) for the complex of about 0.5 microM.

  9. A cinema of presence and proximity: Gunvor Nelson's collage films and the aesthetics of the signaletic material before the electronic signal

    Directory of Open Access Journals (Sweden)

    John Sundholm

    2012-06-01

    Full Text Available This essay argues for the importance of an intersubjective and impure film theory in which the signal and the signaletic is considered as figures for approaching film. This in order to make the argument that the signaletic mode indeed enables a novel perspective on moving image history. The aesthetics of the signaletic has thus a history preceding that of electronic media, in particular when it comes to animation and experimental film. When constructing such an archaeology, however, dichotomies into sign and signal should be avoided; otherwise, the complexity of many of the films is reduced. In order to illuminate the latter point, four films by Gunvor Nelson is analyzed (both analog and digital, showing not only how both sign and signal interact but also how the aesthetics of the signal and the signaletic material is not dependant on the electronic as such.

  10. Echosonography with proximity sensors

    International Nuclear Information System (INIS)

    Thaisiam, W; Laithong, T; Meekhun, S; Chaiwathyothin, N; Thanlarp, P; Danworaphong, S

    2013-01-01

    We propose the use of a commercial ultrasonic proximity sensor kit for profiling an altitude-varying surface by employing echosonography. The proximity sensor kit, two identical transducers together with its dedicated operating circuit, is used as a profiler for the construction of an image. Ultrasonic pulses are emitted from one of the transducers and received by the other. The time duration between the pulses allows us to determine the traveling distance of each pulse. In the experiment, the circuit is used with the addition of two copper wires for directing the outgoing and incoming signals to an oscilloscope. The time of flight of ultrasonic pulses can thus be determined. Square grids of 5 × 5 cm 2 are made from fishing lines, forming pixels in the image. The grids are designed to hold the detection unit in place, about 30 cm above a flat surface. The surface to be imaged is constructed to be height varying and placed on the flat surface underneath the grids. Our result shows that an image of the profiled surface can be created by varying the location of the detection unit along the grid. We also investigate the deviation in relation to the time of flight of the ultrasonic pulse. Such an experiment should be valuable for conveying the concept of ultrasonic imaging to physical and medical science undergraduate students. Due to its simplicity, the setup could be made in any undergraduate laboratory relatively inexpensively and it requires no complex parts. The results illustrate the concept of echosonography. (paper)

  11. A novel signal transduction protein: Combination of solute binding and tandem PAS-like sensor domains in one polypeptide chain: Periplasmic Ligand Binding Protein Dret_0059

    Energy Technology Data Exchange (ETDEWEB)

    Wu, R. [Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne Illinois 60439; Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Wilton, R. [Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Cuff, M. E. [Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne Illinois 60439; Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Structural Biology Center, Argonne National Laboratory, Argonne Illinois 60439; Endres, M. [Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne Illinois 60439; Babnigg, G. [Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne Illinois 60439; Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Edirisinghe, J. N. [Mathematics and Computer Science Division, Argonne National Laboratory, Argonne Illinois 60439; Computation Institute, University of Chicago, Chicago Illinois 60637; Henry, C. S. [Mathematics and Computer Science Division, Argonne National Laboratory, Argonne Illinois 60439; Computation Institute, University of Chicago, Chicago Illinois 60637; Joachimiak, A. [Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne Illinois 60439; Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Structural Biology Center, Argonne National Laboratory, Argonne Illinois 60439; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago Illinois 60637; Schiffer, M. [Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439; Pokkuluri, P. R. [Biosciences Division, Argonne National Laboratory, Argonne Illinois 60439

    2017-03-06

    We report the structural and biochemical characterization of a novel periplasmic ligand-binding protein, Dret_0059, from Desulfohalobium retbaense DSM 5692, an organism isolated from the Salt Lake Retba in Senegal. The structure of the protein consists of a unique combination of a periplasmic solute binding protein (SBP) domain at the N-terminal and a tandem PAS-like sensor domain at the C-terminal region. SBP domains are found ubiquitously and their best known function is in solute transport across membranes. PAS-like sensor domains are commonly found in signal transduction proteins. These domains are widely observed as parts of many protein architectures and complexes but have not been observed previously within the same polypeptide chain. In the structure of Dret_0059, a ketoleucine moiety is bound to the SBP, whereas a cytosine molecule is bound in the distal PAS-like domain of the tandem PAS-like domain. Differential scanning flourimetry support the binding of ligands observed in the crystal structure. There is significant interaction between the SBP and tandem PAS-like domains, and it is possible that the binding of one ligand could have an effect on the binding of the other. We uncovered three other proteins with this structural architecture in the non-redundant sequence data base, and predict that they too bind the same substrates. The genomic context of this protein did not offer any clues for its function. We did not find any biological process in which the two observed ligands are coupled. The protein Dret_0059 could be involved in either signal transduction or solute transport.

  12. 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.

  13. Processing of cell-surface signalling anti-sigma factors prior to signal recognition is aconserved autoproteolytic mechanism that produces two functional domains.

    NARCIS (Netherlands)

    Bastiaansen, K.C.J.T.; Otero-Asman, J.R.; Luirink, J.; Bitter, W.; Llamas, M.A.

    2015-01-01

    Cell-surface signalling (CSS) enables Gram-negative bacteria to transduce an environmental signal into a cytosolic response. This regulatory cascade involves an outer membrane receptor that transmits the signal to an anti-sigma factor in the cytoplasmic membrane, allowing the activation of an

  14. The DNA binding and activation domains of Gal4p are sufficient for conveying its regulatory signals.

    OpenAIRE

    Ding, W V; Johnston, S A

    1997-01-01

    The transcriptional activation function of the Saccharomyces cerevisiae activator Gal4p is known to rely on a DNA binding activity at its amino terminus and an activation domain at its carboxy terminus. Although both domains are required for activation, truncated forms of Gal4p containing only these domains activate poorly in vivo. Also, mutations in an internal conserved region of Gal4p inactivate the protein, suggesting that this internal region has some function critical to the activity of...

  15. Progesterone receptor (PR) polyproline domain (PPD) mediates inhibition of epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer cells.

    Science.gov (United States)

    Kawprasertsri, Sornsawan; Pietras, Richard J; Marquez-Garban, Diana C; Boonyaratanakornkit, Viroj

    2016-05-01

    Recent evidence has suggested a possible role for progesterone receptor (PR) in the progression of non-small cell lung cancer (NSCLC). However, little is known concerning roles of PR in NSCLC. PR contains a polyproline domain (PPD), which directly binds to the SH3 domain of signaling molecules. Because PPD-SH3 interactions are essential for EGFR signaling, we hypothesized that the presence of PR-PPD interfered with EGFR-mediated signaling and cell proliferation. We examined the role of PR-PPD in cell proliferation and signaling by stably expressing PR-B, or PR-B with disrupting mutations in the PPD (PR-BΔSH3), from a tetracycline-regulated promoter in A549 NSCLC cells. PR-B dose-dependently inhibited cell growth in the absence of ligand, and progestin (R5020) treatment further suppressed the growth. Treatment with RU486 abolished PR-B- and R5020-mediated inhibition of cell proliferation. Expression of PR-BΔSH3 and treatment with R5020 or RU486 had no effect on cell proliferation. Furthermore, PR-B expression but not PR-BΔSH3 expression reduced EGF-induced A549 proliferation and activation of ERK1/2, in the absence of ligand. Taken together, our data demonstrated the significance of PR extranuclear signaling through PPD interactions in EGFR-mediated proliferation and signaling in NSCLC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.

    Science.gov (United States)

    Tatzel, Katharina; Kuroki, Lindsay; Dmitriev, Igor; Kashentseva, Elena; Curiel, David T; Goedegebuure, S Peter; Powell, Matthew A; Mutch, David G; Hawkins, William G; Spitzer, Dirk

    2016-03-03

    TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.

  17. The Role of Bioacoustic Signals in Koala Sexual Selection: Insights from Seasonal Patterns of Associations Revealed with GPS-Proximity Units.

    Directory of Open Access Journals (Sweden)

    William Ellis

    Full Text Available Despite being a charismatic and well-known species, the social system of the koala (Phascolarctos cinereus--the only extant member of the family Phascolarctidae is poorly known and much of the koala's sociality and mating behaviors remain un-quantified. We evaluated these using proximity logging-GPS enabled tracking collars on wild koalas and discuss their implications for the mating system of this species. The frequency and duration of male-female encounters increased during the breeding season, with male-male encounters quite uncommon, suggesting little direct mating competition. By comparison, female-female interactions were very common across both seasons. Body mass of males was not correlated with their interactions with females during the breeding season, although male size is associated with a variety of acoustic parameters indicating individuality. We hypothesise that vocal advertising reduces the likelihood of male-male encounters in the breeding season while increasing the rate of male-female encounters. We suggest that male mating-season bellows function to reduce physical confrontations with other males allowing them to space themselves apart, while, at the same time, attracting females. We conclude that indirect male-male competition, female mate choice, and possibly female competition, mediate sexual selection in koalas.

  18. The Role of Bioacoustic Signals in Koala Sexual Selection: Insights from Seasonal Patterns of Associations Revealed with GPS-Proximity Units

    Science.gov (United States)

    Whipple, Bill; Barth, Ben; Johnston, Stephen; Seddon, Jenny; Melzer, Alistair; Higgins, Damien

    2015-01-01

    Despite being a charismatic and well-known species, the social system of the koala (Phascolarctos cinereus—the only extant member of the family Phascolarctidae) is poorly known and much of the koala’s sociality and mating behaviors remain un-quantified. We evaluated these using proximity logging-GPS enabled tracking collars on wild koalas and discuss their implications for the mating system of this species. The frequency and duration of male-female encounters increased during the breeding season, with male-male encounters quite uncommon, suggesting little direct mating competition. By comparison, female-female interactions were very common across both seasons. Body mass of males was not correlated with their interactions with females during the breeding season, although male size is associated with a variety of acoustic parameters indicating individuality. We hypothesise that vocal advertising reduces the likelihood of male-male encounters in the breeding season while increasing the rate of male-female encounters. We suggest that male mating-season bellows function to reduce physical confrontations with other males allowing them to space themselves apart, while, at the same time, attracting females. We conclude that indirect male-male competition, female mate choice, and possibly female competition, mediate sexual selection in koalas. PMID:26154295

  19. Understanding and eliminating artifact signals from diffusely scattered pump beam in measurements of rough samples by time-domain thermoreflectance (TDTR)

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Bo [Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576 (Singapore); Koh, Yee Kan, E-mail: mpekyk@nus.edu.sg [Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576 (Singapore); Centre of Advanced 2D Materials, National University of Singapore, Singapore 117542 (Singapore)

    2016-06-15

    Time-domain thermoreflectance (TDTR) is a pump-probe technique frequently applied to measure the thermal transport properties of bulk materials, nanostructures, and interfaces. One of the limitations of TDTR is that it can only be employed to samples with a fairly smooth surface. For rough samples, artifact signals are collected when the pump beam in TDTR measurements is diffusely scattered by the rough surface into the photodetector, rendering the TDTR measurements invalid. In this paper, we systemically studied the factors affecting the artifact signals due to the pump beam leaked into the photodetector and thus established the origin of the artifact signals. We find that signals from the leaked pump beam are modulated by the probe beam due to the phase rotation induced in the photodetector by the illumination of the probe beam. As a result of the modulation, artifact signals due to the leaked pump beam are registered in TDTR measurements as the out-of-phase signals. We then developed a simple approach to eliminate the artifact signals due to the leaked pump beam. We verify our leak-pump correction approach by measuring the thermal conductivity of a rough InN sample, when the signals from the leaked pump beam are significant. We also discuss the advantages of our new method over the two-tint approach and its limitations. Our new approach enables measurements of the thermal conductivity of rough samples using TDTR.

  20. Inhibition of Wnt/β-catenin signaling by a soluble collagen-derived frizzled domain interacting with Wnt3a and the receptors frizzled 1 and 8.

    Directory of Open Access Journals (Sweden)

    Ismaïl Hendaoui

    Full Text Available The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs, which have a cysteine-rich domain (CRD structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18 inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.

  1. Charge-Domain Signal Processing of Direct RF Sampling Mixer with Discrete-Time Filters in Bluetooth and GSM Receivers

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available RF circuits for multi-GHz frequencies have recently migrated to low-cost digital deep-submicron CMOS processes. Unfortunately, this process environment, which is optimized only for digital logic and SRAM memory, is extremely unfriendly for conventional analog and RF designs. We present fundamental techniques recently developed that transform the RF and analog circuit design complexity to digitally intensive domain for a wireless RF transceiver, so that it enjoys benefits of digital and switched-capacitor approaches. Direct RF sampling techniques allow great flexibility in reconfigurable radio design. Digital signal processing concepts are used to help relieve analog design complexity, allowing one to reduce cost and power consumption in a reconfigurable design environment. The ideas presented have been used in Texas Instruments to develop two generations of commercial digital RF processors: a single-chip Bluetooth radio and a single-chip GSM radio. We further present details of the RF receiver front end for a GSM radio realized in a 90-nm digital CMOS technology. The circuit consisting of low-noise amplifier, transconductance amplifier, and switching mixer offers 32.5 dB dynamic range with digitally configurable voltage gain of 40 dB down to 7.5 dB. A series of decimation and discrete-time filtering follows the mixer and performs a highly linear second-order lowpass filtering to reject close-in interferers. The front-end gains can be configured with an automatic gain control to select an optimal setting to form a trade-off between noise figure and linearity and to compensate the process and temperature variations. Even under the digital switching activity, noise figure at the 40 dB maximum gain is 1.8 dB and +50 dBm IIP2 at the 34 dB gain. The variation of the input matching versus multiple gains is less than 1 dB. The circuit in total occupies 3.1 mm 2 . The LNA, TA, and mixer consume less than 15.3 mA at a supply voltage of 1.4 V.

  2. Charge-Domain Signal Processing of Direct RF Sampling Mixer with Discrete-Time Filters in Bluetooth and GSM Receivers

    Directory of Open Access Journals (Sweden)

    Ho Yo-Chuol

    2006-01-01

    Full Text Available RF circuits for multi-GHz frequencies have recently migrated to low-cost digital deep-submicron CMOS processes. Unfortunately, this process environment, which is optimized only for digital logic and SRAM memory, is extremely unfriendly for conventional analog and RF designs. We present fundamental techniques recently developed that transform the RF and analog circuit design complexity to digitally intensive domain for a wireless RF transceiver, so that it enjoys benefits of digital and switched-capacitor approaches. Direct RF sampling techniques allow great flexibility in reconfigurable radio design. Digital signal processing concepts are used to help relieve analog design complexity, allowing one to reduce cost and power consumption in a reconfigurable design environment. The ideas presented have been used in Texas Instruments to develop two generations of commercial digital RF processors: a single-chip Bluetooth radio and a single-chip GSM radio. We further present details of the RF receiver front end for a GSM radio realized in a 90-nm digital CMOS technology. The circuit consisting of low-noise amplifier, transconductance amplifier, and switching mixer offers dB dynamic range with digitally configurable voltage gain of 40 dB down to dB. A series of decimation and discrete-time filtering follows the mixer and performs a highly linear second-order lowpass filtering to reject close-in interferers. The front-end gains can be configured with an automatic gain control to select an optimal setting to form a trade-off between noise figure and linearity and to compensate the process and temperature variations. Even under the digital switching activity, noise figure at the 40 dB maximum gain is 1.8 dB and dBm IIP2 at the 34 dB gain. The variation of the input matching versus multiple gains is less than 1 dB. The circuit in total occupies 3.1 . The LNA, TA, and mixer consume less than mA at a supply voltage of 1.4 V.

  3. Interactions between the S-Domain Receptor Kinases and AtPUB-ARM E3 Ubiquitin Ligases Suggest a Conserved Signaling Pathway in Arabidopsis1[W][OA

    Science.gov (United States)

    Samuel, Marcus A.; Mudgil, Yashwanti; Salt, Jennifer N.; Delmas, Frédéric; Ramachandran, Shaliny; Chilelli, Andrea; Goring, Daphne R.

    2008-01-01

    The Arabidopsis (Arabidopsis thaliana) genome encompasses multiple receptor kinase families with highly variable extracellular domains. Despite their large numbers, the various ligands and the downstream interacting partners for these kinases have been deciphered only for a few members. One such member, the S-receptor kinase, is known to mediate the self-incompatibility (SI) response in Brassica. S-receptor kinase has been shown to interact and phosphorylate a U-box/ARM-repeat-containing E3 ligase, ARC1, which, in turn, acts as a positive regulator of the SI response. In an effort to identify conserved signaling pathways in Arabidopsis, we performed yeast two-hybrid analyses of various S-domain receptor kinase family members with representative Arabidopsis plant U-box/ARM-repeat (AtPUB-ARM) E3 ligases. The kinase domains from S-domain receptor kinases were found to interact with ARM-repeat domains from AtPUB-ARM proteins. These kinase domains, along with M-locus protein kinase, a positive regulator of SI response, were also able to phosphorylate the ARM-repeat domains in in vitro phosphorylation assays. Subcellular localization patterns were investigated using transient expression assays in tobacco (Nicotiana tabacum) BY-2 cells and changes were detected in the presence of interacting kinases. Finally, potential links to the involvement of these interacting modules to the hormone abscisic acid (ABA) were investigated. Interestingly, AtPUB9 displayed redistribution to the plasma membrane of BY-2 cells when either treated with ABA or coexpressed with the active kinase domain of ARK1. As well, T-DNA insertion mutants for ARK1 and AtPUB9 lines were altered in their ABA sensitivity during germination and acted at or upstream of ABI3, indicating potential involvement of these proteins in ABA responses. PMID:18552232

  4. Interactions between the S-domain receptor kinases and AtPUB-ARM E3 ubiquitin ligases suggest a conserved signaling pathway in Arabidopsis.

    Science.gov (United States)

    Samuel, Marcus A; Mudgil, Yashwanti; Salt, Jennifer N; Delmas, Frédéric; Ramachandran, Shaliny; Chilelli, Andrea; Goring, Daphne R

    2008-08-01

    The Arabidopsis (Arabidopsis thaliana) genome encompasses multiple receptor kinase families with highly variable extracellular domains. Despite their large numbers, the various ligands and the downstream interacting partners for these kinases have been deciphered only for a few members. One such member, the S-receptor kinase, is known to mediate the self-incompatibility (SI) response in Brassica. S-receptor kinase has been shown to interact and phosphorylate a U-box/ARM-repeat-containing E3 ligase, ARC1, which, in turn, acts as a positive regulator of the SI response. In an effort to identify conserved signaling pathways in Arabidopsis, we performed yeast two-hybrid analyses of various S-domain receptor kinase family members with representative Arabidopsis plant U-box/ARM-repeat (AtPUB-ARM) E3 ligases. The kinase domains from S-domain receptor kinases were found to interact with ARM-repeat domains from AtPUB-ARM proteins. These kinase domains, along with M-locus protein kinase, a positive regulator of SI response, were also able to phosphorylate the ARM-repeat domains in in vitro phosphorylation assays. Subcellular localization patterns were investigated using transient expression assays in tobacco (Nicotiana tabacum) BY-2 cells and changes were detected in the presence of interacting kinases. Finally, potential links to the involvement of these interacting modules to the hormone abscisic acid (ABA) were investigated. Interestingly, AtPUB9 displayed redistribution to the plasma membrane of BY-2 cells when either treated with ABA or coexpressed with the active kinase domain of ARK1. As well, T-DNA insertion mutants for ARK1 and AtPUB9 lines were altered in their ABA sensitivity during germination and acted at or upstream of ABI3, indicating potential involvement of these proteins in ABA responses.

  5. Proximity detection system underground

    Energy Technology Data Exchange (ETDEWEB)

    Denis Kent [Mine Site Technologies (Australia)

    2008-04-15

    Mine Site Technologies (MST) with the support ACARP and Xstrata Coal NSW, as well as assistance from Centennial Coal, has developed a Proximity Detection System to proof of concept stage as per plan. The basic aim of the project was to develop a system to reduce the risk of the people coming into contact with vehicles in an uncontrolled manner (i.e. being 'run over'). The potential to extend the developed technology into other areas, such as controls for vehicle-vehicle collisions and restricting access of vehicle or people into certain zones (e.g. non FLP vehicles into Hazardous Zones/ERZ) was also assessed. The project leveraged off MST's existing Intellectual Property and experience gained with our ImPact TRACKER tagging technology, allowing the development to be fast tracked. The basic concept developed uses active RFID Tags worn by miners underground to be detected by vehicle mounted Readers. These Readers in turn provide outputs that can be used to alert a driver (e.g. by light and/or audible alarm) that a person (Tag) approaching within their vicinity. The prototype/test kit developed proved the concept and technology, the four main components being: Active RFID Tags to send out signals for detection by vehicle mounted receivers; Receiver electronics to detect RFID Tags approaching within the vicinity of the unit to create a long range detection system (60 m to 120 m); A transmitting/exciter device to enable inner detection zone (within 5 m to 20 m); and A software/hardware device to process & log incoming Tags reads and create certain outputs. Tests undertaken in the laboratory and at a number of mine sites, confirmed the technology path taken could form the basis of a reliable Proximity Detection/Alert System.

  6. Perinatal Na+ Overload Programs Raised Renal Proximal Na+ Transport and Enalapril-Sensitive Alterations of Ang II Signaling Pathways during Adulthood

    Science.gov (United States)

    Cabral, Edjair V.; Vieira-Filho, Leucio D.; Silva, Paulo A.; Nascimento, Williams S.; Aires, Regina S.; Oliveira, Fabiana S. T.; Luzardo, Ricardo; Vieyra, Adalberto; Paixão, Ana D. O.

    2012-01-01

    Background High Na+ intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na+ overload-programmed alterations in Na+ transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. Methodology/Principal Findings Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na++K+)ATPase expression and activity. Ouabain-insensitive Na+-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT2 receptor expression decreased while AT1 expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na++K+)ATPase, partially recovered the response of Na+-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na+ or not. In addition, treatment with enalapril per se reduced AT2 receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na+-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. Conclusions/Significance Maternal Na+ overload programmed alterations in renal Na+ transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril

  7. Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling.

    Science.gov (United States)

    Araki, Tsuyoshi; Kawata, Takefumi; Williams, Jeffrey G

    2012-07-10

    SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism.

  8. Olfactory receptor signaling is regulated by the post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) scaffold multi-PDZ domain protein 1.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2009-12-01

    The unique ability of mammals to detect and discriminate between thousands of different odorant molecules is governed by the diverse array of olfactory receptors expressed by olfactory sensory neurons in the nasal epithelium. Olfactory receptors consist of seven transmembrane domain G protein-coupled receptors and comprise the largest gene superfamily in the mammalian genome. We found that approximately 30% of olfactory receptors possess a classical post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) domain binding motif in their C-termini. PDZ domains have been established as sites for protein-protein interaction and play a central role in organizing diverse cell signaling assemblies. In the present study, we show that multi-PDZ domain protein 1 (MUPP1) is expressed in the apical compartment of olfactory sensory neurons. Furthermore, on heterologous co-expression with olfactory sensory neurons, MUPP1 was shown to translocate to the plasma membrane. We found direct interaction of PDZ domains 1 + 2 of MUPP1 with the C-terminus of olfactory receptors in vitro. Moreover, the odorant-elicited calcium response of OR2AG1 showed a prolonged decay in MUPP1 small interfering RNA-treated cells. We have therefore elucidated the first building blocks of the putative \\'olfactosome\\

  9. Changes in signal transducer and activator of transcription 3 (STAT3) dynamics induced by complexation with pharmacological inhibitors of Src homology 2 (SH2) domain dimerization.

    Science.gov (United States)

    Resetca, Diana; Haftchenary, Sina; Gunning, Patrick T; Wilson, Derek J

    2014-11-21

    The activity of the transcription factor signal transducer and activator of transcription 3 (STAT3) is dysregulated in a number of hematological and solid malignancies. Development of pharmacological STAT3 Src homology 2 (SH2) domain interaction inhibitors holds great promise for cancer therapy, and a novel class of salicylic acid-based STAT3 dimerization inhibitors that includes orally bioavailable drug candidates has been recently developed. The compounds SF-1-066 and BP-1-102 are predicted to bind to the STAT3 SH2 domain. However, given the highly unstructured and dynamic nature of the SH2 domain, experimental confirmation of this prediction was elusive. We have interrogated the protein-ligand interaction of STAT3 with these small molecule inhibitors by means of time-resolved electrospray ionization hydrogen-deuterium exchange mass spectrometry. Analysis of site-specific evolution of deuterium uptake induced by the complexation of STAT3 with SF-1-066 or BP-1-102 under physiological conditions enabled the mapping of the in silico predicted inhibitor binding site to the STAT3 SH2 domain. The binding of both inhibitors to the SH2 domain resulted in significant local decreases in dynamics, consistent with solvent exclusion at the inhibitor binding site and increased rigidity of the inhibitor-complexed SH2 domain. Interestingly, inhibitor binding induced hot spots of allosteric perturbations outside of the SH2 domain, manifesting mainly as increased deuterium uptake, in regions of STAT3 important for DNA binding and nuclear localization. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. SINA: A test system for proximity fuses

    Science.gov (United States)

    Ruizenaar, M. G. A.

    1989-04-01

    SINA, a signal generator that can be used for testing proximity fuses, is described. The circuitry of proximity fuses is presented; the output signal of the RF circuit results from a mixing of the emitted signal and received signal that is Doppler shifted in frequency by the relative motion of the fuse with respect to the reflecting target of surface. With SINA, digitized and stored target and clutter signals (previously measured) can be transformed to Doppler signals, for example during a real flight. SINA can be used for testing fuse circuitry, for example in the verification of results of computer simulations of the low frequency Doppler signal processing. The software of SINA and its use are explained.

  11. IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

    Science.gov (United States)

    Floss, D M; Schönberg, M; Franke, M; Horstmeier, F C; Engelowski, E; Schneider, A; Rosenfeldt, E M; Scheller, J

    2017-11-09

    IL-35 and IL-39 are recently discovered shared members of the IL-6- and IL-12-type cytokine family with immune-suppressive capacity. IL-35 has been reported to induce the formation of four different receptor complexes: gp130:IL-12β2, gp130:gp130, IL-12β2:IL-12β2, and IL-12β2:WSX-1. IL-39 was proposed to form a gp130:IL-23R receptor complex. IL-35, but not IL-39, has been reported to activate non-conventional STAT signaling, depending on the receptor complex and target cell. Analyses of IL-35 and IL-39 are, however, hampered by the lack of biologically active recombinant IL-35 and IL-39 proteins. Therefore, we engineered chimeric cytokine receptors to accomplish synthetic IL-35 and IL- 39 signaling by shuffling the extra- and intracellular domains of IL-6/IL-12-type cytokine receptors, resulting in biological activity for all previously described IL-35 receptor complexes. Moreover, we found that the proposed IL-39 receptor complex is biologically active and discovered two additional biologically active synthetic receptor combinations, gp130/IL-12Rβ1 and IL-23R/IL-12Rβ2. Surprisingly, synthetic IL-35 activation led to more canonical STAT signaling of all receptor complexes. In summary, our receptor shuffling approach highlights an interchangeable, modular domain structure among IL-6- and IL-12-type cytokine receptors and enabled synthetic IL-35 and IL-39 signaling.

  12. Suppressor of Cytokine Signaling (SOCS 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.

    Directory of Open Access Journals (Sweden)

    Edmond M Linossi

    Full Text Available Suppressor of Cytokine Signaling (SOCS5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR. Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2 autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.

  13. Data reduction, radial velocities and stellar parameters from spectra in the very low signal-to-noise domain

    Science.gov (United States)

    Malavolta, Luca

    2013-10-01

    Large astronomical facilities usually provide data reduction pipeline designed to deliver ready-to-use scientific data, and too often as- tronomers are relying on this to avoid the most difficult part of an astronomer job Standard data reduction pipelines however are usu- ally designed and tested to have good performance on data with av- erage Signal to Noise Ratio (SNR) data, and the issues that are related with the reduction of data in the very low SNR domain are not taken int account properly. As a result, informations in data with low SNR are not optimally exploited. During the last decade our group has collected thousands of spec- tra using the GIRAFFE spectrograph at Very Large Telescope (Chile) of the European Southern Observatory (ESO) to determine the ge- ometrical distance and dynamical state of several Galactic Globular Clusters but ultimately the analysis has been hampered by system- atics in data reduction, calibration and radial velocity measurements. Moreover these data has never been exploited to get other informa- tions like temperature and metallicity of stars, because considered too noisy for these kind of analyses. In this thesis we focus our attention on data reduction and analysis of spectra with very low SNR. The dataset we analyze in this thesis comprises 7250 spectra for 2771 stars of the Globular Cluster M 4 (NGC 6121) in the wavelength region 5145-5360Å obtained with GIRAFFE. Stars from the upper Red Giant Branch down to the Main Sequence have been observed in very different conditions, including nights close to full moon, and reaching SNR - 10 for many spectra in the dataset. We will first review the basic steps of data reduction and spec- tral extraction, adapting techniques well tested in other field (like photometry) but still under-developed in spectroscopy. We improve the wavelength dispersion solution and the correction of radial veloc- ity shift between day-time calibrations and science observations by following a completely

  14. Differential Regulation of Disheveled in a Novel Vegetal Cortical Domain in Sea Urchin Eggs and Embryos: Implications for the Localized Activation of Canonical Wnt Signaling

    Science.gov (United States)

    Peng, ChiehFu Jeff; Wikramanayake, Athula H.

    2013-01-01

    Pattern formation along the animal-vegetal (AV) axis in sea urchin embryos is initiated when canonical Wnt (cWnt) signaling is activated in vegetal blastomeres. The mechanisms that restrict cWnt signaling to vegetal blastomeres are not well understood, but there is increasing evidence that the egg’s vegetal cortex plays a critical role in this process by mediating localized “activation” of Disheveled (Dsh). To investigate how Dsh activity is regulated along the AV axis, sea urchin-specific Dsh antibodies were used to examine expression, subcellular localization, and post-translational modification of Dsh during development. Dsh is broadly expressed during early sea urchin development, but immunolocalization studies revealed that this protein is enriched in a punctate pattern in a novel vegetal cortical domain (VCD) in the egg. Vegetal blastomeres inherit this VCD during embryogenesis, and at the 60-cell stage Dsh puncta are seen in all cells that display nuclear β-catenin. Analysis of Dsh post-translational modification using two-dimensional Western blot analysis revealed that compared to Dsh pools in the bulk cytoplasm, this protein is differentially modified in the VCD and in the 16-cell stage micromeres that partially inherit this domain. Dsh localization to the VCD is not directly affected by disruption of microfilaments and microtubules, but unexpectedly, microfilament disruption led to degradation of all the Dsh pools in unfertilized eggs over a period of incubation suggesting that microfilament integrity is required for maintaining Dsh stability. These results demonstrate that a pool of differentially modified Dsh in the VCD is selectively inherited by the vegetal blastomeres that activate cWnt signaling in early embryos, and suggests that this domain functions as a scaffold for localized Dsh activation. Localized cWnt activation regulates AV axis patterning in many metazoan embryos. Hence, it is possible that the VCD is an evolutionarily conserved

  15. 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.

  16. A Class of Optimal Rectangular Filtering Matrices for Single-Channel Signal Enhancement in the Time Domain

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

    2013-01-01

    In this paper, we introduce a new class of op- timal rectangular filtering matrices for single-channel speech enhancement. The new class of filters exploits the fact that the dimension of the signal subspace is lower than that of the full space. By doing this, extra degrees of freedom...... in the filters, that are otherwise reserved for preserving the signal subspace, can be used for achieving an improved output signal-to-noise ratio (SNR). Moreover, the filters allow for explicit control of the tradeoff between noise reduction and speech distortion via the chosen rank of the signal subspace...... and real signals. The results show a number of interesting things. Firstly, they show how speech distortion can be traded for noise reduction and vice versa in a seamless manner. Moreover, the introduced filter designs are capable of achieving both the upper and lower bounds for the output SNR via...

  17. Proximity credentials: A survey

    International Nuclear Information System (INIS)

    Wright, L.J.

    1987-04-01

    Credentials as a means of identifying individuals have traditionally been a photo badge and more recently, the coded credential. Another type of badge, the proximity credential, is making inroads in the personnel identification field. This badge can be read from a distance instead of being veiewed by a guard or inserted into a reading device. This report reviews proximity credentials, identifies the companies marketing or developing proximity credentials, and describes their respective credentials. 3 tabs

  18. ProxImaL: efficient image optimization using proximal algorithms

    KAUST Repository

    Heide, Felix

    2016-07-11

    Computational photography systems are becoming increasingly diverse, while computational resources-for example on mobile platforms-are rapidly increasing. As diverse as these camera systems may be, slightly different variants of the underlying image processing tasks, such as demosaicking, deconvolution, denoising, inpainting, image fusion, and alignment, are shared between all of these systems. Formal optimization methods have recently been demonstrated to achieve state-of-the-art quality for many of these applications. Unfortunately, different combinations of natural image priors and optimization algorithms may be optimal for different problems, and implementing and testing each combination is currently a time-consuming and error-prone process. ProxImaL is a domain-specific language and compiler for image optimization problems that makes it easy to experiment with different problem formulations and algorithm choices. The language uses proximal operators as the fundamental building blocks of a variety of linear and nonlinear image formation models and cost functions, advanced image priors, and noise models. The compiler intelligently chooses the best way to translate a problem formulation and choice of optimization algorithm into an efficient solver implementation. In applications to the image processing pipeline, deconvolution in the presence of Poisson-distributed shot noise, and burst denoising, we show that a few lines of ProxImaL code can generate highly efficient solvers that achieve state-of-the-art results. We also show applications to the nonlinear and nonconvex problem of phase retrieval.

  19. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  20. Proximal Probes Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Proximal Probes Facility consists of laboratories for microscopy, spectroscopy, and probing of nanostructured materials and their functional properties. At the...

  1. Cloning of a novel phosphotyrosine binding domain containing molecule, Odin, involved in signaling by receptor tyrosine kinases

    DEFF Research Database (Denmark)

    Pandey, A.; Blagoev, B.; Kratchmarova, I.

    2002-01-01

    . Deletion analysis showed that the phosphotyrosine binding domain of Odin is not required for its tyrosine phosphorylation. Overexpression of Odin, but not an unrelated adapter protein, Grb2, inhibited EGF-induced activation of c-Fos promoter. Microinjection of wild-type or a mutant version lacking the PTB...

  2. The C-terminal domain of Rac1 contains two motifs that control targeting and signaling specificity

    NARCIS (Netherlands)

    van Hennik, Paula B.; ten Klooster, Jean Paul; Halstead, Jon R.; Voermans, Carlijn; Anthony, Eloise C.; Divecha, Nullin; Hordijk, Peter L.

    2003-01-01

    Rho-like GTPases control a wide range of cellular functions such as integrin- and cadherin-mediated adhesion, cell motility, and gene expression. The hypervariable C-terminal domain of these GTPases has been implicated in membrane association and effector binding. We found that cell-permeable

  3. Design and implementation of a data acquisition system for the study of dynamics signals in the time Domain

    International Nuclear Information System (INIS)

    Daza, Arnoldo; Hinojosa, Ana; Diaz, Xavier; Neira, Oscar

    2011-01-01

    The purpose of this research was to design and implement a data acquisition system for the study of dynamic signals in the time in order of nanoseconds, through the use of electronic instrumentation to obtain the temporal profiles of light signals, such as pulses of light from a laser or fluorescent light signals. To carry out the design and implementation of the data acquisition system proposed, we used a rapid response transducer and a data acquisition card of high speed. As well, it was developed a graphical user interface for visualization, analysis and study of the data acquired. Thus, it was possible to perform the digitization of a pulse on the order of nanoseconds, as well as the acquisition of fluorescence signals of different wavelengths, from which to obtain theoretical and experimental valuable knowledge based on the physics of spectroscopy.

  4. Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription

    Energy Technology Data Exchange (ETDEWEB)

    Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Eizuru, Yoshito [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2010-06-04

    Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3{beta} (GSK-3{beta}) and to negatively regulate its activity, leading to stimulation of GSK-3{beta}-dependent {beta}-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a {beta}-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3{beta} complex. These data reveal for the first time that I-mfa domain proteins interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3{beta} complex.

  5. Signal-to-noise characterization of time-gated intensifiers used for wide-field time-domain FLIM

    Energy Technology Data Exchange (ETDEWEB)

    McGinty, J; Requejo-Isidro, J; Munro, I; Talbot, C B; Dunsby, C; Neil, M A A; French, P M W [Photonics Group, Blackett Laboratory, Imperial College London, Prince Consort Road, London, SW7 2BW (United Kingdom); Kellett, P A; Hares, J D, E-mail: james.mcginty@imperial.ac.u [Kentech Instruments Ltd, Isis Building, Howbery Park, Wallingford, OX10 8BA (United Kingdom)

    2009-07-07

    Time-gated imaging using gated optical intensifiers provides a means to realize high speed fluorescence lifetime imaging (FLIM) for the study of fast events and for high throughput imaging. We present a signal-to-noise characterization of CCD-coupled micro-channel plate gated intensifiers used with this technique and determine the optimal acquisition parameters (intensifier gain voltage, CCD integration time and frame averaging) for measuring mono-exponential fluorescence lifetimes in the shortest image acquisition time for a given signal flux. We explore the use of unequal CCD integration times for different gate delays and show that this can improve the lifetime accuracy for a given total acquisition time.

  6. Plasticity of the PAS domain and a potential role for signal transduction in the histidine kinase DcuS

    NARCIS (Netherlands)

    Etzkorn, M.; Kneuper, H.; Dünnwald, P.; Vijayan, V.; Krämer, J.; Griesinger, C.; Becker, S.; Unden, G.; Baldus, M.

    2008-01-01

    The mechanistic understanding of how membrane-embedded sensor kinases recognize signals and regulate kinase activity is currently limited. Here we report structure-function relationships of the multidomain membrane sensor kinase DcuS using solidstate NMR, structural modeling and mutagenesis.

  7. A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.

    Directory of Open Access Journals (Sweden)

    Ricardo Núñez Miguel

    2007-08-01

    Full Text Available The Toll-like receptor 4 (TLR4 is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3 and nuclear factor kappaB (NFkappaB respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu.

  8. Arabidopsis COLD SHOCK DOMAIN PROTEIN2 is a RNA chaperone that is regulated by cold and developmental signals

    International Nuclear Information System (INIS)

    Sasaki, Kentaro; Kim, Myung-Hee; Imai, Ryozo

    2007-01-01

    Bacterial cold shock proteins (CSPs) are RNA chaperones that unwind RNA secondary structures. Arabidopsis COLD SHOCK DOMAIN PROTEIN2 (AtCSP2) contains a domain that is shared with bacterial CSPs. Here we showed that AtCSP2 binds to RNA and unwinds nucleic acid duplex. Heterologous expression of AtCSP2 complemented cold sensitivity of an Escherichia coli csp quadruple mutant, indicating that AtCSP2 function as a RNA chaperone in E. coli. AtCSP2 mRNA and protein levels increased during cold acclimation, but the protein accumulation was most prominent after 10 days of cold treatment. AtCSP2 promoter::GUS transgenic plants revealed that AtCSP2 is expressed only in root and shoot apical regions during vegetative growth but is expressed in reproductive organs such as pollens, ovules and embryos. These data indicated that AtCSP2 is involved in developmental processes as well as cold adaptation. Localization of AtCSP2::GFP in nucleolus and cytoplasm suggested different nuclear and cytosolic RNA targets

  9. Ultra-high energy cosmic rays: analysis of extensive air showers and their associated electromagnetic signal in the MHz domain

    International Nuclear Information System (INIS)

    Revenu, B.

    2012-01-01

    In this HDR (accreditation to supervise research) report, the author proposes a review of the present results in the field of ultra-high energy cosmic rays. After a presentation of some results about the Fermi mechanism to accelerate cosmic rays, the author more particularly addresses the reconstruction of air showers, and the search for sources. He also addresses the radio signal emitted by air shower secondary positrons and electrons. He proposes an overview of the present knowledge on the basis of present experiments. Data show that the electric field is mainly due to the influence of the Earth magnetic field which acts on electrons and positrons, but more recently, the contribution due to electrons in excess seems to appear in data. The author reports the last advances in the field of simulation of the electric field, with notably the prediction of new signal produced by the disappearance of the air shower during its absorption by the soil [fr

  10. The Fas-associated death domain protein/caspase-8/c-FLIP signaling pathway is involved in TNF-induced activation of ERK

    International Nuclear Information System (INIS)

    Lueschen, Silke; Falk, Markus; Scherer, Gudrun; Ussat, Sandra; Paulsen, Maren; Adam-Klages, Sabine

    2005-01-01

    The cytokine TNF activates multiple signaling pathways leading to cellular responses ranging from proliferation and survival to apoptosis. While most of these pathways have been elucidated in detail over the past few years, the molecular mechanism leading to the activation of the MAP kinases ERK remains ill defined and is controversially discussed. Therefore, we have analyzed TNF-induced ERK activation in various human and murine cell lines and show that it occurs in a cell-type-specific manner. In addition, we provide evidence for the involvement of the signaling components Fas-associated death domain protein (FADD), caspase-8, and c-FLIP in the pathway activating ERK in response to TNF. This conclusion is based on the following observations: (I) Overexpression of FADD, caspase-8, or a c-FLIP protein containing the death effector domains only leads to enhanced and prolonged ERK activation after TNF treatment. (II) TNF-induced ERK activation is strongly diminished in the absence of FADD. Interestingly, the enzymatic function of caspase-8 is not required for TNF-induced ERK activation. Additional evidence suggests a role for this pathway in the proliferative response of murine fibroblasts to TNF

  11. The Arabidopsis KH-Domain RNA-Binding Protein ESR1 Functions in Components of Jasmonate Signalling, Unlinking Growth Restraint and Resistance to Stress.

    Directory of Open Access Journals (Sweden)

    Louise F Thatcher

    Full Text Available Glutathione S-transferases (GSTs play important roles in the protection of cells against toxins and oxidative damage where one Arabidopsis member, GSTF8, has become a commonly used marker gene for early stress and defense responses. A GSTF8 promoter fragment fused to the luciferase reporter gene was used in a forward genetic screen for Arabidopsis mutants with up-regulated GSTF8 promoter activity. This identified the esr1-1 (enhanced stress response 1 mutant which also conferred increased resistance to the fungal pathogen Fusarium oxysporum. Through positional cloning, the ESR1 gene was found to encode a KH-domain containing RNA-binding protein (At5g53060. Whole transcriptome sequencing of esr1-1 identified altered expression of genes involved in responses to biotic and abiotic stimuli, hormone signaling pathways and developmental processes. In particular was an overall significant enrichment for jasmonic acid (JA mediated processes in the esr1-1 down-regulated dataset. A subset of these genes were tested for MeJA inducibility and we found the expression of some but not all were reduced in esr1-1. The esr1-1 mutant was not impaired in other aspects of JA-signalling such as JA- sensitivity or development, suggesting ESR1 functions in specific components of the JA-signaling pathway. Examination of salicylic acid (SA regulated marker genes in esr1-1 showed no increase in basal or SA induced expression suggesting repression of JA-regulated genes is not due to antagonistic SA-JA crosstalk. These results define new roles for KH-domain containing proteins with ESR1 unlinking JA-mediated growth and defense responses.

  12. Improving the signal visibility of optical-disk-drive sensors by analyte patterning and frequency-domain analysis

    International Nuclear Information System (INIS)

    Schaefer, S; Chau, K J

    2011-01-01

    One limitation of using compact disks (CDs) and optical disk drives for sensing and imaging of analytes placed on a CD is the fluctuations in the voltage signal from the disk drive generated while reading the data on the CD. In this study, we develop a simple, low-cost strategy for sensing and identification using CDs and optical disk drives that spectrally separates contributions to the voltage signal caused by an analyte intentionally placed onto the CD and that caused by the underlying data on the CD. Analytes are printed onto a CD surface with fixed spatial periodicity. As the laser beam in an optical disk drive scans over the section of the CD containing the analyte pattern, the intensity of the laser beam incident onto the photodiode integrated into the disk drive is modulated at a frequency dependent on the spatial periodicity of the analyte pattern and the speed of the optical-disk-drive motor. Fourier transformation of the voltage signal from the optical disk drive yields peaks in the frequency spectrum with amplitudes and locations that enable analyte sensing and identification, respectively. We study the influence of analyte area coverage, pattern periodicity, and CD rotational frequency on the peaks in the frequency spectrum associated with the patterned analyte. We apply this technique to discriminate differently-colored analytes, perform trigger-free detection of multiple analytes distributed on a single CD, and detect at least two different, overlapped analyte patterns on a single CD. The extension of this technique for sensing and identification of colorimetric chemical reagents is discussed

  13. Automatic sleep staging using empirical mode decomposition, discrete wavelet transform, time-domain, and nonlinear dynamics features of heart rate variability signals.

    Science.gov (United States)

    Ebrahimi, Farideh; Setarehdan, Seyed-Kamaledin; Ayala-Moyeda, Jose; Nazeran, Homer

    2013-10-01

    The conventional method for sleep staging is to analyze polysomnograms (PSGs) recorded in a sleep lab. The electroencephalogram (EEG) is one of the most important signals in PSGs but recording and analysis of this signal presents a number of technical challenges, especially at home. Instead, electrocardiograms (ECGs) are much easier to record and may offer an attractive alternative for home sleep monitoring. The heart rate variability (HRV) signal proves suitable for automatic sleep staging. Thirty PSGs from the Sleep Heart Health Study (SHHS) database were used. Three feature sets were extracted from 5- and 0.5-min HRV segments: time-domain features, nonlinear-dynamics features and time-frequency features. The latter was achieved by using empirical mode decomposition (EMD) and discrete wavelet transform (DWT) methods. Normalized energies in important frequency bands of HRV signals were computed using time-frequency methods. ANOVA and t-test were used for statistical evaluations. Automatic sleep staging was based on HRV signal features. The ANOVA followed by a post hoc Bonferroni was used for individual feature assessment. Most features were beneficial for sleep staging. A t-test was used to compare the means of extracted features in 5- and 0.5-min HRV segments. The results showed that the extracted features means were statistically similar for a small number of features. A separability measure showed that time-frequency features, especially EMD features, had larger separation than others. There was not a sizable difference in separability of linear features between 5- and 0.5-min HRV segments but separability of nonlinear features, especially EMD features, decreased in 0.5-min HRV segments. HRV signal features were classified by linear discriminant (LD) and quadratic discriminant (QD) methods. Classification results based on features from 5-min segments surpassed those obtained from 0.5-min segments. The best result was obtained from features using 5-min HRV

  14. Statistical and time domain signal analysis of the thermal behaviour of wind turbine drive train components under dynamic operation conditions

    International Nuclear Information System (INIS)

    Nienhaus, K; Baltes, R; Bernet, C; Hilbert, M

    2012-01-01

    Gearboxes and generators are fundamental components of all electrical machines and the backbone of all electricity generation. Since the wind energy represents one of the key energy sources of the future, the number of wind turbines installed worldwide is rapidly increasing. Unlike in the past wind turbines are more often positioned in arctic as well as in desert like regions, and thereby exposed to harsh environmental conditions. Especially the temperature in those regions is a key factor that defines the design and choice of components and materials of the drive train. To optimize the design and health monitoring under varying temperatures it is important to understand the thermal behaviour dependent on environmental and machine parameters. This paper investigates the behaviour of the stator temperature of the double fed induction generator of a wind turbine. Therefore, different scenarios such as start of the turbine after a long period of no load, stop of the turbine after a long period of full load and others are isolated and analysed. For each scenario the dependences of the temperature on multiple wind turbine parameters such as power, speed and torque are studied. With the help of the regression analysis for multiple variables, it is pointed out which parameters have high impact on the thermal behaviour. Furthermore, an analysis was done to study the dependences in the time domain. The research conducted is based on 10 months of data of a 2 MW wind turbine using an adapted data acquisition system for high sampled data. The results appear promising, and lead to a better understanding of the thermal behaviour of a wind turbine drive train. Furthermore, the results represent the base of future research of drive trains under harsh environmental conditions, and it can be used to improve the fault diagnosis and design of electrical machines.

  15. Coordinated regulation by two VPS9 domain-containing guanine nucleotide exchange factors in small GTPase Rab5 signaling pathways in fission yeast

    International Nuclear Information System (INIS)

    Tsukamoto, Yuta; Kagiwada, Satoshi; Shimazu, Sayuri; Takegawa, Kaoru; Noguchi, Tetsuko; Miyamoto, Masaaki

    2015-01-01

    The small GTPase Rab5 is reported to regulate various cellular functions, such as vesicular transport and endocytosis. VPS9 domain-containing proteins are thought to activate Rab5(s) by their guanine-nucleotide exchange activities. Numerous VPS9 proteins have been identified and are structurally conserved from yeast to mammalian cells. However, the functional relationships among VPS9 proteins in cells remain unclear. Only one Rab5 and two VPS9 proteins were identified in the Schizosaccharomyces pombe genome. Here, we examined the cellular function of two VPS9 proteins and the relationship between these proteins in cellular functions. Vps901-GFP and Vps902-GFP exhibited dotted signals in vegetative and differentiated cells. vps901 deletion mutant (Δvps901) cells exhibited a phenotype deficient in the mating process and responses to high concentrations of ions, such as calcium and metals, and Δvps901Δvps902 double mutant cells exhibited round cell shapes similar to ypt5-909 (Rab5 mutant allele) cells. Deletion of both vps901 and vps902 genes completely abolished the mating process and responses to various stresses. A lack of vacuole formation and aberrant inner cell membrane structures were also observed in Δvps901Δvps902 cells by electron microscopy. These data strongly suggest that Vps901 and Vps902 are cooperatively involved in the regulation of cellular functions, such as cell morphology, sexual development, response to ion stresses, and vacuole formation, via Rab5 signaling pathways in fission yeast cells. - Highlights: • Roles of Rab5 activator VPS9 proteins in cellular functions. • Cooperation between VPS9 proteins in Rab5 signaling pathway. • Roles of each VPS9 protein in Rab5 signaling pathway are discussed

  16. Coordinated regulation by two VPS9 domain-containing guanine nucleotide exchange factors in small GTPase Rab5 signaling pathways in fission yeast

    Energy Technology Data Exchange (ETDEWEB)

    Tsukamoto, Yuta [Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe 657-8501 (Japan); Kagiwada, Satoshi [Department of Biological Sciences, Faculty of Science, Nara Women' s University, Kitauoyanishi-machi, Nara 630-8506 (Japan); Shimazu, Sayuri [Center for Supports to Research and Education Activities, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe 657-8501 (Japan); Takegawa, Kaoru [Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan); Noguchi, Tetsuko [Department of Biological Sciences, Faculty of Science, Nara Women' s University, Kitauoyanishi-machi, Nara 630-8506 (Japan); Miyamoto, Masaaki, E-mail: miya@kobe-u.ac.jp [Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe 657-8501 (Japan); Center for Supports to Research and Education Activities, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe 657-8501 (Japan)

    2015-03-20

    The small GTPase Rab5 is reported to regulate various cellular functions, such as vesicular transport and endocytosis. VPS9 domain-containing proteins are thought to activate Rab5(s) by their guanine-nucleotide exchange activities. Numerous VPS9 proteins have been identified and are structurally conserved from yeast to mammalian cells. However, the functional relationships among VPS9 proteins in cells remain unclear. Only one Rab5 and two VPS9 proteins were identified in the Schizosaccharomyces pombe genome. Here, we examined the cellular function of two VPS9 proteins and the relationship between these proteins in cellular functions. Vps901-GFP and Vps902-GFP exhibited dotted signals in vegetative and differentiated cells. vps901 deletion mutant (Δvps901) cells exhibited a phenotype deficient in the mating process and responses to high concentrations of ions, such as calcium and metals, and Δvps901Δvps902 double mutant cells exhibited round cell shapes similar to ypt5-909 (Rab5 mutant allele) cells. Deletion of both vps901 and vps902 genes completely abolished the mating process and responses to various stresses. A lack of vacuole formation and aberrant inner cell membrane structures were also observed in Δvps901Δvps902 cells by electron microscopy. These data strongly suggest that Vps901 and Vps902 are cooperatively involved in the regulation of cellular functions, such as cell morphology, sexual development, response to ion stresses, and vacuole formation, via Rab5 signaling pathways in fission yeast cells. - Highlights: • Roles of Rab5 activator VPS9 proteins in cellular functions. • Cooperation between VPS9 proteins in Rab5 signaling pathway. • Roles of each VPS9 protein in Rab5 signaling pathway are discussed.

  17. Vaccinia Virus Protein C6 Inhibits Type I IFN Signalling in the Nucleus and Binds to the Transactivation Domain of STAT2.

    Directory of Open Access Journals (Sweden)

    Jennifer H Stuart

    2016-12-01

    Full Text Available The type I interferon (IFN response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells. Ectopic expression of C6 inhibits the induction of interferon stimulated genes (ISGs in response to IFNα treatment at both the mRNA and protein level. C6 inhibits the IFNα-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT signalling pathway at a late stage, downstream of STAT1 and STAT2 phosphorylation, nuclear translocation and binding of the interferon stimulated gene factor 3 (ISGF3 complex to the interferon stimulated response element (ISRE. Mechanistically, C6 associates with the transactivation domain of STAT2 and this might explain how C6 inhibits the type I IFN signalling very late in the pathway. During virus infection C6 reduces ISRE-dependent gene expression despite the presence of the viral protein phosphatase VH1 that dephosphorylates STAT1 and STAT2. The ability of a cytoplasmic replicating virus to dampen the immune response within the nucleus, and the ability of viral immunomodulators such as C6 to inhibit multiple stages of the innate immune response by distinct mechanisms, emphasizes the intricacies of host-pathogen interactions and viral immune evasion.

  18. Neighborhoods and manageable proximity

    Directory of Open Access Journals (Sweden)

    Stavros Stavrides

    2011-08-01

    Full Text Available The theatricality of urban encounters is above all a theatricality of distances which allow for the encounter. The absolute “strangeness” of the crowd (Simmel 1997: 74 expressed, in its purest form, in the absolute proximity of a crowded subway train, does not generally allow for any movements of approach, but only for nervous hostile reactions and submissive hypnotic gestures. Neither forced intersections in the course of pedestrians or vehicles, nor the instantaneous crossing of distances by the technology of live broadcasting and remote control give birth to places of encounter. In the forced proximity of the metropolitan crowd which haunted the city of the 19th and 20th century, as well as in the forced proximity of the tele-presence which haunts the dystopic prospect of the future “omnipolis” (Virilio 1997: 74, the necessary distance, which is the stage of an encounter between different instances of otherness, is dissipated.

  19. Predicting the effect of spectral subtraction on the speech recognition threshold based on the signal-to-noise ratio in the envelope domain

    DEFF Research Database (Denmark)

    Jørgensen, Søren; Dau, Torsten

    2011-01-01

    rarely been evaluated perceptually in terms of speech intelligibility. This study analyzed the effects of the spectral subtraction strategy proposed by Berouti at al. [ICASSP 4 (1979), 208-211] on the speech recognition threshold (SRT) obtained with sentences presented in stationary speech-shaped noise....... The SRT was measured in five normal-hearing listeners in six conditions of spectral subtraction. The results showed an increase of the SRT after processing, i.e. a decreased speech intelligibility, in contrast to what is predicted by the Speech Transmission Index (STI). Here, another approach is proposed......, denoted the speech-based envelope power spectrum model (sEPSM) which predicts the intelligibility based on the signal-to-noise ratio in the envelope domain. In contrast to the STI, the sEPSM is sensitive to the increased amount of the noise envelope power as a consequence of the spectral subtraction...

  20. Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) levels in patients with overt and subclinical hyperthyroidism: effects of treatment.

    Science.gov (United States)

    Erem, Cihangir; Civan, Nadim; Coskun, Hulya; Mentese, Ahmet; Suleyman, Akile Karacin; Altay, Diler Us; Akgul, Zeynep; Deger, Orhan

    2016-06-01

    Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) has been shown to increase in parallel with platelet activation in acute ischaemic and thrombotic diseases. There has been no study evaluating SCUBE1 levels in patients with overt hyperthyroidism (OHyper) and subclinical hyperthyroidism (SHyper), conditions which are known to show impairment of both endothelial and platelet function. This study sought to evaluate SCUBE1 concentrations in patients with SHyper and OHyper, and assessed the effects of antithyroid drug (ATD) therapy on circulating SCUBE1 levels. Forty-five untreated patients with OHyper, 20 untreated patients with SHyper and 30 age- and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. Compared with the control subjects, SCUBE1 levels were significantly increased in patients with SHyper and OHyper (P hyperthyroidism, especially in the subclinical period. © 2015 John Wiley & Sons Ltd.

  1. Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes.

    Science.gov (United States)

    Chuang, L M; Hausdorff, S F; Myers, M G; White, M F; Birnbaum, M J; Kahn, C R

    1994-11-04

    Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. The Ras-enhanced oocyte maturation response, but not the elevated basal level of MAP and S6 kinase, was partially blocked by the SH2-p85, but not SH2-GRB2. These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins.

  2. Activatory and Inhibitory Fcγ Receptors Augment Rituximab-mediated Internalization of CD20 Independent of Signaling via the Cytoplasmic Domain*

    Science.gov (United States)

    Vaughan, Andrew T.; Chan, Claude H. T.; Klein, Christian; Glennie, Martin J.; Beers, Stephen A.; Cragg, Mark S.

    2015-01-01

    Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcγR, FcγRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20·mAb·FcγRIIb complex follows, the rate of which correlates with FcγRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcγRIIb, this interaction fails to augment the rate of CD20·mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process. We have assessed the molecular requirements for the internalization process and demonstrate that in contrast to internalization of IgG immune complexes, FcγRIIb-augmented internalization of rituximab-ligated CD20 occurs independently of the FcγRIIb ITIM, indicating that signaling downstream of FcγRIIb is not required. In transfected cells, activatory FcγRI, FcγRIIa, and FcγRIIIa augmented internalization of rituximab-ligated CD20 in a similar manner. However, FcγRIIa mediated a slower rate of internalization than cells expressing equivalent levels of the highly homologous FcγRIIb. The difference was maintained in cells expressing FcγRIIa and FcγRIIb lacking cytoplasmic domains and in which the transmembrane domains had been exchanged. This difference may be due to increased degradation of FcγRIIa, which traffics to lysosomes independently of rituximab. We conclude that the cytoplasmic domain of FcγR is not required for promoting internalization of rituximab-ligated CD20. Instead, we propose that FcγR provides a structural role in augmenting endocytosis that differs from that employed during the endocytosis of immune complexes. PMID:25568316

  3. Differences in time-domain and spectral indexes of skin-surface laser-Doppler signals between controls and breast-cancer subjects.

    Science.gov (United States)

    Hsiu, Hsin; Chen, Chao-Tsung; Hung, Shuo-Hui; Chen, Guan-Zhang; Huang, Yu-Ling

    2018-04-13

    There is an urgent need to improve the early diagnosis of breast cancer. The present study applied spectral and beat-to-beat analyses to laser-Doppler (LDF) data sequences measured on the skin surface on the back of the right hands, with the aim of comparing the different peripheral microcirculatory-blood-flow (MBF) perfusion condition between breast-cancer and control subjects. ECG and LDF signals were obtained simultaneously and noninvasively from 23 breast-cancer patients and 23 age-matched control subjects. Time-domain beat-to-beat indexes and their variability parameters were calculated. Spectral indexes were calculated using the Morlet wavelet transform. The beat-to-beat LDF pulse width and its variability were significantly smaller in cancer patients than in the controls. The energy contributions of endothelial-, neural-, and myogenic-related frequency bands were also significantly smaller in cancer patients. The present study has revealed significant differences in the beat-to-beat and spectral indexes of skin-surface-acquired LDF signals between control subjects and breast-cancer patients. This illustrates that LDF indexes may be useful for monitoring the changes in the MBF perfusion condition induced by breast cancer. Since the breast-cancer patients were at TNM stages 0- 2, the present findings may aid the development of indexes for detecting breast cancer.

  4. Proximal collagenous gastroenteritides:

    DEFF Research Database (Denmark)

    Nielsen, Ole Haagen; Riis, Lene Buhl; Danese, Silvio

    2014-01-01

    AIM: While collagenous colitis represents the most common form of the collagenous gastroenteritides, the collagenous entities affecting the proximal part of the gastrointestinal tract are much less recognized and possibly overlooked. The aim was to summarize the latest information through a syste...

  5. Proximal femoral fractures

    DEFF Research Database (Denmark)

    Palm, Henrik; Teixidor, Jordi

    2015-01-01

    searched the homepages of the national heath authorities and national orthopedic societies in West Europe and found 11 national or regional (in case of no national) guidelines including any type of proximal femoral fracture surgery. RESULTS: Pathway consensus is outspread (internal fixation for un...

  6. Proximate Analysis of Coal

    Science.gov (United States)

    Donahue, Craig J.; Rais, Elizabeth A.

    2009-01-01

    This lab experiment illustrates the use of thermogravimetric analysis (TGA) to perform proximate analysis on a series of coal samples of different rank. Peat and coke are also examined. A total of four exercises are described. These are dry exercises as students interpret previously recorded scans. The weight percent moisture, volatile matter,…

  7. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine

    Science.gov (United States)

    Okazaki, Taku; Maeda, Akito; Nishimura, Hiroyuki; Kurosaki, Tomohiro; Honjo, Tasuku

    2001-01-01

    PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (FcγRIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca2+ mobilization, and tyrosine phosphorylation of effector molecules, including Igβ, Syk, phospholipase C-γ2 (PLCγ2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling. PMID:11698646

  8. PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer’s amyloid-β precursor protein via a tissue-specific proximal regulatory element (PRE

    Directory of Open Access Journals (Sweden)

    Lahiri Debomoy K

    2013-01-01

    Full Text Available Abstract Background Alzheimer’s disease (AD is intimately tied to amyloid-β (Aβ peptide. Extraneuronal brain plaques consisting primarily of Aβ aggregates are a hallmark of AD. Intraneuronal Aβ subunits are strongly implicated in disease progression. Protein sequence mutations of the Aβ precursor protein (APP account for a small proportion of AD cases, suggesting that regulation of the associated gene (APP may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or “proximal regulatory element” (PRE, at −76/−47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. Results EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 (AP2, nm23 nucleoside diphosphate kinase/metastatic inhibitory protein (PuF, and specificity protein 1 (SP1. These sites crossed a known single nucleotide polymorphism (SNP. EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. Conclusions We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also

  9. Domains and domain loss

    DEFF Research Database (Denmark)

    Haberland, Hartmut

    2005-01-01

    politicians and in the media, especially in the discussion whether some languages undergo ‘domain loss’ vis-à-vis powerful international languages like English. An objection that has been raised here is that domains, as originally conceived, are parameters of language choice and not properties of languages...

  10. Quantum Proximity Resonances

    International Nuclear Information System (INIS)

    Heller, E.J.

    1996-01-01

    It is well known that at long wavelengths λ an s-wave scatterer can have a scattering cross section σ on the order of λ 2 , much larger than its physical size, as measured by the range of its potential. Very interesting phenomena can arise when two or more identical scatterers are placed close together, well within one wavelength. We show that, for a pair of identical scatterers, an extremely narrow p-wave open-quote open-quote proximity close-quote close-quote resonance develops from a broader s-wave resonance of the individual scatterers. A new s-wave resonance of the pair also appears. The relation of these proximity resonances (so called because they appear when the scatterers are close together) to the Thomas and Efimov effects is discussed. copyright 1996 The American Physical Society

  11. Insights into signal transduction by a hybrid FixL: Denaturation study of on and off states of a multi-domain oxygen sensor.

    Science.gov (United States)

    Guimarães, Wellinson G; Gondim, Ana C S; Costa, Pedro Mikael da Silva; Gilles-Gonzalez, Marie-Alda; Lopes, Luiz G F; Carepo, Marta S P; Sousa, Eduardo H S

    2017-07-01

    FixL from Rhizobium etli (ReFixL) is a hybrid oxygen sensor protein. Signal transduction in ReFixL is effected by a switch off of the kinase activity on binding of an oxygen molecule to ferrous heme iron in another domain. Cyanide can also inhibit the kinase activity upon binding to the heme iron in the ferric state. The unfolding by urea of the purified full-length ReFixL in both active pentacoordinate form, met-FixL(Fe III ) and inactive cyanomet-FixL (Fe III -CN - ) form was monitored by UV-visible absorption spectroscopy, circular dichroism (CD) and fluorescence spectroscopy. The CD and UV-visible absorption spectroscopy revealed two states during unfolding, whereas fluorescence spectroscopy identified a three-state unfolding mechanism. The unfolding mechanism was not altered for the active compared to the inactive state; however, differences in the ΔG H2O were observed. According to the CD results, compared to cyanomet-FixL, met-FixL was more stable towards chemical denaturation by urea (7.2 vs 4.8kJmol -1 ). By contrast, electronic spectroscopy monitoring of the Soret band showed cyanomet-FixL to be more stable than met-FixL (18.5 versus 36.2kJmol -1 ). For the three-state mechanism exhibited by fluorescence, the ΔG H2O for both denaturation steps were higher for the active-state met-FixL than for cyanomet-FixL. The overall stability of met-FixL is higher in comparison to cyanomet-FixL suggesting a more compact protein in the active form. Nonetheless, hydrogen bonding by bound cyanide in the inactive state promotes the stability of the heme domain. This work supports a model of signal transduction by FixL that is likely shared by other heme-based sensors. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. MR imaging of proximal femur: age-related changes

    International Nuclear Information System (INIS)

    Kim, Ju Heon; Jeon, Woo Jin; Sohn, Cheol Ho; Park, Mi Ok; Lee, Seong Mun; Joo, Yang Gu; Suh, Soo Jhi; Pyun, Young Sik

    1995-01-01

    The purpose of this study is to illustrate MR patterns of signal intensity of proximal femur in normal subjects according to the age distribution. T1-weighted MR images of the proximal femur in 125 subjects, aged 13 days to 25 years, were retrospectively analyzed. Age distribution was classified to 4 groups; below 4 months, 5 months to 4 years, 5 years to 14 years, and 15 years to 25 years. By the age of 4 months, the non-ossified femoral epiphysis was seen as intermediate-signal-intensity cartilage. At 5 months-4 years, the ossified femoral capital epiphysis was seen within intermediate-signal-intensity cartilage and appeared as decreased or increased signal-intensity red or yellow marrow surrounded by a rim of low-signal-intensity cortical bone. At 5-14 years, the ossified femoral capital and greater trochanteric epiphysis were seen within the intermediate-signal-intensity cartilage and appeared as decreased or increased signal-intensity red or yellow marrow. At 15-25 years, the proximal metaphyseal marrow showed increased signal intensity. Four patterns of the metaphyseal marrow were recognized by Ricci et al. The frequency of pattern 1 a progressively decreased with age. Pattern 2 and 3 were visible in the 15-25 years age group. An understanding of the spectrum of normal age-related change of the proximal femoral cartilage and marrow patterns serves as the foundation for interpretation of proximal femur pathologies

  13. Activatory and inhibitory Fcγ receptors augment rituximab-mediated internalization of CD20 independent of signaling via the cytoplasmic domain.

    Science.gov (United States)

    Vaughan, Andrew T; Chan, Claude H T; Klein, Christian; Glennie, Martin J; Beers, Stephen A; Cragg, Mark S

    2015-02-27

    Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcγR, FcγRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20·mAb·FcγRIIb complex follows, the rate of which correlates with FcγRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcγRIIb, this interaction fails to augment the rate of CD20·mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process. We have assessed the molecular requirements for the internalization process and demonstrate that in contrast to internalization of IgG immune complexes, FcγRIIb-augmented internalization of rituximab-ligated CD20 occurs independently of the FcγRIIb ITIM, indicating that signaling downstream of FcγRIIb is not required. In transfected cells, activatory FcγRI, FcγRIIa, and FcγRIIIa augmented internalization of rituximab-ligated CD20 in a similar manner. However, FcγRIIa mediated a slower rate of internalization than cells expressing equivalent levels of the highly homologous FcγRIIb. The difference was maintained in cells expressing FcγRIIa and FcγRIIb lacking cytoplasmic domains and in which the transmembrane domains had been exchanged. This difference may be due to increased degradation of FcγRIIa, which traffics to lysosomes independently of rituximab. We conclude that the cytoplasmic domain of FcγR is not required for promoting internalization of rituximab-ligated CD20. Instead, we propose that FcγR provides a structural role in augmenting endocytosis that differs from that employed during the endocytosis of immune complexes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Modulation of catalytic activity in multi-domain protein tyrosine phosphatases.

    Directory of Open Access Journals (Sweden)

    Lalima L Madan

    Full Text Available Signaling mechanisms involving protein tyrosine phosphatases govern several cellular and developmental processes. These enzymes are regulated by several mechanisms which include variation in the catalytic turnover rate based on redox stimuli, subcellular localization or protein-protein interactions. In the case of Receptor Protein Tyrosine Phosphatases (RPTPs containing two PTP domains, phosphatase activity is localized in their membrane-proximal (D1 domains, while the membrane-distal (D2 domain is believed to play a modulatory role. Here we report our analysis of the influence of the D2 domain on the catalytic activity and substrate specificity of the D1 domain using two Drosophila melanogaster RPTPs as a model system. Biochemical studies reveal contrasting roles for the D2 domain of Drosophila Leukocyte antigen Related (DLAR and Protein Tyrosine Phosphatase on Drosophila chromosome band 99A (PTP99A. While D2 lowers the catalytic activity of the D1 domain in DLAR, the D2 domain of PTP99A leads to an increase in the catalytic activity of its D1 domain. Substrate specificity, on the other hand, is cumulative, whereby the individual specificities of the D1 and D2 domains contribute to the substrate specificity of these two-domain enzymes. Molecular dynamics simulations on structural models of DLAR and PTP99A reveal a conformational rationale for the experimental observations. These studies reveal that concerted structural changes mediate inter-domain communication resulting in either inhibitory or activating effects of the membrane distal PTP domain on the catalytic activity of the membrane proximal PTP domain.

  15. Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin α5β1 and ERK-dependent signaling pathways.

    Directory of Open Access Journals (Sweden)

    Douglas N Clarke

    Full Text Available Perlecan Domain V (DV promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs following stroke. In this study, we define the specific mechanism of DV interaction with the α(5β(1 integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5β(1 and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction of DV with α(5β(1. Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1α. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV's induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC-neuronal co-culture system. Collectively, our findings expand our understanding of DV's mechanism of action on BECs, and further support its potential as a novel stroke therapy.

  16. Perlecan Domain V Induces VEGf Secretion in Brain Endothelial Cells through Integrin α5β1 and ERK-Dependent Signaling Pathways

    Science.gov (United States)

    Clarke, Douglas N.; Al Ahmad, Abraham; Lee, Boyeon; Parham, Christi; Auckland, Lisa; Fertala, Andrezj; Kahle, Michael; Shaw, Courtney S.; Roberts, Jill; Bix, Gregory J.

    2012-01-01

    Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α5β1 integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV’s angio-modulatory activity outside of the brain, binds poorly to α5β1 and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV’s DGR sequence as an important element for the interaction of DV with α5β1. Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1α. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV’s induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC-neuronal co-culture system. Collectively, our findings expand our understanding of DV’s mechanism of action on BECs, and further support its potential as a novel stroke therapy. PMID:23028886

  17. A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling.

    NARCIS (Netherlands)

    Nagpal, K.; Plantinga, T.S.; Wong, J.; Monks, B.G.; Gay, N.J.; Netea, M.G.; Fitzgerald, K.A.; Golenbock, D.

    2009-01-01

    The adapter protein MyD88 adapter-like (Mal), encoded by TIR-domain containing adapter protein (Tirap) (MIM 606252), is the most polymorphic of the five adapter proteins involved in Toll-like receptor signaling, harboring eight non-synonymous single nucleotide polymorphisms in its coding region. We

  18. Proximity friction reexamined

    International Nuclear Information System (INIS)

    Krappe, H.J.

    1989-01-01

    The contribution of inelastic excitations to radial and tangential friction form-factors in heavy-ion collisions is investigated in the frame-work of perturbation theory. The dependence of the form factors on the essential geometrical and level-density parameters of the scattering system is exhibited in a rather closed form. The conditions for the existence of time-local friction coefficients are discussed. Results are compared to form factors from other models, in particular the transfer-related proximity friction. For the radial friction coefficient the inelastic excitation mechanism seems to be the dominant contribution in peripheral collisions. (orig.)

  19. Proximal femoral fractures.

    Science.gov (United States)

    Webb, Lawrence X

    2002-01-01

    Fractures of the proximal femur include fractures of the head, neck, intertrochanteric, and subtrochanteric regions. Head fractures commonly accompany dislocations. Neck fractures and intertrochanteric fractures occur with greatest frequency in elderly patients with a low bone mineral density and are produced by low-energy mechanisms. Subtrochanteric fractures occur in a predominantly strong cortical osseous region which is exposed to large compressive stresses. Implants used to address these fractures must be able to accommodate significant loads while the fractures consolidate. Complications secondary to these injuries produce significant morbidity and include infection, nonunion, malunion, decubitus ulcers, fat emboli, deep venous thrombosis, pulmonary embolus, pneumonia, myocardial infarction, stroke, and death.

  20. Children's proximal societal conditions

    DEFF Research Database (Denmark)

    Stanek, Anja Hvidtfeldt

    2018-01-01

    that is above or outside the institutional setting or the children’s everyday life, but something that is represented through societal structures and actual persons participating (in political ways) within the institutional settings, in ways that has meaning to children’s possibilities to participate, learn...... and develop. Understanding school or kindergarten as (part of) the children’s proximal societal conditions for development and learning, means for instance that considerations about an inclusive agenda are no longer simply thoughts about the school – for economic reasons – having space for as many pupils...... as possible (schools for all). Such thoughts can be supplemented by reflections about which version of ‘the societal’ we wish to present our children with, and which version of ‘the societal’ we wish to set up as the condition for children’s participation and development. The point is to clarify or sharpen...

  1. PROXIMITY MANAGEMENT IN CRISIS CONDITIONS

    Directory of Open Access Journals (Sweden)

    Ion Dorin BUMBENECI

    2010-01-01

    Full Text Available The purpose of this study is to evaluate the level of assimilation for the terms "Proximity Management" and "Proximity Manager", both in the specialized literature and in practice. The study has two parts: the theoretical research of the two terms, and an evaluation of the use of Proximity management in 32 companies in Gorj, Romania. The object of the evaluation resides in 27 companies with less than 50 employees and 5 companies with more than 50 employees.

  2. Transverse and Longitudinal proximity effect

    Science.gov (United States)

    Jalan, Pryianka; Chand, Hum; Srianand, Raghunathan

    2018-04-01

    With close pairs (˜1.5arcmin) of quasars (QSOs), absorption in the spectra of a background quasar in the vicinity of a foreground quasar can be used to study the environment of the latter quasar at kpc-Mpc scales. For this we used a sample of 205 quasar pairs from the Sloan Digital Sky-Survey Data Release 12 (SDSS DR12) in the redshift range of 2.5 to 3.5 by studying their H I Ly-α absorption. We study the environment of QSOs both in the longitudinal as well as in the transverse direction by carrying out a statistical comparison of the Ly-α absorption lines in the quasar vicinity to that of the absorption lines caused by the inter-galactic medium (IGM). This comparison was done with IGM, matched in absorption redshift and signal-to-noise ratio (SNR) to that of the proximity region. In contrast to the measurements along the line-of-sight, the regions transverse to the quasars exhibit enhanced H I Ly-α absorption. This discrepancy can either be interpreted as due to an anisotropic emission from the quasars or as a consequence of their finite lifetime.

  3. The E3 ubiquitin ligase protein associated with Myc (Pam) regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling in vivo through N- and C-terminal domains.

    Science.gov (United States)

    Han, Sangyeul; Kim, Sun; Bahl, Samira; Li, Lin; Burande, Clara F; Smith, Nicole; James, Marianne; Beauchamp, Roberta L; Bhide, Pradeep; DiAntonio, Aaron; Ramesh, Vijaya

    2012-08-31

    Pam and its homologs (the PHR protein family) are large E3 ubiquitin ligases that function to regulate synapse formation and growth in mammals, zebrafish, Drosophila, and Caenorhabditis elegans. Phr1-deficient mouse models (Phr1(Δ8,9) and Phr1(Magellan), with deletions in the N-terminal putative guanine exchange factor region and the C-terminal ubiquitin ligase region, respectively) exhibit axon guidance/outgrowth defects and striking defects of major axon tracts in the CNS. Our earlier studies identified Pam to be associated with tuberous sclerosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapamycin (mTOR) signaling. Here, we examine the potential involvement of the TSC/mTOR complex 1(mTORC1) signaling pathway in Phr1-deficient mouse models. We observed attenuation of mTORC1 signaling in the brains of both Phr1(Δ8,9) and Phr1(Magellan) mouse models. Our results establish that Pam regulates TSC/mTOR signaling in vitro and in vivo through two distinct domains. To further address whether Pam regulates mTORC1 through two functionally independent domains, we undertook heterozygous mutant crossing between Phr1(Δ8,9) and Phr1(Magellan) mice to generate a compound heterozygous model to determine whether these two domains can complement each other. mTORC1 signaling was not attenuated in the brains of double mutants (Phr1(Δ8,9/Mag)), confirming that Pam displays dual regulation of the mTORC1 pathway through two functional domains. Our results also suggest that although dysregulation of mTORC1 signaling may be responsible for the corpus callosum defects, other neurodevelopmental defects observed with Phr1 deficiency are independent of mTORC1 signaling. The ubiquitin ligase complex containing Pam-Fbxo45 likely targets additional synaptic and axonal proteins, which may explain the overlapping neurodevelopmental defects observed in Phr1 and Fbxo45 deficiency.

  4. Domain analysis

    DEFF Research Database (Denmark)

    Hjørland, Birger

    2017-01-01

    The domain-analytic approach to knowledge organization (KO) (and to the broader field of library and information science, LIS) is outlined. The article reviews the discussions and proposals on the definition of domains, and provides an example of a domain-analytic study in the field of art studies....... Varieties of domain analysis as well as criticism and controversies are presented and discussed....

  5. The insulin and IGF1 receptor kinase domains are functional dimers in the activated state

    Science.gov (United States)

    Cabail, M. Zulema; Li, Shiqing; Lemmon, Eric; Bowen, Mark E.; Hubbard, Stevan R.; Miller, W. Todd

    2015-03-01

    The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.

  6. Proximal iliotibial band syndrome: case report

    Directory of Open Access Journals (Sweden)

    Guilherme Guadagnini Falotico

    2013-08-01

    Full Text Available OBJECTIVE: The overuse injuries in the hip joint occur commonly in sports practitioners and currently due to technical advances in diagnostic imaging, especially magnetic resonance imaging (MRI, are often misdiagnosed. Recently, a group of people were reported, all female, with pain and swelling in the pelvic region.T2-weighted MRI showed increased signal in the enthesis of the iliotibial band (ITB along the lower border of the iliac tubercle. We report a case of a 34 year old woman, non-professional runner, with pain at the iliac crest with no history of trauma and whose MRI was compatible with the proximal iliotibial band syndrome.

  7. Scintillation proximity assay

    International Nuclear Information System (INIS)

    Hart, H.

    1980-01-01

    In a method of immunological assay two different classes of particles which interact at short distances to produce characteristic detectable signals are employed in a modification of the usual latex fixation test. In one embodiment an aqueous suspension of antigen coated tritiated latex particles (LH) and antigen coated polystyrene scintillant particles (L*) is employed to assay antibody in the aqueous medium. The amount of (LH) (L*) dimer formation and higher order aggregation induced and therefore the concentration of antibody (or antigen) present which caused the aggregation can be determined by using standard liquid scintillation counting equipment. (author)

  8. A proximal point algorithm with generalized proximal distances to BEPs

    OpenAIRE

    Bento, G. C.; Neto, J. X. Cruz; Lopes, J. O.; Soares Jr, P. A.; Soubeyran, A.

    2014-01-01

    We consider a bilevel problem involving two monotone equilibrium bifunctions and we show that this problem can be solved by a proximal point method with generalized proximal distances. We propose a framework for the convergence analysis of the sequences generated by the algorithm. This class of problems is very interesting because it covers mathematical programs and optimization problems under equilibrium constraints. As an application, we consider the problem of the stability and change dyna...

  9. Fractures of the proximal humerus

    DEFF Research Database (Denmark)

    Brorson, Stig

    2013-01-01

    Fractures of the proximal humerus have been diagnosed and managed since the earliest known surgical texts. For more than four millennia the preferred treatment was forceful traction, closed reduction, and immobilization with linen soaked in combinations of oil, honey, alum, wine, or cerate......, classification of proximal humeral fractures remains a challenge for the conduct, reporting, and interpretation of clinical trials. The evidence for the benefits of surgery in complex fractures of the proximal humerus is weak. In three systematic reviews I studied the outcome after locking plate osteosynthesis...

  10. Seeing Beyond the Painting Surface with Terahertz Time-Domain Imaging (THz-TDI): a signal separation method for extracting images of buried individual layers in paintings

    DEFF Research Database (Denmark)

    Filtenborg, Troels Folke; Skou-Hansen, Jakob; Koch Dandolo, Corinna Ludovica

    2015-01-01

    and denoising methods used to resolve temporal features of THz reflected signals, they result impractical if applied to large images analysis. Therefore, we presented a simple, fast and effective method to separate single THz pulses of interest from the entire signal recorded at each spatial coordinate...

  11. Ligand binding by PDZ domains

    DEFF Research Database (Denmark)

    Chi, Celestine N.; Bach, Anders; Strømgaard, Kristian

    2012-01-01

    , for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well...... as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context....

  12. Extracellular Signal-Regulated Kinase 2 (ERK2) Phosphorylation Sites and Docking Domain on the Nuclear Pore Complex Protein Tpr Cooperatively Regulate ERK2-Tpr Interaction

    Czech Academy of Sciences Publication Activity Database

    Vomastek, Tomáš; Iwanicky, M. P.; Burack, W. R.; Tiwari, D.; Kumar, D.; Parsons, J. T.; Weber, M. J.; Nandicoori, V. K.

    2008-01-01

    Roč. 28, č. 22 (2008), s. 6954-6966 ISSN 0270-7306 R&D Projects: GA AV ČR IAA500200716 Institutional research plan: CEZ:AV0Z50200510 Keywords : erk * docking domain * cell growth Subject RIV: EE - Microbiology, Virology Impact factor: 5.942, year: 2008

  13. Concrete domains

    OpenAIRE

    Kahn, G.; Plotkin, G.D.

    1993-01-01

    This paper introduces the theory of a particular kind of computation domains called concrete domains. The purpose of this theory is to find a satisfactory framework for the notions of coroutine computation and sequentiality of evaluation.

  14. Domain Engineering

    Science.gov (United States)

    Bjørner, Dines

    Before software can be designed we must know its requirements. Before requirements can be expressed we must understand the domain. So it follows, from our dogma, that we must first establish precise descriptions of domains; then, from such descriptions, “derive” at least domain and interface requirements; and from those and machine requirements design the software, or, more generally, the computing systems.

  15. The fibronectin III-1 domain activates a PI3-Kinase/Akt signaling pathway leading to αvβ5 integrin activation and TRAIL resistance in human lung cancer cells

    International Nuclear Information System (INIS)

    Cho, Christina; Horzempa, Carol; Jones, David; McKeown-Longo, Paula J.

    2016-01-01

    Fibronectin is a mechanically sensitive protein which is organized in the extracellular matrix as a network of interacting fibrils. The lung tumor stroma is enriched for fibronectin which is thought to contribute to metastasis and drug resistance. Fibronectin is an elastic, multi-modular protein made up of individually folded domains, some of which can stretch in response to increased mechanical tension. Very little is known about the relationship of fibronectin’s unfolded domains to lung cancer resistance to chemotherapy. In the present study, we evaluated the impact of unfolding the first Type III domain of fibronectin (FnIII-1c) on TNF-related apoptosis inducing ligand (TRAIL) resistance. NCI-H460 non-small cell lung cancer cells were treated with FnIII-1c then assessed for TRAIL-induced apoptosis. Subsequent analysis of FnIII-1c-mediated signaling pathways was also completed. Human non-small cell lung cancer tissue sections were assessed for the expression of vitronectin by immunohistochemistry. FnIII-1c inhibited TRAIL-induced activation of caspase 8 and subsequent apoptosis in NCI-H460 lung cancer cells. FnIII-1c treatment was associated with the activation of the phosphatidylinositol-3-kinase/alpha serine/threonine kinase (PI3K/Akt) pathway and the αvβ5 integrin receptor for vitronectin, both of which were required for TRAIL resistance. Immunohistochemical staining of sections from non-small cell lung cancers showed that vitronectin was localized around blood vessels and in the tumor-stroma interface. Unfolding of Type III domains within the fibronectin matrix may promote TRAIL resistance through the activation of a PI3K/Akt/αvβ5 signaling axis and point to a novel mechanism by which changes in secondary structure of fibronectin contribute to cancer cell resistance to apoptosis

  16. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading

    DEFF Research Database (Denmark)

    Iba, K; Albrechtsen, R; Gilpin, B

    2000-01-01

    The ADAMs (a disintegrin and metalloprotease) family of proteins is involved in a variety of cellular interactions, including cell adhesion and ecto- domain shedding. Here we show that ADAM 12 binds to cell surface syndecans. Three forms of recombinant ADAM 12 were used in these experiments......-dependent manner attach to ADAM 12 via members of the syndecan family. After binding to syndecans, mesenchymal cells spread and form focal adhesions and actin stress fibers. Integrin beta1 was responsible for cell spreading because function-blocking monoclonal antibodies completely inhibited cell spreading......, and chondroblasts lacking beta1 integrin attached but did not spread. These data suggest that mesenchymal cells use syndecans as the initial receptor for the ADAM 12 cysteine-rich domain-mediated cell adhesion, and then the beta1 integrin to induce cell spreading. Interestingly, carcinoma cells attached but did...

  17. Signal to Noise Ratio (SNR Enhancement Comparison of Impulse-, Coding- and Novel Linear-Frequency-Chirp-Based Optical Time Domain Reflectometry (OTDR for Passive Optical Network (PON Monitoring Based on Unique Combinations of Wavelength Selective Mirrors

    Directory of Open Access Journals (Sweden)

    Christopher M. Bentz

    2014-03-01

    Full Text Available We compare optical time domain reflectometry (OTDR techniques based on conventional single impulse, coding and linear frequency chirps concerning their signal to noise ratio (SNR enhancements by measurements in a passive optical network (PON with a maximum one-way attenuation of 36.6 dB. A total of six subscribers, each represented by a unique mirror pair with narrow reflection bandwidths, are installed within a distance of 14 m. The spatial resolution of the OTDR set-up is 3.0 m.

  18. Preliminary study on leadership proximity

    Directory of Open Access Journals (Sweden)

    Ghinea Valentina Mihaela

    2017-07-01

    Full Text Available In general, it is agreed that effective leadership requires a certain degree of proximity, either physical or mental, which enables leaders to maintain control over their followers and communicate their vision. Although we agree with the leadership proximity principles which states that leaders are able to efficiently serve only those people with whom they interact frequently, in this article we focus instead on the disadvantages of being too close and the way in which close proximity can actually hurt the effectiveness of leadership. The main effects that we discuss regard the way in which proximity and familiarity allow followers to see the weaknesses and faults of the leader much more easily and thus diminish the leader’s heroic aura, and the emotional bias that results from a leader being too familiar with his followers which will impede the process of rational decision making. As a result, we argue that there exists a functional proximity which allows the leader the necessary space in which to perform effective identity work and to hide the backstage aspects of leadership, while also allowing him an emotional buffer zone which will enable him to maintain the ability to see clearly and make rational decisions.

  19. Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity.

    Science.gov (United States)

    Minus, Matthew B; Liu, Wei; Vohidov, Farrukh; Kasembeli, Moses M; Long, Xin; Krueger, Michael J; Stevens, Alexandra; Kolosov, Mikhail I; Tweardy, David J; Sison, Edward Allan R; Redell, Michele S; Ball, Zachary T

    2015-10-26

    Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Crystal Structure of the FERM Domain of Focal Adhesion Kinase

    International Nuclear Information System (INIS)

    Ceccarelli, D.; Song, H.; Poy, F.; Schaller, M.; Eck, M.

    2006-01-01

    Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. Through phosphorylation of proteins assembled at the cytoplasmic tails of integrins, FAK promotes signaling events that modulate cellular growth, survival, and migration. The amino-terminal region of FAK contains a region of sequence homology with band 4.1 and ezrin/radixin/moesin (ERM) proteins termed a FERM domain. FERM domains are found in a variety of signaling and cytoskeletal proteins and are thought to mediate intermolecular interactions with partner proteins and phospholipids at the plasma membrane and intramolecular regulatory interactions. Here we report two crystal structures of an NH2-terminal fragment of avian FAK containing the FERM domain and a portion of the regulatory linker that connects the FERM and kinase domains. The tertiary folds of the three subdomains (F1, F2, and F3) are similar to those of known FERM structures despite low sequence conservation. Differences in the sequence and relative orientation of the F3 subdomain alters the nature of the interdomain interface, and the phosphoinositide binding site found in ERM family FERM domains is not present in FAK. A putative protein interaction site on the F3 lobe is masked by the proximal region of the linker. Additionally, in one structure the adjacent Src SH3 and SH2 binding sites in the linker associate with the surfaces of the F3 and F1 lobes, respectively. These structural features suggest the possibility that protein interactions of the FAK FERM domain can be regulated by binding of Src kinases to the linker segment

  1. Three domains of SLP-76 are required for its optimal function in a T cell line.

    Science.gov (United States)

    Musci, M A; Motto, D G; Ross, S E; Fang, N; Koretzky, G A

    1997-08-15

    We and others have shown that overexpression of SLP-76 augments TCR-stimulated IL-2 promoter activity in the Jurkat T cell line. In this report we investigate the signaling mechanisms through which SLP-76 mediates its effect on T cell activation. We show that overexpressed SLP-76 acts downstream of TCR-stimulated protein tyrosine kinases, but does not affect calcium signaling. Overexpression of SLP-76 does, however, augment TCR stimulation of both ERK (extracellular signal-regulated kinase) activity and a reporter construct driven by activating protein-1 binding sites. Structure/function analysis reveals that three distinct regions of SLP-76, each important for protein associations, are required for augmentation of TCR-induced nuclear factor-AT activity. These data suggest that SLP-76 functions as an adapter molecule that requires three unique domains to link proximal TCR signals in T cells.

  2. The Asia 2 specific signal peptide region and other domains in fusion protein genes characterized Asia 1 and Asia 2 canine distemper viruses

    Science.gov (United States)

    Sultan, Serageldeen; Charoenvisal, Nataya; Lan, Nguyen Thi; Yamaguchi, Ryoji; Maeda, Ken; Kai, Kazushige

    2009-01-01

    Background Although the presence of Asia 2 group of canine distemper virus (CDV) was known by the sequencing and phylogenetic analysis of hemagglutinin (H) gene, the fusion (F) protein gene sequence of Asia 2 group had not been identified. So, the sequence analysis of F gene was carried out to elucidate the genotypic varaitons among Asian isolates. Results The phylogenetic analysis of F and H gene sequences from fourteen CDV isolates obtained from diseased dogs in Japan and Thailand indicated that the F genes had a new initiation codon and extra 27 nucleotides upstream of the usual open reading frame (ORF) and the F proteins had extra 9 amino acids at the N-terminal position only in Asia 2 isolates. On the contrary, the Asia 1 isolates had three extra putative N-glycosylation sites (two sites in the signal peptide region and one site in the F1 region) except for two strains of Th12 and Ac96I (two sites in signal peptide region) adding to four putative N-glycosylation sites that were conserved among all Asian isolates and Onderstepoort strain. In addition to this difference in N-glycosylation sites, the signal peptide region had a great diversity between Asia 1 and Asia 2 isolates. Also, characteristic amino acids were detected for some strains. Conclusion Asia 2 isolates were distinguished from other CDV lineages by the extra 27 nucleotide sequence. The signal peptide region of F gene gives a remarkable differentiation between Asia 1 and Asia 2 isolates. Strains Th12 and Ac96I were differentiated from other Asia 1 strains by the F protein glycosylation sites. PMID:19807927

  3. Glial loss of the metallo β-lactamase domain containing protein, SWIP-10, induces age- and glutamate-signaling dependent, dopamine neuron degeneration.

    Directory of Open Access Journals (Sweden)

    Chelsea L Gibson

    2018-03-01

    Full Text Available Across phylogeny, glutamate (Glu signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson's disease, where theories suggest that excitotoxic insults may accelerate a naturally occurring process of dopamine (DA neuron degeneration. In C. elegans, mutation of the glial expressed gene, swip-10, results in Glu-dependent DA neuron hyperexcitation that leads to elevated DA release, triggering DA signaling-dependent motor paralysis. Here, we demonstrate that swip-10 mutations induce premature and progressive DA neuron degeneration, with light and electron microscopy studies demonstrating the presence of dystrophic dendritic processes, as well as shrunken and/or missing cell soma. As with paralysis, DA neuron degeneration in swip-10 mutants is rescued by glial-specific, but not DA neuron-specific expression of wildtype swip-10, consistent with a cell non-autonomous mechanism. Genetic studies implicate the vesicular Glu transporter VGLU-3 and the cystine/Glu exchanger homolog AAT-1 as potential sources of Glu signaling supporting DA neuron degeneration. Degeneration can be significantly suppressed by mutations in the Ca2+ permeable Glu receptors, nmr-2 and glr-1, in genes that support intracellular Ca2+ signaling and Ca2+-dependent proteolysis, as well as genes involved in apoptotic cell death. Our studies suggest that Glu stimulation of nematode DA neurons in early larval stages, without the protective actions of SWIP-10, contributes to insults that ultimately drive DA neuron degeneration. The swip-10 model may provide an efficient platform for the identification of molecular mechanisms that enhance risk for Parkinson's disease and/or the identification of agents that can limit neurodegenerative disease progression.

  4. The EAL domain protein YciR acts as a trigger enzyme in a c-di-GMP signalling cascade in E. coli biofilm control

    Science.gov (United States)

    Lindenberg, Sandra; Klauck, Gisela; Pesavento, Christina; Klauck, Eberhard; Hengge, Regine

    2013-01-01

    C-di-GMP—which is produced by diguanylate cyclases (DGC) and degraded by specific phosphodiesterases (PDEs)—is a ubiquitous second messenger in bacterial biofilm formation. In Escherichia coli, several DGCs (YegE, YdaM) and PDEs (YhjH, YciR) and the MerR-like transcription factor MlrA regulate the transcription of csgD, which encodes a biofilm regulator essential for producing amyloid curli fibres of the biofilm matrix. Here, we demonstrate that this system operates as a signalling cascade, in which c-di-GMP controlled by the DGC/PDE pair YegE/YhjH (module I) regulates the activity of the YdaM/YciR pair (module II). Via multiple direct interactions, the two module II proteins form a signalling complex with MlrA. YciR acts as a connector between modules I and II and functions as a trigger enzyme: its direct inhibition of the DGC YdaM is relieved when it binds and degrades c-di-GMP generated by module I. As a consequence, YdaM then generates c-di-GMP and—by direct and specific interaction—activates MlrA to stimulate csgD transcription. Trigger enzymes may represent a general principle in local c-di-GMP signalling. PMID:23708798

  5. Identification of avascular necrosis in the dysplastic proximal femoral epiphysis

    International Nuclear Information System (INIS)

    Mandell, G.A.; Harcke, H.T.; MacKenzie, W.G.; Bassett, G.S.; Scott, C.I. Jr.; Wills, J.S.

    1989-01-01

    Bilateral radiographic irregularities and deformities of the proximal femoral epiphyses are features of both multiple epiphyseal dysplasia and bilateral idiopathic avascular necrosis. In the past these entities have been difficult to differentiate. This report documents radiographically the occurrence of avascular necrosis in 10 patients with multiple epiphyseal dysplasia by recognizing the superimposition of sclerosis and subchondral fissuring on pre-existing symmetrically irregular proximal femoral ossification centers. Scintigraphic (photopenia) or magnetic resonance (loss of signal) criteria of avascular necrosis confirm its added presence and help to establish an imaging scheme to identify avascular necrosis superimposed on multiple epiphyseal dysplasia. (orig.)

  6. Identification of avascular necrosis in the dysplastic proximal femoral epiphysis

    Energy Technology Data Exchange (ETDEWEB)

    Mandell, G A; Harcke, H T [Alfred I. duPont Inst., Wilmington, DE (USA). Dept. of Medical Imaging; MacKenzie, W G; Bassett, G S [Alfred I. duPont Inst., Wilmington, DE (USA). Dept. of Orthopaedics; Scott, Jr, C I [Alfred I. duPont Inst., Wilmington, DE (USA). Dept. of Genetics; Wills, J S [Medical Center of Delaware, Newark, DE (USA). Dept. of Radiology

    1989-07-01

    Bilateral radiographic irregularities and deformities of the proximal femoral epiphyses are features of both multiple epiphyseal dysplasia and bilateral idiopathic avascular necrosis. In the past these entities have been difficult to differentiate. This report documents radiographically the occurrence of avascular necrosis in 10 patients with multiple epiphyseal dysplasia by recognizing the superimposition of sclerosis and subchondral fissuring on pre-existing symmetrically irregular proximal femoral ossification centers. Scintigraphic (photopenia) or magnetic resonance (loss of signal) criteria of avascular necrosis confirm its added presence and help to establish an imaging scheme to identify avascular necrosis superimposed on multiple epiphyseal dysplasia. (orig.).

  7. Correction of Misclassifications Using a Proximity-Based Estimation Method

    Directory of Open Access Journals (Sweden)

    Shmulevich Ilya

    2004-01-01

    Full Text Available An estimation method for correcting misclassifications in signal and image processing is presented. The method is based on the use of context-based (temporal or spatial information in a sliding-window fashion. The classes can be purely nominal, that is, an ordering of the classes is not required. The method employs nonlinear operations based on class proximities defined by a proximity matrix. Two case studies are presented. In the first, the proposed method is applied to one-dimensional signals for processing data that are obtained by a musical key-finding algorithm. In the second, the estimation method is applied to two-dimensional signals for correction of misclassifications in images. In the first case study, the proximity matrix employed by the estimation method follows directly from music perception studies, whereas in the second case study, the optimal proximity matrix is obtained with genetic algorithms as the learning rule in a training-based optimization framework. Simulation results are presented in both case studies and the degree of improvement in classification accuracy that is obtained by the proposed method is assessed statistically using Kappa analysis.

  8. Coordination and redox state-dependent structural changes of the heme-based oxygen sensor AfGcHK associated with intraprotein signal transduction.

    Science.gov (United States)

    Stranava, Martin; Man, Petr; Skálová, Tereza; Kolenko, Petr; Blaha, Jan; Fojtikova, Veronika; Martínek, Václav; Dohnálek, Jan; Lengalova, Alzbeta; Rosůlek, Michal; Shimizu, Toru; Martínková, Markéta

    2017-12-22

    The heme-based oxygen sensor histidine kinase Af GcHK is part of a two-component signal transduction system in bacteria. O 2 binding to the Fe(II) heme complex of its N-terminal globin domain strongly stimulates autophosphorylation at His 183 in its C-terminal kinase domain. The 6-coordinate heme Fe(III)-OH - and -CN - complexes of Af GcHK are also active, but the 5-coordinate heme Fe(II) complex and the heme-free apo-form are inactive. Here, we determined the crystal structures of the isolated dimeric globin domains of the active Fe(III)-CN - and inactive 5-coordinate Fe(II) forms, revealing striking structural differences on the heme-proximal side of the globin domain. Using hydrogen/deuterium exchange coupled with mass spectrometry to characterize the conformations of the active and inactive forms of full-length Af GcHK in solution, we investigated the intramolecular signal transduction mechanisms. Major differences between the active and inactive forms were observed on the heme-proximal side (helix H5), at the dimerization interface (helices H6 and H7 and loop L7) of the globin domain and in the ATP-binding site (helices H9 and H11) of the kinase domain. Moreover, separation of the sensor and kinase domains, which deactivates catalysis, increased the solvent exposure of the globin domain-dimerization interface (helix H6) as well as the flexibility and solvent exposure of helix H11. Together, these results suggest that structural changes at the heme-proximal side, the globin domain-dimerization interface, and the ATP-binding site are important in the signal transduction mechanism of Af GcHK. We conclude that Af GcHK functions as an ensemble of molecules sampling at least two conformational states. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Crystallization and preliminary crystal structure analysis of the ligand-binding domain of PqsR (MvfR), the Pseudomonas quinolone signal (PQS) responsive quorum-sensing transcription factor of Pseudomonas aeruginosa

    International Nuclear Information System (INIS)

    Xu, Ningna; Yu, Shen; Moniot, Sébastien; Weyand, Michael; Blankenfeldt, Wulf

    2012-01-01

    The ligand-binding domain of the transcription factor PqsR from P. aeruginosa has been crystallized and initial phases have been obtained using SAD data from seleno-l-methionine-labelled crystals. The opportunistic bacterial pathogen Pseudomonas aeruginosa employs three transcriptional regulators, LasR, RhlR and PqsR, to control the transcription of a large subset of its genes in a cell-density-dependent process known as quorum sensing. Here, the recombinant production, crystallization and structure solution of the ligand-binding domain of PqsR (MvfR), the LysR-type transcription factor that responds to the Pseudomonas quinolone signal (PQS), a quinolone-based quorum-sensing signal that is unique to P. aeruginosa and possibly a small number of other bacteria, is reported. PqsR regulates the expression of many virulence genes and may therefore be an interesting drug target. The ligand-binding domain (residues 91–319) was produced as a fusion with SUMO, and hexagonal-shaped crystals of purified PqsR-91–319 were obtained using the vapour-diffusion method. Crystallization in the presence of a PQS precursor allowed data collection to 3.25 Å resolution on a synchrotron beamline, and initial phases have been obtained using single-wavelength anomalous diffraction data from seleno-l-methionine-labelled crystals, revealing the space group to be P6 5 22, with unit-cell parameters a = b = 116–120, c = 115–117 Å

  10. 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.

  11. ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) regulates jasmonic acid and abscisic acid biosynthesis and signaling through binding to a novel cis-element.

    Science.gov (United States)

    Chen, Hsing-Yu; Hsieh, En-Jung; Cheng, Mei-Chun; Chen, Chien-Yu; Hwang, Shih-Ying; Lin, Tsan-Piao

    2016-07-01

    ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) of Arabidopsis thaliana is an AP2/ERF domain transcription factor that regulates jasmonate (JA) biosynthesis and is induced by methyl JA treatment. The regulatory mechanism of ORA47 remains unclear. ORA47 is shown to bind to the cis-element (NC/GT)CGNCCA, which is referred to as the O-box, in the promoter of ABI2. We proposed that ORA47 acts as a connection between ABA INSENSITIVE1 (ABI1) and ABI2 and mediates an ABI1-ORA47-ABI2 positive feedback loop. PORA47:ORA47-GFP transgenic plants were used in a chromatin immunoprecipitation (ChIP) assay to show that ORA47 participates in the biosynthesis and/or signaling pathways of nine phytohormones. Specifically, many abscisic acid (ABA) and JA biosynthesis and signaling genes were direct targets of ORA47 under stress conditions. The JA content of the P35S:ORA47-GR lines was highly induced under wounding and moderately induced under water stress relative to that of the wild-type plants. The wounding treatment moderately increased ABA accumulation in the transgenic lines, whereas the water stress treatment repressed the ABA content. ORA47 is proposed to play a role in the biosynthesis of JA and ABA and in regulating the biosynthesis and/or signaling of a suite of phytohormone genes when plants are subjected to wounding and water stress. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  12. High-throughput determination of RNA structure by proximity ligation.

    Science.gov (United States)

    Ramani, Vijay; Qiu, Ruolan; Shendure, Jay

    2015-09-01

    We present an unbiased method to globally resolve RNA structures through pairwise contact measurements between interacting regions. RNA proximity ligation (RPL) uses proximity ligation of native RNA followed by deep sequencing to yield chimeric reads with ligation junctions in the vicinity of structurally proximate bases. We apply RPL in both baker's yeast (Saccharomyces cerevisiae) and human cells and generate contact probability maps for ribosomal and other abundant RNAs, including yeast snoRNAs, the RNA subunit of the signal recognition particle and the yeast U2 spliceosomal RNA homolog. RPL measurements correlate with established secondary structures for these RNA molecules, including stem-loop structures and long-range pseudoknots. We anticipate that RPL will complement the current repertoire of computational and experimental approaches in enabling the high-throughput determination of secondary and tertiary RNA structures.

  13. A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5α important for NF-κB/AP-1 signaling and HIV-1 restriction

    Directory of Open Access Journals (Sweden)

    Marie-Édith Nepveu-Traversy

    2016-01-01

    Full Text Available TRIM5α from the rhesus macaque (TRIM5αRh is a restriction factor that shows strong activity against HIV-1. TRIM5αRh binds specifically to HIV-1 capsid (CA through its B30.2/PRYSPRY domain shortly after entry of the virus into the cytoplasm. Recently, three putative SUMO interacting motifs (SIMs have been identified in the PRYSPRY domain of human and macaque TRIM5α. However, structural modeling of this domain suggested that two of them were buried in the hydrophobic core of the protein, implying that interaction with SUMO was implausible, while the third one was not relevant to restriction. In light of these results, we re-analyzed the TRIM5αRh PRYSPRY sequence and identified an additional putative SIM (435VIIC438 which we named SIM4. This motif is exposed at the surface of the PRYSPRY domain, allowing potential interactions with SUMO or SUMOylated proteins. Introducing a double mutation in SIM4 (V435K, I436K did not alter stability, unlike mutations in SIM1. SIM4-mutated TRIM5αRh failed to bind HIV-1CA and lost the ability to restrict this virus. Accordingly, SIM4 undergoes significant variation among primates and substituting this motif with naturally occurring SIM4 variants affected HIV-1 restriction by TRIM5αRh, suggesting a direct role in capsid recognition. Interestingly, SIM4-mutated TRIM5αRh also failed to activate NF-κB and AP-1-mediated transcription. Although there is no direct evidence that SIM4 is involved in direct interaction with SUMO or a SUMOylated protein, mutating this motif strongly reduced co-localization of TRIM5αRh with SUMO-1 and with PML, a SUMOylated nuclear protein. In conclusion, this new putative SIM is crucial for both direct interaction with incoming capsids and for NF-κB/AP-1 signaling. We speculate that the latter function is mediated by interactions of SIM4 with a SUMOylated protein involved in the NF-κB/AP-1 signaling pathways.

  14. Electromagnetic properties of proximity systems

    Science.gov (United States)

    Kresin, Vladimir Z.

    1985-07-01

    Magnetic screening in the proximity system Sα-Mβ, where Mβ is a normal metal N, semiconductor (semimetal), or a superconductor, is studied. Main attention is paid to the low-temperature region where nonlocality plays an important role. The thermodynamic Green's-function method is employed in order to describe the behavior of the proximity system in an external field. The temperature and thickness dependences of the penetration depth λ are obtained. The dependence λ(T) differs in a striking way from the dependence in usual superconductors. The strong-coupling effect is taken into account. A special case of screening in a superconducting film backed by a size-quantizing semimetal film is considered. The results obtained are in good agreement with experimental data.

  15. Electromagnetic properties of proximity systems

    International Nuclear Information System (INIS)

    Kresin, V.Z.

    1985-01-01

    Magnetic screening in the proximity system S/sub α/-M/sub β/, where M/sub β/ is a normal metal N, semiconductor (semimetal), or a superconductor, is studied. Main attention is paid to the low-temperature region where nonlocality plays an important role. The thermodynamic Green's-function method is employed in order to describe the behavior of the proximity system in an external field. The temperature and thickness dependences of the penetration depth lambda are obtained. The dependence lambda(T) differs in a striking way from the dependence in usual superconductors. The strong-coupling effect is taken into account. A special case of screening in a superconducting film backed by a size-quantizing semimetal film is considered. The results obtained are in good agreement with experimental data

  16. Proximity effect at Millikelvin temperatures

    International Nuclear Information System (INIS)

    Mota, A.C.

    1986-01-01

    Proximity effects have been studied extensively for the past 25 years. Typically, they are in films several thousand angstroms thick at temperatures not so far below T/sub CNS/, the transition temperature of the NS system. Interesting is, however, the proximity effect at temperatures much lower than T/sub CNS/. In this case, the Cooper-pair amplitudes are not small and very long pair penetration lengths into the normal metal can be expected. Thus, we have observed pair penetration lengths. For these investigations very suitable specimens are commercial wires of one filament of NbTi or Nb embedded in a copper matrix. The reasons are the high transmission coefficient at the interface between the copper and the superconductor and the fact that the copper in these commercial wires is rather clean with electron free paths between 5 to 10 μm long. In this paper, the magnetic properties of thick proximity systems in the range of temperatures between T/sub CNS/ and 5 x 10/sup -4/ T/sub CNS/ in both low and high magnetic fields are discussed

  17. Structural interactions between lipids, water and S1-S4 voltage-sensing domains.

    Science.gov (United States)

    Krepkiy, Dmitriy; Gawrisch, Klaus; Swartz, Kenton J

    2012-11-02

    Membrane proteins serve crucial signaling and transport functions, yet relatively little is known about their structures in membrane environments or how lipids interact with these proteins. For voltage-activated ion channels, X-ray structures suggest that the mobile voltage-sensing S4 helix would be exposed to the membrane, and functional studies reveal that lipid modification can profoundly alter channel activity. Here, we use solid-state NMR to investigate structural interactions of lipids and water with S1-S4 voltage-sensing domains and to explore whether lipids influence the structure of the protein. Our results demonstrate that S1-S4 domains exhibit extensive interactions with lipids and that these domains are heavily hydrated when embedded in a membrane. We also find evidence for preferential interactions of anionic lipids with S1-S4 domains and that these interactions have lifetimes on the timescale of ≤ 10(-3)s. Arg residues within S1-S4 domains are well hydrated and are positioned in close proximity to lipids, exhibiting local interactions with both lipid headgroups and acyl chains. Comparative studies with a positively charged lipid lacking a phosphodiester group reveal that this lipid modification has only modest effects on the structure and hydration of S1-S4 domains. Taken together, our results demonstrate that Arg residues in S1-S4 voltage-sensing domains reside in close proximity to the hydrophobic interior of the membrane yet are well hydrated, a requirement for carrying charge and driving protein motions in response to changes in membrane voltage. Published by Elsevier Ltd.

  18. Response of SCP-2L domain of human MFE-2 to ligand removal: binding site closure and burial of peroxisomal targeting signal.

    Science.gov (United States)

    Lensink, M F; Haapalainen, A M; Hiltunen, J K; Glumoff, T; Juffer, A H

    2002-10-11

    In the study of the structure and function relationship of human MFE-2, we have investigated the dynamics of human MFE-2SCP-2L (hSCP-2L) and its response to ligand removal. A comparison was made with homologous rabbit SCP-2. Breathing and a closing motion are found, identifiable with an adjustment in size and a closing off of the binding pocket. Crucial residues for structural integrity have been identified. Particularly mobile areas of the protein are loop 1 that is connecting helices A and C in space, and helix D, next to the entrance of the pocket. In hSCP-2L, the binding pocket gets occupied by Phe93, which is making a tight hydrophobic contact with Trp36. In addition, it is found that the C-terminal peroxisomal targeting signal (PTS1) that is solvent exposed in the complexed structure becomes buried when no ligand is present. Moreover, an anti-correlation exists between burial of PTS1 and the size of the binding pocket. The results are in accordance with plant nsLTPs, where a similar accommodation of binding pocket size was found after ligand binding/removal. Furthermore, the calculations support the suggestion of a ligand-assisted targeting mechanism.

  19. Equilibrium properties of proximity effect

    International Nuclear Information System (INIS)

    Esteve, D.; Pothier, H.; Gueron, S.; Birge, N.O.; Devoret, M.

    1996-01-01

    The proximity effect in diffusive normal-superconducting (NS) nano-structures is described by the Usadel equations for the electron pair correlations. We show that these equations obey a variational principle with a potential which generalizes the Ginzburg-Landau energy functional. We discuss simple examples of NS circuits using this formalism. In order to test the theoretical predictions of the Usadel equations, we have measured the density of states as a function of energy on a long N wire in contact with a S wire at one end, at different distances from the NS interface. (authors)

  20. Equilibrium properties of proximity effect

    Energy Technology Data Exchange (ETDEWEB)

    Esteve, D.; Pothier, H.; Gueron, S.; Birge, N.O.; Devoret, M.

    1996-12-31

    The proximity effect in diffusive normal-superconducting (NS) nano-structures is described by the Usadel equations for the electron pair correlations. We show that these equations obey a variational principle with a potential which generalizes the Ginzburg-Landau energy functional. We discuss simple examples of NS circuits using this formalism. In order to test the theoretical predictions of the Usadel equations, we have measured the density of states as a function of energy on a long N wire in contact with a S wire at one end, at different distances from the NS interface. (authors). 12 refs.

  1. Calibration of TAMA300 in time domain

    International Nuclear Information System (INIS)

    Telada, Souichi; Tatsumi, Daisuke; Akutsu, Tomomi; Ando, Masaki; Kanda, Nobuyuki

    2005-01-01

    We could reconstruct the strain of gravitational wave signals from acquired data in the time domain by using the infinite impulse response filter technique in TAMA300. We would like to analyse the waveform in the time domain for burst-like signal, merger phase waveform of binary neutron stars, and so on. We established the way to make a continuous time-series gravitational wave strain signal. We compared the time-domain reconstruction with the Fourier-space reconstruction. Both coincided within 3% in the observation range. We could also produce the voltage signal which would be recorded by the data-acquisition system from a simulated gravitational wave. This is useful for some analyses of simulations and signal injections. We could extract the waveform of the hardware injection signal in an observational run in the time domain. The extracted waveform was similar to the injection signal

  2. Domain crossing

    DEFF Research Database (Denmark)

    Schraefel, M. C.; Rouncefield, Mark; Kellogg, Wendy

    2012-01-01

    In CSCW, how much do we need to know about another domain/culture before we observe, intersect and intervene with designs. What optimally would that other culture need to know about us? Is this a “how long is a piece of string” question, or an inquiry where we can consider a variety of contexts a...

  3. The YARHG domain: an extracellular domain in search of a function.

    Directory of Open Access Journals (Sweden)

    Penny Coggill

    Full Text Available We have identified a new bacterial protein domain that we hypothesise binds to peptidoglycan. This domain is called the YARHG domain after the most highly conserved sequence-segment. The domain is found in the extracellular space and is likely to be composed of four alpha-helices. The domain is found associated with protein kinase domains, suggesting it is associated with signalling in some bacteria. The domain is also found associated with three different families of peptidases. The large number of different domains that are found associated with YARHG suggests that it is a useful functional module that nature has recombined multiple times.

  4. Protein domain organisation: adding order

    Directory of Open Access Journals (Sweden)

    Kummerfeld Sarah K

    2009-01-01

    degree of clustering and more domain pairs in forward and reverse orientation in different proteins relative to random graphs with identical degree distributions. While these features were statistically over-represented, they are still fairly rare. Looking in detail at the proteins involved, we found strong functional relationships within each cluster. In addition, the domains tended to be involved in protein-protein interaction and are able to function as independent structural units. A particularly striking example was the human Jak-STAT signalling pathway which makes use of a set of domains in a range of orders and orientations to provide nuanced signaling functionality. This illustrated the importance of functional and structural constraints (or lack thereof on domain organisation.

  5. Protein domain organisation: adding order.

    Science.gov (United States)

    Kummerfeld, Sarah K; Teichmann, Sarah A

    2009-01-29

    reverse orientation in different proteins relative to random graphs with identical degree distributions. While these features were statistically over-represented, they are still fairly rare. Looking in detail at the proteins involved, we found strong functional relationships within each cluster. In addition, the domains tended to be involved in protein-protein interaction and are able to function as independent structural units. A particularly striking example was the human Jak-STAT signalling pathway which makes use of a set of domains in a range of orders and orientations to provide nuanced signaling functionality. This illustrated the importance of functional and structural constraints (or lack thereof) on domain organisation.

  6. Realities of proximity facility siting

    International Nuclear Information System (INIS)

    DeMott, D.L.

    1981-01-01

    Numerous commercial nuclear power plant sites have 2 to 3 reactors located together, and a group of Facilities with capabilities for fuel fabrication, a nuclear reactor, a storage area for spent fuel, and a maintenance area for contaminated equipment and radioactive waste storage are being designed and constructed in the US. The proximity of these facilities to each other provides that the ordinary flow of materials remain within a limited area. Interactions between the various facilities include shared resources such as communication, fire protection, security, medical services, transportation, water, electrical, personnel, emergency planning, transport of hazardous material between facilities, and common safety and radiological requirements between facilities. This paper will explore the advantages and disadvantages of multiple facilities at one site. Problem areas are identified, and recommendations for planning and coordination are discussed

  7. Trusted Domain

    DEFF Research Database (Denmark)

    Hjorth, Theis Solberg; Torbensen, Rune

    2012-01-01

    remote access via IP-based devices such as smartphones. The Trusted Domain platform fits existing legacy technologies by managing their interoperability and access controls, and it seeks to avoid the security issues of relying on third-party servers outside the home. It is a distributed system...... of wireless standards, limited resources of embedded systems, etc. Taking these challenges into account, we present a Trusted Domain home automation platform, which dynamically and securely connects heterogeneous networks of Short-Range Wireless devices via simple non-expert user. interactions, and allows......In the digital age of home automation and with the proliferation of mobile Internet access, the intelligent home and its devices should be accessible at any time from anywhere. There are many challenges such as security, privacy, ease of configuration, incompatible legacy devices, a wealth...

  8. 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.

  9. comparative proximate composition and antioxidant vitamins

    African Journals Online (AJOL)

    DR. AMINU

    Keywords: Comparative, proximate composition, antioxidant vitamins, honey. INTRODUCTION ... solution of inverted sugars and complex mixture of other saccharides ... enzymatic browning in apple slices and grape juice. (Khan, 1985).

  10. Proximate, Mineral and Phytochemical Composition of Dioscorea ...

    African Journals Online (AJOL)

    ADOWIE PERE

    Keywords: Dioscorea dumetorum, proximate composition, mineral analysis, phytochemical screening ... were analyzed using atomic absorption ... determined using a Hack Dr/200 Spectrophotometer. ... Lead Acetate. +. +. + .... cosmetics.

  11. Proximate composition and antinutrient content of pumpkin ...

    African Journals Online (AJOL)

    Proximate composition and antinutrient content of pumpkin ( Cucurbita pepo ) and sorghum ( Sorghum bicolor ) flour blends fermented with Lactobacillus plantarum , Aspergillus niger and Bacillus subtilis.

  12. Mapping the signal peptide binding and oligomer contact sites of the core subunit of the pea twin arginine protein translocase.

    Science.gov (United States)

    Ma, Xianyue; Cline, Kenneth

    2013-03-01

    Twin arginine translocation (Tat) systems of thylakoid and bacterial membranes transport folded proteins using the proton gradient as the sole energy source. Tat substrates have hydrophobic signal peptides with an essential twin arginine (RR) recognition motif. The multispanning cpTatC plays a central role in Tat operation: It binds the signal peptide, directs translocase assembly, and may facilitate translocation. An in vitro assay with pea (Pisum sativum) chloroplasts was developed to conduct mutagenesis and analysis of cpTatC functions. Ala scanning mutagenesis identified mutants defective in substrate binding and receptor complex assembly. Mutations in the N terminus (S1) and first stromal loop (S2) caused specific defects in signal peptide recognition. Cys matching between substrate and imported cpTatC confirmed that S1 and S2 directly and specifically bind the RR proximal region of the signal peptide. Mutations in four lumen-proximal regions of cpTatC were defective in receptor complex assembly. Copurification and Cys matching analyses suggest that several of the lumen proximal regions may be important for cpTatC-cpTatC interactions. Surprisingly, RR binding domains of adjacent cpTatCs directed strong cpTatC-cpTatC cross-linking. This suggests clustering of binding sites on the multivalent receptor complex and explains the ability of Tat to transport cross-linked multimers. Transport of substrate proteins cross-linked to the signal peptide binding site tentatively identified mutants impaired in the translocation step.

  13. Proximal Participation: A Pathway into Work

    Science.gov (United States)

    Chan, Selena

    2013-01-01

    In a longitudinal case study of apprentices, the term proximal participation was coined to describe the entry process of young people, with unclear career destinations, into the trade of baking. This article unravels the significance of proximal participation in the decision-making processes of young people who enter a trade through initial…

  14. Bimalleolar ankle fracture with proximal fibular fracture

    NARCIS (Netherlands)

    Colenbrander, R. J.; Struijs, P. A. A.; Ultee, J. M.

    2005-01-01

    A 56-year-old female patient suffered a bimalleolar ankle fracture with an additional proximal fibular fracture. This is an unusual fracture type, seldom reported in literature. It was operatively treated by open reduction and internal fixation of the lateral malleolar fracture. The proximal fibular

  15. Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling.

    Science.gov (United States)

    Supper, Verena; Schiller, Herbert B; Paster, Wolfgang; Forster, Florian; Boulègue, Cyril; Mitulovic, Goran; Leksa, Vladimir; Ohradanova-Repic, Anna; Machacek, Christian; Schatzlmaier, Philipp; Zlabinger, Gerhard J; Stockinger, Hannes

    2016-02-01

    The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression. Copyright © 2016 by The American Association of Immunologists, Inc.

  16. Proximal Alternating Direction Method with Relaxed Proximal Parameters for the Least Squares Covariance Adjustment Problem

    Directory of Open Access Journals (Sweden)

    Minghua Xu

    2014-01-01

    Full Text Available We consider the problem of seeking a symmetric positive semidefinite matrix in a closed convex set to approximate a given matrix. This problem may arise in several areas of numerical linear algebra or come from finance industry or statistics and thus has many applications. For solving this class of matrix optimization problems, many methods have been proposed in the literature. The proximal alternating direction method is one of those methods which can be easily applied to solve these matrix optimization problems. Generally, the proximal parameters of the proximal alternating direction method are greater than zero. In this paper, we conclude that the restriction on the proximal parameters can be relaxed for solving this kind of matrix optimization problems. Numerical experiments also show that the proximal alternating direction method with the relaxed proximal parameters is convergent and generally has a better performance than the classical proximal alternating direction method.

  17. Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site.

    Science.gov (United States)

    Ulaganathan, Vijay K; Sperl, Bianca; Rapp, Ulf R; Ullrich, Axel

    2015-12-24

    Variant rs351855-G/A is a commonly occurring single-nucleotide polymorphism of coding regions in exon 9 of the fibroblast growth factor receptor FGFR4 (CD334) gene (c.1162G>A). It results in an amino-acid change at codon 388 from glycine to arginine (p.Gly388Arg) in the transmembrane domain of the receptor. Despite compelling genetic evidence for the association of this common variant with cancers of the bone, breast, colon, prostate, skin, lung, head and neck, as well as soft-tissue sarcomas and non-Hodgkin lymphoma, the underlying biological mechanism has remained elusive. Here we show that substitution of the conserved glycine 388 residue to a charged arginine residue alters the transmembrane spanning segment and exposes a membrane-proximal cytoplasmic signal transducer and activator of transcription 3 (STAT3) binding site Y(390)-(P)XXQ(393). We demonstrate that such membrane-proximal STAT3 binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently co-localize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo. Thus, our findings elucidate the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggest that germline variants of cell-surface molecules that recruit STAT3 to the inner cell membrane are a significant risk for cancer prognosis and disease progression.

  18. Reduced Insulin Receptor Expression Enhances Proximal Tubule Gluconeogenesis.

    Science.gov (United States)

    Pandey, Gaurav; Shankar, Kripa; Makhija, Ekta; Gaikwad, Anil; Ecelbarger, Carolyn; Mandhani, Anil; Srivastava, Aneesh; Tiwari, Swasti

    2017-02-01

    Reduced insulin receptor protein levels have been reported in the kidney cortex from diabetic humans and animals. We recently reported that, targeted deletion of insulin receptor (IR) from proximal tubules (PT) resulted in hyperglycemia in non-obese mice. To elucidate the mechanism, we examined human proximal tubule cells (hPTC) and C57BL/6 mice fed with high-fat diet (HFD, 60% fat for 20 weeks). Immunoblotting revealed a significantly lower protein level of IR in HFD compare to normal chow diet (NCD). Furthermore, a blunted rise in p-AKT 308 levels in the kidney cortex of HFD mice was observed in response to acute insulin (0.75 IU/kg body weight, i.p) relative to NCD n = 8/group, P gluconeogenesis. Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP/DEXA-stimulated hPTC cells (n = 3, P gluconeogenesis and PEPCK induction was significantly attenuated in IR (siRNA) silenced hPTC (n = 3, P gluconeogenesis. Thus reduced insulin signaling of the proximal tubule may contribute to hyperglycemia in the metabolic syndrome via elevated gluconeogenesis. J. Cell. Biochem. 118: 276-285, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Proximal Hamstring Tendinosis and Partial Ruptures.

    Science.gov (United States)

    Startzman, Ashley N; Fowler, Oliver; Carreira, Dominic

    2017-07-01

    Proximal hamstring tendinosis and partial hamstring origin ruptures are painful conditions of the proximal thigh and hip that may occur in the acute, chronic, or acute on chronic setting. Few publications exist related to their diagnosis and management. This systematic review discusses the incidence, treatment, and prognosis of proximal hamstring tendinosis and partial hamstring ruptures. Conservative treatment measures include nonsteroidal anti-inflammatory drugs, physical therapy, rest, and ice. If these measures fail, platelet-rich plasma or shockwave therapy may be considered. When refractory to conservative management, these injuries may be treated with surgical debridement and hamstring reattachment. [Orthopedics. 2017; 40(4):e574-e582.]. Copyright 2017, SLACK Incorporated.

  20. .Gov Domains API

    Data.gov (United States)

    General Services Administration — This dataset offers the list of all .gov domains, including state, local, and tribal .gov domains. It does not include .mil domains, or other federal domains outside...

  1. Promoting proximal formative assessment with relational discourse

    Science.gov (United States)

    Scherr, Rachel E.; Close, Hunter G.; McKagan, Sarah B.

    2012-02-01

    The practice of proximal formative assessment - the continual, responsive attention to students' developing understanding as it is expressed in real time - depends on students' sharing their ideas with instructors and on teachers' attending to them. Rogerian psychology presents an account of the conditions under which proximal formative assessment may be promoted or inhibited: (1) Normal classroom conditions, characterized by evaluation and attention to learning targets, may present threats to students' sense of their own competence and value, causing them to conceal their ideas and reducing the potential for proximal formative assessment. (2) In contrast, discourse patterns characterized by positive anticipation and attention to learner ideas increase the potential for proximal formative assessment and promote self-directed learning. We present an analysis methodology based on these principles and demonstrate its utility for understanding episodes of university physics instruction.

  2. THE PROXIMATE COMPOSITION OF AFRICAN BUSH MANGO ...

    African Journals Online (AJOL)

    BIG TIMMY

    Information regarding previous studies on these physico-chemical ... This behaviour may be attributed to its high myristic acid ... The authors express deep appreciation to the. Heads of ... of a typical rural processing method on the proximate ...

  3. Proximate composition and nutritional characterization of Chia ...

    African Journals Online (AJOL)

    ... dairy product associated with several beneficial nutritional and health effects. ... The results for amino acids showed that the essential and non-essential amino ... proximate composition and nutritional (amino acids, fatty acids, and minerals ...

  4. Proximal focal femoral deficiency: A case report

    Directory of Open Access Journals (Sweden)

    Shashank Sharma

    2015-01-01

    Full Text Available Proximal focal femoral deficiency (PFFD is a rare congenital anomaly resulting in limb shortening and disability in young. The exact cause of the disease is not known and it may present as varying grades of affection involving the proximal femur and the acetabulum. Recognition of this rare abnormality on radiographs can help manage these cases better since early institution of therapy may help in achieving adequate growth of the femur.

  5. Proximity sensor system development. CRADA final report

    International Nuclear Information System (INIS)

    Haley, D.C.; Pigoski, T.M.

    1998-01-01

    Lockheed Martin Energy Research Corporation (LMERC) and Merritt Systems, Inc. (MSI) entered into a Cooperative Research and Development Agreement (CRADA) for the development and demonstration of a compact, modular proximity sensing system suitable for application to a wide class of manipulator systems operated in support of environmental restoration and waste management activities. In teleoperated modes, proximity sensing provides the manipulator operator continuous information regarding the proximity of the manipulator to objects in the workspace. In teleoperated and robotic modes, proximity sensing provides added safety through the implementation of active whole arm collision avoidance capabilities. Oak Ridge National Laboratory (ORNL), managed by LMERC for the United States Department of Energy (DOE), has developed an application specific integrated circuit (ASIC) design for the electronics required to support a modular whole arm proximity sensing system based on the use of capacitive sensors developed at Sandia National Laboratories. The use of ASIC technology greatly reduces the size of the electronics required to support the selected sensor types allowing deployment of many small sensor nodes over a large area of the manipulator surface to provide maximum sensor coverage. The ASIC design also provides a communication interface to support sensor commands from and sensor data transmission to a distributed processing system which allows modular implementation and operation of the sensor system. MSI is a commercial small business specializing in proximity sensing systems based upon infrared and acoustic sensors

  6. Proximity sensor system development. CRADA final report

    Energy Technology Data Exchange (ETDEWEB)

    Haley, D.C. [Oak Ridge National Lab., TN (United States); Pigoski, T.M. [Merrit Systems, Inc. (United States)

    1998-01-01

    Lockheed Martin Energy Research Corporation (LMERC) and Merritt Systems, Inc. (MSI) entered into a Cooperative Research and Development Agreement (CRADA) for the development and demonstration of a compact, modular proximity sensing system suitable for application to a wide class of manipulator systems operated in support of environmental restoration and waste management activities. In teleoperated modes, proximity sensing provides the manipulator operator continuous information regarding the proximity of the manipulator to objects in the workspace. In teleoperated and robotic modes, proximity sensing provides added safety through the implementation of active whole arm collision avoidance capabilities. Oak Ridge National Laboratory (ORNL), managed by LMERC for the United States Department of Energy (DOE), has developed an application specific integrated circuit (ASIC) design for the electronics required to support a modular whole arm proximity sensing system based on the use of capacitive sensors developed at Sandia National Laboratories. The use of ASIC technology greatly reduces the size of the electronics required to support the selected sensor types allowing deployment of many small sensor nodes over a large area of the manipulator surface to provide maximum sensor coverage. The ASIC design also provides a communication interface to support sensor commands from and sensor data transmission to a distributed processing system which allows modular implementation and operation of the sensor system. MSI is a commercial small business specializing in proximity sensing systems based upon infrared and acoustic sensors.

  7. The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.

    Science.gov (United States)

    Toth, Csaba; Funke, Sarah; Nitsche, Vanessa; Liverts, Anna; Zlachevska, Viktoriya; Gasis, Marcia; Wiek, Constanze; Hanenberg, Helmut; Mahotka, Csaba; Schirmacher, Peter; Heikaus, Sebastian

    2017-05-02

    Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic

  8. Récuperation d'horloge d'un signal OTDM à 640 Gbit/s transmis sur 50 km par boucle à verrouillage de phase opto-électronique utilisant un dispositif en Niobate de Lithium à inversion de domaines

    DEFF Research Database (Denmark)

    Gomez, F.; Ware, Agis C.; Oxenløwe, Leif Katsuo

    2008-01-01

    L'extraction d'horloge d'un signal OTDM à 640 Gbit/s, transmis sur 50 km, à partir d'une boucle à verrouillage de phase utilisant l'effet non-linéaire de mélange à trois ondes dans un composant de niobate de lithium à inversion de domaines a été mise en oeuvre.......L'extraction d'horloge d'un signal OTDM à 640 Gbit/s, transmis sur 50 km, à partir d'une boucle à verrouillage de phase utilisant l'effet non-linéaire de mélange à trois ondes dans un composant de niobate de lithium à inversion de domaines a été mise en oeuvre....

  9. Signal processing for boiling noise detection

    International Nuclear Information System (INIS)

    Ledwidge, T.J.; Black, J.L.

    1989-01-01

    The present paper deals with investigations of acoustic signals from a boiling experiment performed on the KNS I loop at KfK Karlsruhe. Signals have been analysed in frequency as well as in time domain. Signal characteristics successfully used to detect the boiling process have been found in time domain. (author). 6 refs, figs

  10. Flexible time domain averaging technique

    Science.gov (United States)

    Zhao, Ming; Lin, Jing; Lei, Yaguo; Wang, Xiufeng

    2013-09-01

    Time domain averaging(TDA) is essentially a comb filter, it cannot extract the specified harmonics which may be caused by some faults, such as gear eccentric. Meanwhile, TDA always suffers from period cutting error(PCE) to different extent. Several improved TDA methods have been proposed, however they cannot completely eliminate the waveform reconstruction error caused by PCE. In order to overcome the shortcomings of conventional methods, a flexible time domain averaging(FTDA) technique is established, which adapts to the analyzed signal through adjusting each harmonic of the comb filter. In this technique, the explicit form of FTDA is first constructed by frequency domain sampling. Subsequently, chirp Z-transform(CZT) is employed in the algorithm of FTDA, which can improve the calculating efficiency significantly. Since the signal is reconstructed in the continuous time domain, there is no PCE in the FTDA. To validate the effectiveness of FTDA in the signal de-noising, interpolation and harmonic reconstruction, a simulated multi-components periodic signal that corrupted by noise is processed by FTDA. The simulation results show that the FTDA is capable of recovering the periodic components from the background noise effectively. Moreover, it can improve the signal-to-noise ratio by 7.9 dB compared with conventional ones. Experiments are also carried out on gearbox test rigs with chipped tooth and eccentricity gear, respectively. It is shown that the FTDA can identify the direction and severity of the eccentricity gear, and further enhances the amplitudes of impulses by 35%. The proposed technique not only solves the problem of PCE, but also provides a useful tool for the fault symptom extraction of rotating machinery.

  11. Method of signal analysis

    International Nuclear Information System (INIS)

    Berthomier, Charles

    1975-01-01

    A method capable of handling the amplitude and the frequency time laws of a certain kind of geophysical signals is described here. This method is based upon the analytical signal idea of Gabor and Ville, which is constructed either in the time domain by adding an imaginary part to the real signal (in-quadrature signal), or in the frequency domain by suppressing negative frequency components. The instantaneous frequency of the initial signal is then defined as the time derivative of the phase of the analytical signal, and his amplitude, or envelope, as the modulus of this complex signal. The method is applied to three types of magnetospheric signals: chorus, whistlers and pearls. The results obtained by analog and numerical calculations are compared to results obtained by classical systems using filters, i.e. based upon a different definition of the concept of frequency. The precision with which the frequency-time laws are determined leads then to the examination of the principle of the method and to a definition of instantaneous power density spectrum attached to the signal, and to the first consequences of this definition. In this way, a two-dimensional representation of the signal is introduced which is less deformed by the analysis system properties than the usual representation, and which moreover has the advantage of being obtainable practically in real time [fr

  12. Locking plate fixation for proximal humerus fractures.

    LENUS (Irish Health Repository)

    Burke, Neil G

    2012-02-01

    Locking plates are increasingly used to surgically treat proximal humerus fractures. Knowledge of the bone quality of the proximal humerus is important. Studies have shown the medial and dorsal aspects of the proximal humeral head to have the highest bone strength, and this should be exploited by fixation techniques, particularly in elderly patients with osteoporosis. The goals of surgery for proximal humeral fractures should involve minimal soft tissue dissection and achieve anatomic reduction of the head complex with sufficient stability to allow for early shoulder mobilization. This article reviews various treatment options, in particular locking plate fixation. Locking plate fixation is associated with a high complication rate, such as avascular necrosis (7.9%), screw cutout (11.6%), and revision surgery (13.7%). These complications are frequently due to the varus deformation of the humeral head. Strategic screw placement in the humeral head would minimize the possibility of loss of fracture reduction and potential hardware complications. Locking plate fixation is a good surgical option for the management of proximal humerus fractures. Complications can be avoided by using better bone stock and by careful screw placement in the humeral head.

  13. Giant proximity effect in ferromagnetic bilayers

    Science.gov (United States)

    Ramos, Silvia; Charlton, Tim; Quintanilla, Jorge; Suter, Andreas; Moodera, Jagadeesh; Prokscha, Thomas; Salman, Zaher; Forgan, Ted

    2013-03-01

    The proximity effect is a phenomenon where an ordered state leaks from a material into an adjacent one over some finite distance, ξ. For superconductors, this distance is ~ the coherence length. Nevertheless much longer-range, ``giant'' proximity effects have been observed in cuprate junctions. This surprising effect can be understood as a consequence of critical opalescence. Since this occurs near all second order phase transitions, giant proximity effects should be very general and, in particular, they should be present in magnetic systems. The ferromagnetic proximity effect has the advantage that its order parameter (magnetization) can be observed directly. We investigate the above phenomenon in Co/EuS bilayer films, where both materials undergo ferromagnetic transitions but at rather different temperatures (bulk TC of 1400K for Co and 16.6K for EuS). A dramatic increase in the range of the proximity effect is expected near the TC of EuS. We present the results of our measurements of the magnetization profiles as a function of temperature, carried out using the complementary techniques of low energy muon rotation and polarized neutron reflectivity. Work supported by EPSRC, STFC and ONR grant N00014-09-1-0177 and NSF grant DMR 0504158.

  14. Proximity of signallers can maintain sexual signal variation under stabilizing selection

    NARCIS (Netherlands)

    van Wijk, M.; Heath, J.; Lievers, R.; Schal, C.; Groot, A.T.

    2017-01-01

    How sexual communication systems can evolve under stabilizing selection is still a paradox in evolutionary biology. In moths, females emit a species-specific sex pheromone, consisting of a blend of biochemically related components, to which males are attracted. Although males appear to exert strong

  15. Digital signal processing

    CERN Document Server

    O'Shea, Peter; Hussain, Zahir M

    2011-01-01

    In three parts, this book contributes to the advancement of engineering education and that serves as a general reference on digital signal processing. Part I presents the basics of analog and digital signals and systems in the time and frequency domain. It covers the core topics: convolution, transforms, filters, and random signal analysis. It also treats important applications including signal detection in noise, radar range estimation for airborne targets, binary communication systems, channel estimation, banking and financial applications, and audio effects production. Part II considers sel

  16. Proximity operations concept design study, task 6

    Science.gov (United States)

    Williams, A. N.

    1990-01-01

    The feasibility of using optical technology to perform the mission of the proximity operations communications subsystem on Space Station Freedom was determined. Proximity operations mission requirements are determined and the relationship to the overall operational environment of the space station is defined. From this information, the design requirements of the communication subsystem are derived. Based on these requirements, a preliminary design is developed and the feasibility of implementation determined. To support the Orbital Maneuvering Vehicle and National Space Transportation System, the optical system development is straightforward. The requirements on extra-vehicular activity are such as to allow large fields of uncertainty, thus exacerbating the acquisition problem; however, an approach is given that could mitigate this problem. In general, it is found that such a system could indeed perform the proximity operations mission requirement, with some development required to support extra-vehicular activity.

  17. Endomedullar nail of metacarpal and proximal phalanges

    International Nuclear Information System (INIS)

    Mendez Olaya, Francisco Javier; Sanchez Mesa, Pedro Antonio

    2002-01-01

    Prospective study, series of cases; it included patients with diaphysis fractures and union diaphysis-neck or union diaphysis-base of metacarpal and proximal phalanges, in whom was practiced anterograde intramedullary nailing previous closed reduction of the fracture, using prevent intramedullary nail of 1.6 mm. (cem 16) for the metacarpal fractures, and two nail prevent of 1.0 mm. (cem 10) for the proximal phalangeal fractures. Indications: transverse and oblique short fractures, spiral and with comminuting bicortical. Pursuit average is 5.7 months. Frequency surgical intervened patient: 2.2 each month, using this surgical technique a total of 20 (twenty) patients have been operated, 21 (twenty one) fractures; 16 (sixteen) metacarcal fractures and 5 (five) proximal phalangeal fractures, all of them tested using clinical and radiological parameters. Results: good 82%, regular 18%, and bad 0% obtaining bony consolidation and early rehabilitation with incorporation to their habitual works

  18. Correlation between social proximity and mobility similarity.

    Science.gov (United States)

    Fan, Chao; Liu, Yiding; Huang, Junming; Rong, Zhihai; Zhou, Tao

    2017-09-20

    Human behaviors exhibit ubiquitous correlations in many aspects, such as individual and collective levels, temporal and spatial dimensions, content, social and geographical layers. With rich Internet data of online behaviors becoming available, it attracts academic interests to explore human mobility similarity from the perspective of social network proximity. Existent analysis shows a strong correlation between online social proximity and offline mobility similarity, namely, mobile records between friends are significantly more similar than between strangers, and those between friends with common neighbors are even more similar. We argue the importance of the number and diversity of common friends, with a counter intuitive finding that the number of common friends has no positive impact on mobility similarity while the diversity plays a key role, disagreeing with previous studies. Our analysis provides a novel view for better understanding the coupling between human online and offline behaviors, and will help model and predict human behaviors based on social proximity.

  19. Evaluation and Management of Proximal Humerus Fractures

    Directory of Open Access Journals (Sweden)

    Ekaterina Khmelnitskaya

    2012-01-01

    Full Text Available Proximal humerus fractures are common injuries, especially among older osteoporotic women. Restoration of function requires a thorough understanding of the neurovascular, musculotendinous, and bony anatomy. This paper addresses the relevant anatomy and highlights various management options, including indication for arthroplasty. In the vast majority of cases, proximal humerus fractures may be treated nonoperatively. In the case of displaced fractures, when surgical intervention may be pursued, numerous constructs have been investigated. Of these, the proximal humerus locking plate is the most widely used. Arthroplasty is generally reserved for comminuted 4-part fractures, head-split fractures, or fractures with significant underlying arthritic changes. Reverse total shoulder arthroplasty is reserved for patients with a deficient rotator cuff, or highly comminuted tuberosities.

  20. The Life Saving Effects of Hospital Proximity

    DEFF Research Database (Denmark)

    Bertoli, Paola; Grembi, Veronica

    We assess the lifesaving effect of hospital proximity using data on fatality rates of road-traffic accidents. While most of the literature on this topic is based on changes in distance to the nearest hospital triggered by hospital closures and use OLS estimates, our identification comes from......) increases the fatality rate by 13.84% on the sample average. This is equal to a 0.92 additional death per every 100 accidents. We show that OLS estimates provide a downward biased measure of the real effect of hospital proximity because they do not fully solve spatial sorting problems. Proximity matters...... more when the road safety is low; the emergency service is not properly organized, and the nearest hospital has lower quality standards....

  1. Proximity functions for general right cylinders

    International Nuclear Information System (INIS)

    Kellerer, A.M.

    1981-01-01

    Distributions of distances between pairs of points within geometrical objects, or the closely related proximity functions and geometric reduction factors, have applications to dosimetric and microdosimetric calculations. For convex bodies these functions are linked to the chord-length distributions that result from random intersections by straight lines. A synopsis of the most important relations is given. The proximity functions and related functions are derived for right cylinders with arbitrary cross sections. The solution utilizes the fact that the squares of the distances between two random points are sums of independently distributed squares of distances parallel and perpendicular to the axis of the cylinder. Analogous formulas are derived for the proximity functions or geometric reduction factors for a cylinder relative to a point. This requires only a minor modification of the solution

  2. Industrial Computed Tomography using Proximal Algorithm

    KAUST Repository

    Zang, Guangming

    2016-04-14

    In this thesis, we present ProxiSART, a flexible proximal framework for robust 3D cone beam tomographic reconstruction based on the Simultaneous Algebraic Reconstruction Technique (SART). We derive the proximal operator for the SART algorithm and use it for minimizing the data term in a proximal algorithm. We show the flexibility of the framework by plugging in different powerful regularizers, and show its robustness in achieving better reconstruction results in the presence of noise and using fewer projections. We compare our framework to state-of-the-art methods and existing popular software tomography reconstruction packages, on both synthetic and real datasets, and show superior reconstruction quality, especially from noisy data and a small number of projections.

  3. [Partial replantation following proximal limb injury].

    Science.gov (United States)

    Dubert, T; Malikov, S A; Dinh, A; Kupatadze, D D; Oberlin, C; Alnot, J Y; Nabokov, B B

    2000-11-01

    Proximal replantation is a technically feasible but life-threatening procedure. Indications must be restricted to patients in good condition with a good functional prognosis. The goal of replantation must be focused not only on reimplanting the amputated limb but also on achieving a good functional outcome. For the lower limb, simple terminalization remains the best choice in many cases. When a proximal amputation is not suitable for replantation, the main aim of the surgical procedure must be to reconstruct a stump long enough to permit fitting a prosthesis preserving the function of the adjacent joint. If the proximal stump beyond the last joint is very short, it may be possible to restore some length by partial replantation of spared tissues from the amputated part. We present here the results we obtained following this policy. This series included 16 cases of partial replantations, 14 involving the lower limb and 2 the upper limb. All were osteocutaneous microsurgical transfers. For the lower limb, all transfers recovered protective sensitivity following tibial nerve repair. The functional calcaeoplantar unit was used in 13 cases. The transfer of this specialized weight bearing tissue provided a stable distal surface making higher support unnecessary. In one case, we raised a 13-cm vascularized tibial segment covered with foot skin for additional length. For the upper limb, the osteocutaneous transfer, based on the radial artery, was not reinnervated, but this lack of sensitivity did not impair prosthesis fitting. One vascular failure was finally amputated. This was the only unsuccessful result. For all other patients, the surgical procedure facilitated prosthesis fitting and preserved the proximal joint function despite an initially very proximal amputation. The advantages of partial replantation are obvious compared with simple terminalization or secondary reconstruction. There is no secondary donor site and, because there is no major muscle mass in the

  4. The developmental spectrum of proximal radioulnar synostosis

    Energy Technology Data Exchange (ETDEWEB)

    Elliott, Alison M. [University of Manitoba, Winnipeg Regional Health Association Program of Genetics and Metabolism, Winnipeg, MB (Canada); University of Manitoba, Department of Paediatrics and Child Health, Winnipeg, MB (Canada); University of Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, MB (Canada); University of Manitoba, WRHA Program of Genetics and Metabolism, Departments of Paediatrics and Child Health, Biochemistry and Medical Genetics, Winnipeg, MB (Canada); Kibria, Lisa [University of Manitoba, Department of School of Medical Rehabilitation, Winnipeg, MB (Canada); Reed, Martin H. [University of Manitoba, Department of Paediatrics and Child Health, Winnipeg, MB (Canada); University of Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, MB (Canada); University of Manitoba, Department of Diagnostic Imaging, Winnipeg, MB (Canada)

    2010-01-15

    Proximal radioulnar synostosis is a rare upper limb malformation. The elbow is first identifiable at 35 days (after conception), at which stage the cartilaginous anlagen of the humerus, radius and ulna are continuous. Subsequently, longitudinal segmentation produces separation of the distal radius and ulna. However, temporarily, the proximal ends are united and continue to share a common perichondrium. We investigated the hypothesis that posterior congenital dislocation of the radial head and proximal radioulnar fusion are different clinical manifestations of the same primary developmental abnormality. Records were searched for ''proximal radioulnar fusion/posterior radial head dislocation'' in patients followed at the local Children's Hospital and Rehabilitation Centre for Children. Relevant radiographic, demographic and clinical data were recorded. Ethics approval was obtained through the University Research Ethics Board. In total, 28 patients met the inclusion criteria. The majority of patients (16) had bilateral involvement; eight with posterior dislocation of the radial head only; five had posterior radial head dislocation with radioulnar fusion and two had radioulnar fusion without dislocation. One patient had bilateral proximal radioulnar fusion and posterior dislocation of the left radial head. Nine patients had only left-sided involvement, and three had only right-sided involvement.The degree of proximal fusion varied, with some patients showing 'complete' proximal fusion and others showing fusion that occurred slightly distal to the radial head: 'partially separated.' Associated disorders in our cohort included Poland syndrome (two patients), Cornelia de Lange syndrome, chromosome anomalies (including tetrasomy X) and Cenani Lenz syndactyly. The suggestion of a developmental relationship between posterior dislocation of the radial head and proximal radioulnar fusion is supported by the fact that both anomalies

  5. Proximity effects in ferromagnet/superconductor structures

    International Nuclear Information System (INIS)

    Yu, H.L.; Sun, G.Y.; Yang, L.Y.; Xing, D.Y.

    2004-01-01

    The Nambu spinor Green's function approach is applied to study proximity effects in ferromagnet/superconductor (FM/SC) structures. They include the induced superconducting order parameter and density of states (DOS) with superconducting feature on the FM side, and spin-dependent DOS within the energy gap on the SC side. The latter indicates an appearance of gapless superconductivity and a coexistence of ferromagnetism and superconductivity in a small regime near the interface. The influence of exchange energy in FM and barrier strength at interface on the proximity effects is discussed

  6. Ultimate and proximate explanations of strong reciprocity.

    Science.gov (United States)

    Vromen, Jack

    2017-08-23

    Strong reciprocity (SR) has recently been subject to heated debate. In this debate, the "West camp" (West et al. in Evol Hum Behav 32(4):231-262, 2011), which is critical of the case for SR, and the "Laland camp" (Laland et al. in Science, 334(6062):1512-1516, 2011, Biol Philos 28(5):719-745, 2013), which is sympathetic to the case of SR, seem to take diametrically opposed positions. The West camp criticizes advocates of SR for conflating proximate and ultimate causation. SR is said to be a proximate mechanism that is put forward by its advocates as an ultimate explanation of human cooperation. The West camp thus accuses advocates of SR for not heeding Mayr's original distinction between ultimate and proximate causation. The Laland camp praises advocates of SR for revising Mayr's distinction. Advocates of SR are said to replace Mayr's uni-directional view on the relation between ultimate and proximate causes by the bi-directional one of reciprocal causation. The paper argues that both the West camp and the Laland camp misrepresent what advocates of SR are up to. The West camp is right that SR is a proximate cause of human cooperation. But rather than putting forward SR as an ultimate explanation, as the West camp argues, advocates of SR believe that SR itself is in need of ultimate explanation. Advocates of SR tend to take gene-culture co-evolutionary theory as the correct meta-theoretical framework for advancing ultimate explanations of SR. Appearances notwithstanding, gene-culture coevolutionary theory does not imply Laland et al.'s notion of reciprocal causation. "Reciprocal causation" suggests that proximate and ultimate causes interact simultaneously, while advocates of SR assume that they interact sequentially. I end by arguing that the best way to understand the debate is by disambiguating Mayr's ultimate-proximate distinction. I propose to reserve "ultimate" and "proximate" for different sorts of explanations, and to use other terms for distinguishing

  7. Infiltrating/sealing proximal caries lesions

    DEFF Research Database (Denmark)

    Martignon, S; Ekstrand, K R; Gomez, J

    2012-01-01

    This randomized split-mouth controlled clinical trial aimed at assessing the therapeutic effects of infiltration vs. sealing for controlling caries progression on proximal surfaces. Out of 90 adult students/patients assessed at university clinics and agreeing to participate, 39, each with 3...... differences in lesion progression between infiltration and placebo (P = 0.0012) and between sealing and placebo (P = 0.0269). The study showed that infiltration and sealing are significantly better than placebo treatment for controlling caries progression on proximal lesions. No significant difference...

  8. Regulation of proximal tubule vacuolar H+-ATPase by PKA and AMP-activated protein kinase

    Science.gov (United States)

    Al-bataineh, Mohammad M.; Gong, Fan; Marciszyn, Allison L.; Myerburg, Michael M.

    2014-01-01

    The vacuolar H+-ATPase (V-ATPase) mediates ATP-driven H+ transport across membranes. This pump is present at the apical membrane of kidney proximal tubule cells and intercalated cells. Defects in the V-ATPase and in proximal tubule function can cause renal tubular acidosis. We examined the role of protein kinase A (PKA) and AMP-activated protein kinase (AMPK) in the regulation of the V-ATPase in the proximal tubule as these two kinases coregulate the V-ATPase in the collecting duct. As the proximal tubule V-ATPases have different subunit compositions from other nephron segments, we postulated that V-ATPase regulation in the proximal tubule could differ from other kidney tubule segments. Immunofluorescence labeling of rat ex vivo kidney slices revealed that the V-ATPase was present in the proximal tubule both at the apical pole, colocalizing with the brush-border marker wheat germ agglutinin, and in the cytosol when slices were incubated in buffer alone. When slices were incubated with a cAMP analog and a phosphodiesterase inhibitor, the V-ATPase accumulated at the apical pole of S3 segment cells. These PKA activators also increased V-ATPase apical membrane expression as well as the rate of V-ATPase-dependent extracellular acidification in S3 cell monolayers relative to untreated cells. However, the AMPK activator AICAR decreased PKA-induced V-ATPase apical accumulation in proximal tubules of kidney slices and decreased V-ATPase activity in S3 cell monolayers. Our results suggest that in proximal tubule the V-ATPase subcellular localization and activity are acutely coregulated via PKA downstream of hormonal signals and via AMPK downstream of metabolic stress. PMID:24553431

  9. Phytochemical screening, proximate analysis and acute toxicity ...

    African Journals Online (AJOL)

    Phytochemical screening results indicate the presence of saponins, flavonoids, phytosterols and phenols. Acute toxicity study showed there was no mortality at 8000 mg/kg of the extract. The results indicate that the plant is rich in phytochemicals and is relatively safe. Key words: Phytochemicals, acute toxicity, proximate ...

  10. PROXIMATE AND ELEMENTAL COMPOSITION OF WHITE GRUBS

    African Journals Online (AJOL)

    DR. AMINU

    This study determined the proximate and mineral element composition of whole white grubs using standard methods of analysis. ... and 12.75 ± 3.65% respectively. Mineral contents of white grub in terms of relative concentration .... of intracellular Ca, bone mineralization, blood coagulation, and plasma membrane potential ...

  11. Phytochemical Screening and Proximate Analysis of Newbouldia ...

    African Journals Online (AJOL)

    The study was conducted to assess the phytochemical and proximate composition of Newboudia laevis leaves and Allium sativum bulb extracts. The leaves and bulbs extracts were analyzed for their chemical composition and antinutritional factors (ANFs) which include moisture, crude protein, crude fat, crude fiber, total ash ...

  12. Phytochemical Screening, Proximate and Mineral Composition of ...

    African Journals Online (AJOL)

    Leaves of sweet potato (Ipomoea batatas) grown in Tepi area was studied for their class of phytochemicals, mineral and proximate composition using standard analytical methods. The phytochemical screening revealed the presence of alkaloids, flavonoid, terpenoids, saponins, quinones, phenol, tannins, amino acid and ...

  13. Phytochemical screening, proximate and elemental analysis of ...

    African Journals Online (AJOL)

    Citrus sinensis was screened for its phytochemical composition and was evaluated for the proximate and elemental analysis. The phytochemical analysis indicated the presence of reducing sugar, saponins, cardiac glycosides, tannins and flavonoids. The elemental analysis indicated the presence of the following mineral ...

  14. Modified Koyanagi Technique in Management of Proximal ...

    African Journals Online (AJOL)

    xp

    Modified Koyanagi Technique in Management of Proximal Hypospadias. Adham Elsaied, Basem Saied, and Mohammed El- ... All operations were performed by the authors,using fine instruments and under 3.5X loupe ... the other needed an operation to close the fistula six months later. The case with meatal recession had ...

  15. Proximity focusing RICH with TOF capabilities

    International Nuclear Information System (INIS)

    Korpar, S.; Adachi, I.; Fujita, K.; Fukushima, T.; Gorisek, A.; Hayashi, D.; Iijima, T.; Ikado, T.; Ishikawa, T.; Kawai, H.; Kozakai, Y.; Krizan, P.; Kuratani, A.; Mazuka, Y.; Nakagawa, T.; Nishida, S.; Ogawa, S.; Pestotnik, R.; Seki, T.; Sumiyoshi, T.; Tabata, M.; Unno, Y.

    2007-01-01

    A proximity focusing RICH counter with a multi-channel micro-channel plate (MCP) PMT was tested as a time-of-flight counter. Cherenkov photons emitted in the radiator medium as well as in the entrance window of the PMT were used for the time-of-flight measurement, and an excellent performance of the counter could be demonstrated

  16. Proximate composition and mycological characterization of peanut ...

    African Journals Online (AJOL)

    SARAH

    2013-12-30

    Dec 30, 2013 ... ABSTRACT. Objective: The aim of this work was to contribute to the food safety of Ivorian consumers by investigating the proximate composition and the toxic fungal contamination of peanut butters offered for retail sale on the different markets of Abidjan. Methodology and results: Peanut butter samples (45) ...

  17. Prosthetic replacement for proximal humeral fractures.

    Science.gov (United States)

    Kontakis, George; Tosounidis, Theodoros; Galanakis, Ioannis; Megas, Panagiotis

    2008-12-01

    The ideal management of complex proximal humeral fractures continues to be debatable. Evolution of proximal humeral fracture management, during the past decade, led to the implementation of many innovations in surgical treatment. Even though the pendulum of treatment seems to swing towards new trends such as locked plating, hemiarthroplasty remains a valid and reliable option that serves the patient's needs well. Hemiarthroplasty is indicated for complex proximal humeral fractures in elderly patients with poor bone stock and when internal fixation is difficult or unreliable. Hemiarthroplasty provides a better result when it is performed early post-injury. Stem height, retroversion and tuberosity positioning are technical aspects of utmost importance. Additionally reverse total shoulder arthroplasty is an alternative new modality that can be used as a primary solution in selected patients with proximal humeral fracture treatment. Failed hemiarthroplasty and fracture sequelae can be successfully managed with reverse total shoulder arthroplasty. Individual decision-making and tailored treatment that takes into consideration the personality of the fracture and the patient's characteristics should be used.

  18. Phytochemistry and proximate composition of ginger ( Zingiber ...

    African Journals Online (AJOL)

    The results of the phytochemical screening showed that alkaloids, carbohydrates, glycosides, proteins, saponins, steroids, flavonoids and terpenoids were present, while reducing sugars, tannins, oils and acid compounds were absent. Similarly, the results of the proximate analysis of the rhizome showed that ginger ...

  19. Disability occurrence and proximity to death

    NARCIS (Netherlands)

    Klijs, Bart; Mackenbach, Johan P.; Kunst, Anton E.

    2010-01-01

    Purpose. This paper aims to assess whether disability occurrence is related more strongly to proximity to death than to age. Method. Self reported disability and vital status were available from six annual waves and a subsequent 12-year mortality follow-up of the Dutch GLOBE longitudinal study.

  20. Proximate composition, bread characteristics and sensory ...

    African Journals Online (AJOL)

    This study was carried out to investigate proximate composition, bread characteristics and sensory evaluation of cocoyam-wheat composite breads at different levels of cocoyam flour substitution for human consumption.A whole wheat bread (WWB) and cocoyam-composite breads (CCB1,CCB 2 and CCB 3) were prepared ...

  1. 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.

  2. Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

    Science.gov (United States)

    Udi, Shiran; Hinden, Liad; Earley, Brian; Drori, Adi; Reuveni, Noa; Hadar, Rivka; Cinar, Resat; Nemirovski, Alina; Tam, Joseph

    2017-12-01

    Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB 1 R) induces nephropathy, whereas CB 1 R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB 1 R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β -oxidation. Collectively, these findings indicate that renal proximal tubule cell CB 1 R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway. Copyright © 2017 by the American Society of Nephrology.

  3. Two Proximal Skin Electrodes — A Respiration Rate Body Sensor

    Directory of Open Access Journals (Sweden)

    Viktor Avbelj

    2012-10-01

    Full Text Available We propose a new body sensor for extracting the respiration rate based on the amplitude changes in the body surface potential differences between two proximal body electrodes. The sensor could be designed as a plaster-like reusable unit that can be easily fixed onto the surface of the body. It could be equipped either with a sufficiently large memory for storing the measured data or with a low-power radio system that can transmit the measured data to a gateway for further processing. We explore the influence of the sensor’s position on the quality of the extracted results using multi-channel ECG measurements and considering all the pairs of two neighboring electrodes as potential respiration-rate sensors. The analysis of the clinical measurements, which also include reference thermistor-based respiration signals, shows that the proposed approach is a viable option for monitoring the respiration frequency and for a rough classification of breathing types. The obtained results were evaluated on a wireless prototype of a respiration body sensor. We indicate the best positions for the respiration body sensor and prove that a single sensor for body surface potential difference on proximal skin electrodes can be used for combined measurements of respiratory and cardiac activities.

  4. Calcium Domains around Single and Clustered IP3 Receptors and Their Modulation by Buffers

    Science.gov (United States)

    Rüdiger, S.; Nagaiah, Ch.; Warnecke, G.; Shuai, J.W.

    2010-01-01

    Abstract We study Ca2+ release through single and clustered IP3 receptor channels on the ER membrane under presence of buffer proteins. Our computational scheme couples reaction-diffusion equations and a Markovian channel model and allows our investigating the effects of buffer proteins on local calcium concentrations and channel gating. We find transient and stationary elevations of calcium concentrations around active channels and show how they determine release amplitude. Transient calcium domains occur after closing of isolated channels and constitute an important part of the channel's feedback. They cause repeated openings (bursts) and mediate increased release due to Ca2+ buffering by immobile proteins. Stationary domains occur during prolonged activity of clustered channels, where the spatial proximity of IP3Rs produces a distinct [Ca2+] scale (0.5–10 μM), which is smaller than channel pore concentrations (>100 μM) but larger than transient levels. While immobile buffer affects transient levels only, mobile buffers in general reduce both transient and stationary domains, giving rise to Ca2+ evacuation and biphasic modulation of release amplitude. Our findings explain recent experiments in oocytes and provide a general framework for the understanding of calcium signals. PMID:20655827

  5. Multiple functional self-association interfaces in plant TIR domains

    NARCIS (Netherlands)

    Zhang, Xiaoxiao; Bernoux, Maud; Bentham, Adam R; Newman, Toby E; Ve, Thomas; Casey, Lachlan W; Raaymakers, Tom M; Hu, Jian; Croll, Tristan I; Schreiber, Karl J; Staskawicz, Brian J; Anderson, Peter A; Sohn, Kee Hoon; Williams, Simon J; Dodds, Peter N; Kobe, Bostjan

    2017-01-01

    The self-association of Toll/interleukin-1 receptor/resistance protein (TIR) domains has been implicated in signaling in plant and animal immunity receptors. Structure-based studies identified different TIR-domain dimerization interfaces required for signaling of the plant nucleotide-binding

  6. Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus.

    Science.gov (United States)

    Strebovsky, Julia; Walker, Patrick; Lang, Roland; Dalpke, Alexander H

    2011-03-01

    Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytoplasmic Janus kinases (Jak) and signal transducer and activator of transcription (STAT) signaling pathways. Previously the authors surprisingly observed that SOCS1 translocated into the nucleus, which was because of the presence of a nuclear localization sequence. This report now hypothesizes that SOCS1 mediates specific functions within the nuclear compartment because it is instantly transported into the nucleus, as shown by photoactivation and live cell imaging in human HEK293 cells. The NFκB component p65 is identified as an interaction partner for SOCS1 but not for other members of the SOCS family. SOCS1 bound to p65 only within the nucleus. By means of its SOCS box domain, SOCS1 operated as a ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of nuclear p65. Thus, SOCS1 limited prolonged p65 signaling and terminated expression of NFκB inducible genes. Using mutants that lack either nuclear translocation or a functional SOCS box, this report identifies genes that are regulated in a manner dependent on the nuclear availability of SOCS1. Data show that beyond its receptor-proximal function in Jak/STAT signaling, SOCS1 also regulates the duration of NFκB signaling within the cell nucleus, thus exerting a heretofore unrecognized function.

  7. Introduction: History of SH2 Domains and Their Applications.

    Science.gov (United States)

    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.

  8. Expression of the Grb2-related protein of the lymphoid system in B cell subsets enhances B cell antigen receptor signaling through mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Yankee, Thomas M; Solow, Sasha A; Draves, Kevin D; Clark, Edward A

    2003-01-01

    Adapter proteins play a critical role in regulating signals triggered by Ag receptor cross-linking. These small molecules link receptor proximal events with downstream signaling pathways. In this study, we explore the expression and function of the Grb2-related protein of the lymphoid system (GrpL)/Grb2-related adaptor downstream of Shc adapter protein in human B cells. GrpL is expressed in naive B cells and is down-regulated following B cell Ag receptor ligation. By contrast, germinal center and memory B cells express little or no GrpL. Using human B cell lines, we detected constitutive interactions between GrpL and B cell linker protein, Src homology (SH)2 domain-containing leukocyte protein of 76 kDa, hemopoietic progenitor kinase 1, and c-Cbl. The N-terminal SH3 domain of GrpL binds c-Cbl while the C-terminal SH3 domain binds B cell linker protein and SH2 domain-containing leukocyte protein of 76 kDa. Exogenous expression of GrpL in a GrpL-negative B cell line leads to enhanced Ag receptor-induced extracellular signal-related kinase and p38 mitogen-activated protein kinase phosphorylation. Thus, GrpL expression in human B cell subsets appears to regulate Ag receptor-mediated signaling events.

  9. Proximal tubular hypertrophy and enlarged glomerular and proximal tubular urinary space in obese subjects with proteinuria.

    Directory of Open Access Journals (Sweden)

    Ana Tobar

    Full Text Available BACKGROUND: Obesity is associated with glomerular hyperfiltration, increased proximal tubular sodium reabsorption, glomerular enlargement and renal hypertrophy. A single experimental study reported an increased glomerular urinary space in obese dogs. Whether proximal tubular volume is increased in obese subjects and whether their glomerular and tubular urinary spaces are enlarged is unknown. OBJECTIVE: To determine whether proximal tubules and glomerular and tubular urinary space are enlarged in obese subjects with proteinuria and glomerular hyperfiltration. METHODS: Kidney biopsies from 11 non-diabetic obese with proteinuria and 14 non-diabetic lean patients with a creatinine clearance above 50 ml/min and with mild or no interstitial fibrosis were retrospectively analyzed using morphometric methods. The cross-sectional area of the proximal tubular epithelium and lumen, the volume of the glomerular tuft and of Bowman's space and the nuclei number per tubular profile were estimated. RESULTS: Creatinine clearance was higher in the obese than in the lean group (P=0.03. Proteinuria was similarly increased in both groups. Compared to the lean group, the obese group displayed a 104% higher glomerular tuft volume (P=0.001, a 94% higher Bowman's space volume (P=0.003, a 33% higher cross-sectional area of the proximal tubular epithelium (P=0.02 and a 54% higher cross-sectional area of the proximal tubular lumen (P=0.01. The nuclei number per proximal tubular profile was similar in both groups, suggesting that the increase in tubular volume is due to hypertrophy and not to hyperplasia. CONCLUSIONS: Obesity-related glomerular hyperfiltration is associated with proximal tubular epithelial hypertrophy and increased glomerular and tubular urinary space volume in subjects with proteinuria. The expanded glomerular and urinary space is probably a direct consequence of glomerular hyperfiltration. These effects may be involved in the pathogenesis of obesity

  10. Insights into function of PSI domains from structure of the Met receptor PSI domain

    International Nuclear Information System (INIS)

    Kozlov, Guennadi; Perreault, Audrey; Schrag, Joseph D.; Park, Morag; Cygler, Miroslaw; Gehring, Kalle; Ekiel, Irena

    2004-01-01

    PSI domains are cysteine-rich modules found in extracellular fragments of hundreds of signaling proteins, including plexins, semaphorins, integrins, and attractins. Here, we report the solution structure of the PSI domain from the human Met receptor, a receptor tyrosine kinase critical for proliferation, motility, and differentiation. The structure represents a cysteine knot with short regions of secondary structure including a three-stranded antiparallel β-sheet and two α-helices. All eight cysteines are involved in disulfide bonds with the pattern consistent with that for the PSI domain from Sema4D. Comparison with the Sema4D structure identifies a structurally conserved core comprising the N-terminal half of the PSI domain. Interestingly, this part links adjacent SEMA and immunoglobulin domains in the Sema4D structure, suggesting that the PSI domain serves as a wedge between propeller and immunoglobulin domains and is responsible for the correct positioning of the ligand-binding site of the receptor

  11. Performance of Encounternet Tags: Field Tests of Miniaturized Proximity Loggers for Use on Small Birds.

    Directory of Open Access Journals (Sweden)

    Iris I Levin

    Full Text Available Proximity logging is a new tool for understanding social behavior as it allows for accurate quantification of social networks. We report results from field calibration and deployment tests of miniaturized proximity tags (Encounternet, digital transceivers that log encounters between tagged individuals. We examined radio signal behavior in relation to tag attachment (tag, tag on bird, tag on saline-filled balloon to understand how radio signal strength is affected by the tag mounting technique used for calibration tests. We investigated inter-tag and inter-receiver station variability, and in each calibration test we accounted for the effects of antennae orientation. Additionally, we used data from a live deployment on breeding barn swallows (Hirundo rustica erythrogaster to analyze the quality of the logs, including reciprocal agreement in dyadic logs. We evaluated the impact (in terms of mass changes of tag attachment on the birds. We were able to statistically distinguish between RSSI values associated with different close-proximity (<5 m tag-tag distances regardless of antennae orientation. Inter-tag variability was low, but we did find significant inter-receiver station variability. Reciprocal agreement of dyadic logs was high and social networks were constructed from proximity tag logs based on two different RSSI thresholds. There was no evidence of significant mass loss in the time birds were wearing tags. We conclude that proximity loggers are accurate and effective for quantifying social behavior. However, because RSSI and distance cannot be perfectly resolved, data from proximity loggers are most appropriate for comparing networks based on specific RSSI thresholds. The Encounternet system is flexible and customizable, and tags are now light enough for use on small animals (<50 g.

  12. Performance of Encounternet Tags: Field Tests of Miniaturized Proximity Loggers for Use on Small Birds

    Science.gov (United States)

    Levin, Iris I.; Zonana, David M.; Burt, John M.; Safran, Rebecca J.

    2015-01-01

    Proximity logging is a new tool for understanding social behavior as it allows for accurate quantification of social networks. We report results from field calibration and deployment tests of miniaturized proximity tags (Encounternet), digital transceivers that log encounters between tagged individuals. We examined radio signal behavior in relation to tag attachment (tag, tag on bird, tag on saline-filled balloon) to understand how radio signal strength is affected by the tag mounting technique used for calibration tests. We investigated inter-tag and inter-receiver station variability, and in each calibration test we accounted for the effects of antennae orientation. Additionally, we used data from a live deployment on breeding barn swallows (Hirundo rustica erythrogaster) to analyze the quality of the logs, including reciprocal agreement in dyadic logs. We evaluated the impact (in terms of mass changes) of tag attachment on the birds. We were able to statistically distinguish between RSSI values associated with different close-proximity (station variability. Reciprocal agreement of dyadic logs was high and social networks were constructed from proximity tag logs based on two different RSSI thresholds. There was no evidence of significant mass loss in the time birds were wearing tags. We conclude that proximity loggers are accurate and effective for quantifying social behavior. However, because RSSI and distance cannot be perfectly resolved, data from proximity loggers are most appropriate for comparing networks based on specific RSSI thresholds. The Encounternet system is flexible and customizable, and tags are now light enough for use on small animals (<50g). PMID:26348329

  13. Isolated Proximal Tibiofibular Dislocation during Soccer

    Directory of Open Access Journals (Sweden)

    Casey Chiu

    2015-01-01

    Full Text Available Proximal tibiofibular dislocations are rarely encountered in the Emergency Department (ED. We present a case involving a man presenting to the ED with left knee pain after making a sharp left turn on the soccer field. His physical exam was only remarkable for tenderness over the lateral fibular head. His X-rays showed subtle abnormalities of the tibiofibular joint. The dislocation was reduced and the patient was discharged from the ED with orthopedic follow-up.

  14. Superconducting proximity effect in topological materials

    Science.gov (United States)

    Reeg, Christopher R.

    In recent years, there has been a renewed interest in the proximity effect due to its role in the realization of topological superconductivity. In this dissertation, we discuss several results that have been obtained in the field of proximity-induced superconductivity and relate the results to the search for Majorana fermions. First, we show that repulsive electron-electron interactions can induce a non-Majorana zero-energy bound state at the interface between a conventional superconductor and a normal metal. We show that this state is very sensitive to disorder, owing to its lack of topological protection. Second, we show that Rashba spin-orbit coupling, which is one of the key ingredients in engineering a topological superconductor, induces triplet pairing in the proximity effect. When the spin-orbit coupling is strong (i.e., when the characteristic energy scale for spin-orbit coupling is comparable to the Fermi energy), the induced singlet and triplet pairing amplitudes can be comparable in magnitude. Finally, we discuss how the size of the proximity-induced gap, which appears in a low-dimensional material coupled to a superconductor, evolves as the thickness of the (quasi-)low-dimensional material is increased. We show that the induced gap can be comparable to the bulk energy gap of the underlying superconductor in materials that are much thicker than the Fermi wavelength, even in the presence of an interfacial barrier and strong Fermi surface mismatch. This result has important experimental consequences for topological superconductivity, as a sizable gap is required to isolate and detect the Majorana modes.

  15. [Proximity and breastfeeding at the maternity hospital].

    Science.gov (United States)

    Fradin-Charrier, Anne-Claire

    2015-01-01

    The establishment of breastfeeding, as well as its duration, are facilitated through the proximity of the mother with her new baby. However, in maternity hospitals, breastfeeding mothers very often leave their baby in the nursery at night time. A study carried out in 2014 in several maternity hospitals put forward suggestions and highlighted areas to improve in everyday practice. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Measuring displacement signal with an accelerometer

    International Nuclear Information System (INIS)

    Han, Sang Bo

    2010-01-01

    An effective and simple way to reconstruct displacement signal from a measured acceleration signal is proposed in this paper. To reconstruct displacement signal by means of double-integrating the time domain acceleration signal, the Nyquist frequency of the digital sampling of the acceleration signal should be much higher than the highest frequency component of the signal. On the other hand, to reconstruct displacement signal by taking the inverse Fourier transform, the magnitude of the significant frequency components of the Fourier transform of the acceleration signal should be greater than the 6 dB increment line along the frequency axis. With a predetermined resolution in time and frequency domain, determined by the sampling rate to measure and record the original signal, reconstructing high-frequency signals in the time domain and reconstructing low-frequency signals in the frequency domain will produce biased errors. Furthermore, because of the DC components inevitably included in the sampling process, low-frequency components of the signals are overestimated when displacement signals are reconstructed from the Fourier transform of the acceleration signal. The proposed method utilizes curve-fitting around the significant frequency components of the Fourier transform of the acceleration signal before it is inverse-Fourier transformed. Curve-fitting around the dominant frequency components provides much better results than simply ignoring the insignificant frequency components of the signal

  17. Proximity effects in topological insulator heterostructures

    International Nuclear Information System (INIS)

    Li Xiao-Guang; Wu Guang-Fen; Zhang Gu-Feng; Culcer Dimitrie; Zhang Zhen-Yu; Chen Hua

    2013-01-01

    Topological insulators (TIs) are bulk insulators that possess robust helical conducting states along their interfaces with conventional insulators. A tremendous research effort has recently been devoted to Tl-based heterostructures, in which conventional proximity effects give rise to a series of exotic physical phenomena. This paper reviews our recent studies on the potential existence of topological proximity effects at the interface between a topological insulator and a normal insulator or other topologically trivial systems. Using first-principles approaches, we have realized the tunability of the vertical location of the topological helical state via intriguing dual-proximity effects. To further elucidate the control parameters of this effect, we have used the graphene-based heterostructures as prototypical systems to reveal a more complete phase diagram. On the application side of the topological helical states, we have presented a catalysis example, where the topological helical state plays an essential role in facilitating surface reactions by serving as an effective electron bath. These discoveries lay the foundation for accurate manipulation of the real space properties of the topological helical state in TI-based heterostructures and pave the way for realization of the salient functionality of topological insulators in future device applications. (topical review - low-dimensional nanostructures and devices)

  18. [Augmentation technique on the proximal humerus].

    Science.gov (United States)

    Scola, A; Gebhard, F; Röderer, G

    2015-09-01

    The treatment of osteoporotic fractures is still a challenge. The advantages of augmentation with respect to primary in vitro stability and the clinical use for the proximal humerus are presented in this article. In this study six paired human humeri were randomized into an augmented and a non-augmented group. Osteosynthesis was performed with a PHILOS plate (Synthes®). In the augmented group the two screws finding purchase in the weakest cancellous bone were augmented. The specimens were tested in a 3-part fracture model in a varus bending test. The augmented PHILOS plates withstood significantly more load cycles until failure. The correlation to bone mineral density (BMD) showed that augmentation could partially compensate for low BMD. The augmentation of the screws in locked plating in a proximal humerus fracture model is effective in improving the primary stability in a cyclic varus bending test. The targeted augmentation of two particular screws in a region of low bone quality within the humeral head was almost as effective as four screws with twice the amount of bone cement. Screw augmentation combined with a knowledge of the local bone quality could be more effective in enhancing the primary stability of a proximal humerus locking plate because the effect of augmentation can be exploited more effectively limiting it to the degree required. The technique of augmentation is simple and can be applied in open and minimally invasive procedures. When the correct procedure is used, complications (cement leakage into the joint) can be avoided.

  19. A proximity effect in adults' contamination intuitions

    Directory of Open Access Journals (Sweden)

    Laura R. Kim

    2011-04-01

    Full Text Available Magical beliefs about contagion via contact (Rozin, Nemeroff, Wane, and Sherrod, 1989 may emerge when people overgeneralize real-world mechanisms of contamination beyond their appropriate boundaries (Lindeman and Aarnio, 2007. Do people similarly overextend knowledge of airborne contamination mechanisms? Previous work has shown that very young children believe merely being close to a contamination source can contaminate an item (Springer and Belk 1994; we asked whether this same hyper-avoidant intuition is also reflected in adults' judgments. In two studies, we measured adults' ratings of the desirability of an object that had made contact with a source of contamination, an object nearby that had made no contact with the contaminant, and an object far away that had also made no contact. Adults showed a clear proximity effect, wherein objects near the contamination source were perceived to be less desirable than those far away, even though a separate group of adults unanimously acknowledged that contaminants could not possibly have made contact with either the nearby or far-away object (Study 1. The proximity effect also remained robust when a third group of adults was explicitly told that no contaminating particles had made contact with the objects at any time (Study 2. We discuss implications of our findings for extending the scope of magical contagion effects beyond the contact principle, for understanding the persistence of intuitive theories despite broad acceptance of science-based theories, and for constraining interpretations of the developmental work on proximity beliefs.

  20. RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy.

    Science.gov (United States)

    Nakayama, Tojo; Saitsu, Hirotomo; Endo, Wakaba; Kikuchi, Atsuo; Uematsu, Mitsugu; Haginoya, Kazuhiro; Hino-fukuyo, Naomi; Kobayashi, Tomoko; Iwasaki, Masaki; Tominaga, Teiji; Kure, Shigeo; Matsumoto, Naomichi

    2014-06-01

    Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9 months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be within RBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  1. Wnt signaling positively regulates endothelial cell fate specification in the Fli1a-positive progenitor population via Lef1.

    Science.gov (United States)

    Hübner, Kathleen; Grassme, Kathrin S; Rao, Jyoti; Wenke, Nina K; Zimmer, Cordula L; Korte, Laura; Mu Ller, Katja; Sumanas, Saulius; Greber, Boris; Herzog, Wiebke

    2017-10-01

    During vertebrate embryogenesis, vascular endothelial cells (ECs) and primitive erythrocytes become specified within close proximity in the posterior lateral plate mesoderm (LPM) from a common progenitor. However, the signaling cascades regulating the specification into either lineage remain largely elusive. Here, we analyze the contribution of β-catenin dependent Wnt signaling to EC and erythrocyte specification during zebrafish embryogenesis. We generated novel β-catenin dependent Wnt signaling reporters which, by using destabilized fluorophores (Venus-Pest, dGFP), specifically allow us to detect Wnt signaling responses in narrow time windows as well as in spatially restricted domains, defined by Cre recombinase expression (Tg(axin2 BAC :Venus-Pest) mu288 ; Tg(14TCF:loxP-STOP-loxP-dGFP) mu202 ). We therefore can detect β-catenin dependent Wnt signaling activity in a subset of the Fli1a-positive progenitor population. Additionally, we show that mesodermal Wnt3a-mediated signaling via the transcription factor Lef1 positively regulates EC specification (defined by kdrl expression) at the expense of primitive erythrocyte specification (defined by gata1 expression) in zebrafish embryos. Using mesoderm derived from human embryonic stem cells, we identified the same principle of Wnt signaling dependent EC specification in conjunction with auto-upregulation of LEF1. Our data indicate a novel role of β-catenin dependent Wnt signaling in regulating EC specification during vasculogenesis. Copyright © 2017. Published by Elsevier Inc.

  2. 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 ...

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

    Directory of Open Access Journals (Sweden)

    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.

  4. A Regularized Algorithm for the Proximal Split Feasibility Problem

    Directory of Open Access Journals (Sweden)

    Zhangsong Yao

    2014-01-01

    Full Text Available The proximal split feasibility problem has been studied. A regularized method has been presented for solving the proximal split feasibility problem. Strong convergence theorem is given.

  5. Treatment of proximal ulna and olecranon fractures by dorsal plating

    NARCIS (Netherlands)

    Kloen, Peter; Buijze, Geert A.

    2009-01-01

    OBJECTIVE : Anatomic reconstruction of proximal ulna and olecranon fractures allowing early mobilization and prevention of ulnohumeral arthritis. INDICATIONS : Comminuted olecranon or proximal ulna fractures (including Monteggia fractures), olecranon fractures extending distally from the coronoid

  6. Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor.

    Science.gov (United States)

    Kleinau, Gunnar; Jaeschke, Holger; Mueller, Sandra; Raaka, Bruce M; Neumann, Susanne; Paschke, Ralf; Krause, Gerd

    2008-08-01

    The mechanisms governing transition of the thyroid stimulating hormone (TSH) receptor (TSHR) from basal to active conformations are poorly understood. Considering that constitutively activating mutations (CAMs) and inactivating mutations in each of the extracellular loops (ECLs) trigger only partial TSHR activation or inactivation, respectively, we hypothesized that full signaling occurs via multiple extracellular signal propagation events. Therefore, individual CAMs in the extracellular region were combined to create double and triple mutants. In support of our hypothesis, combinations of mutants in the ECLs are in some cases additive, while in others they are even synergistic, with triple mutant I486A/I568V/V656F exhibiting a 70-fold increase in TSH-independent signaling. The proximity but likely different spatial orientation of the residues of activating and inactivating mutations in each ECL supports a dual functionality to facilitate signal induction and conduction, respectively. This is the first report for G-protein coupled receptors, suggesting that multiple and cooperative signal propagating events at all three ECLs are required for full receptor activation. Our findings provide new insights concerning molecular signal transmission from extracellular domains toward the transmembrane helix bundle of the glycoprotein hormone receptors.

  7. A Real-Time Rejection Circuit to Automatically Reject Multiple Interfering Hopping Signals While Passing a Lower Level Desired Signal.

    Science.gov (United States)

    contain the low level desired frequency components that are passed through an inverse transform device for producing a frequency domain signal of the desired signal uncorrupted by unwanted signals. Patent applications. (RRH)

  8. Large scale 2D spectral compressed sensing in continuous domain

    KAUST Repository

    Cai, Jian-Feng

    2017-06-20

    We consider the problem of spectral compressed sensing in continuous domain, which aims to recover a 2-dimensional spectrally sparse signal from partially observed time samples. The signal is assumed to be a superposition of s complex sinusoids. We propose a semidefinite program for the 2D signal recovery problem. Our model is able to handle large scale 2D signals of size 500 × 500, whereas traditional approaches only handle signals of size around 20 × 20.

  9. Large scale 2D spectral compressed sensing in continuous domain

    KAUST Repository

    Cai, Jian-Feng; Xu, Weiyu; Yang, Yang

    2017-01-01

    We consider the problem of spectral compressed sensing in continuous domain, which aims to recover a 2-dimensional spectrally sparse signal from partially observed time samples. The signal is assumed to be a superposition of s complex sinusoids. We propose a semidefinite program for the 2D signal recovery problem. Our model is able to handle large scale 2D signals of size 500 × 500, whereas traditional approaches only handle signals of size around 20 × 20.

  10. Strong Proximities on Smooth Manifolds and Vorono\\" i Diagrams

    OpenAIRE

    Peters, J. F.; Guadagni, C.

    2015-01-01

    This article introduces strongly near smooth manifolds. The main results are (i) second countability of the strongly hit and far-miss topology on a family $\\mathcal{B}$ of subsets on the Lodato proximity space of regular open sets to which singletons are added, (ii) manifold strong proximity, (iii) strong proximity of charts in manifold atlases implies that the charts have nonempty intersection. The application of these results is given in terms of the nearness of atlases and charts of proxim...

  11. Signals in Communication Engineering History

    Science.gov (United States)

    Consonni, Denise; Silva, Magno T. M.

    2010-01-01

    This paper is a study of various electric signals, which have been employed throughout the history of communication engineering in its two main landmarks: the telegraph and the telephone. The signals are presented in their time and frequency domain representations. The historical order has been followed in the presentation: wired systems, spark…

  12. Critical Proximity as a Methodological Move in Techno-Anthropology

    DEFF Research Database (Denmark)

    Birkbak, Andreas; Petersen, Morten Krogh; Elgaard Jensen, Torben

    2015-01-01

    proximity.’ Critical proximity offers an alternative to critical distance, especially with respect to avoiding premature references to abstract panoramas such as democratization and capitalist exploitation in the quest to conduct ‘critical’ analysis. Critical proximity implies, instead, granting the beings...

  13. 75 FR 5009 - Proximity Detection Systems for Underground Mines

    Science.gov (United States)

    2010-02-01

    ... Proximity Detection Systems for Underground Mines AGENCY: Mine Safety and Health Administration, Labor... information regarding whether the use of proximity detection systems would reduce the risk of accidents where... . Information on MSHA-approved proximity detection systems is available on the Internet at http://www.msha.gov...

  14. An Alphavirus E2 Membrane-Proximal Domain Promotes Envelope Protein Lateral Interactions and Virus Budding

    Directory of Open Access Journals (Sweden)

    Emily A. Byrd

    2017-11-01

    Full Text Available Alphaviruses are members of a group of small enveloped RNA viruses that includes important human pathogens such as Chikungunya virus and the equine encephalitis viruses. The virus membrane is covered by a lattice composed of 80 spikes, each a trimer of heterodimers of the E2 and E1 transmembrane proteins. During virus endocytic entry, the E1 glycoprotein mediates the low-pH-dependent fusion of the virus membrane with the endosome membrane, thus initiating virus infection. While much is known about E1 structural rearrangements during membrane fusion, it is unclear how the E1/E2 dimer dissociates, a step required for the fusion reaction. A recent Alphavirus cryo-electron microscopy reconstruction revealed a previously unidentified D subdomain in the E2 ectodomain, close to the virus membrane. A loop within this region, here referred to as the D-loop, contains two highly conserved histidines, H348 and H352, which were hypothesized to play a role in dimer dissociation. We generated Semliki Forest virus mutants containing the single and double alanine substitutions H348A, H352A, and H348/352A. The three D-loop mutations caused a reduction in virus growth ranging from 1.6 to 2 log but did not significantly affect structural protein biosynthesis or transport, dimer stability, virus fusion, or specific infectivity. Instead, growth reduction was due to inhibition of a late stage of virus assembly at the plasma membrane. The virus particles that are produced show reduced thermostability compared to the wild type. We propose the E2 D-loop as a key region in establishing the E1-E2 contacts that drive glycoprotein lattice formation and promote Alphavirus budding from the plasma membrane.

  15. Proximal sensing for soil carbon accounting

    Science.gov (United States)

    England, Jacqueline R.; Viscarra Rossel, Raphael A.

    2018-05-01

    Maintaining or increasing soil organic carbon (C) is vital for securing food production and for mitigating greenhouse gas (GHG) emissions, climate change, and land degradation. Some land management practices in cropping, grazing, horticultural, and mixed farming systems can be used to increase organic C in soil, but to assess their effectiveness, we need accurate and cost-efficient methods for measuring and monitoring the change. To determine the stock of organic C in soil, one requires measurements of soil organic C concentration, bulk density, and gravel content, but using conventional laboratory-based analytical methods is expensive. Our aim here is to review the current state of proximal sensing for the development of new soil C accounting methods for emissions reporting and in emissions reduction schemes. We evaluated sensing techniques in terms of their rapidity, cost, accuracy, safety, readiness, and their state of development. The most suitable method for measuring soil organic C concentrations appears to be visible-near-infrared (vis-NIR) spectroscopy and, for bulk density, active gamma-ray attenuation. Sensors for measuring gravel have not been developed, but an interim solution with rapid wet sieving and automated measurement appears useful. Field-deployable, multi-sensor systems are needed for cost-efficient soil C accounting. Proximal sensing can be used for soil organic C accounting, but the methods need to be standardized and procedural guidelines need to be developed to ensure proficient measurement and accurate reporting and verification. These are particularly important if the schemes use financial incentives for landholders to adopt management practices to sequester soil organic C. We list and discuss requirements for developing new soil C accounting methods based on proximal sensing, including requirements for recording, verification, and auditing.

  16. Finding a needle in a haystack: the role of electrostatics in target lipid recognition by PH domains.

    Directory of Open Access Journals (Sweden)

    Craig N Lumb

    Full Text Available Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD and molecular dynamics (MD simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5-trisphosphate (PI(3,4,5P₃. The interaction of GRP1-PH with PI(3,4,5P₃ in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic 'decoy' lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5P₃-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as 'decoys', disrupting the interaction of GRP1-PH with the PI(3,4,5P₃ molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5P₃ within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5P₃, forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation.

  17. Signal Words

    Science.gov (United States)

    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  18. Keldysh proximity action for disordered superconductors

    International Nuclear Information System (INIS)

    Feigel'man, M.V.; Larkin, A.I.; Skvortsov, M.A.

    2005-01-01

    We review a novel approach to the superconductive proximity effect in disordered normal-superconducting (N-S) structures. The method is based on the multicharge Keldysh action and is suitable for the treatment of interaction and fluctuation effects. As an application of the formalism, we study the subgap conductance and noise in two-dimensional N-S system in the presence of the electron-electron interaction in the Cooper channel. It is shown that singular nature of the interaction correction at large scales leads to a nonmonotonous temperature, voltage and magnetic field dependence of the Andreev conductance. (author)

  19. Phonon structure in proximity tunnel junctions

    International Nuclear Information System (INIS)

    Zarate, H.G.; Carbotte, J.P.

    1985-01-01

    We have iterated to convergence, for the first time, a set of four coupled real axis Eliashberg equations for the superconducting gap and renormalization functions on each side of a proximity sandwich. We find that the phenomenological procedures developed to extract the size of the normal side electron-phonon interaction from tunneling data are often reasonable but may in some cases need modifications. In all the cases considered the superconducting phonon structure reflected on the normal side, as well as other structures, shows considerable agreement with experiment as to size, shape, and variation with barrier transmission coefficient. Finally, we study the effects of depairing on these structures

  20. Noise measurements on proximity effect bridges

    International Nuclear Information System (INIS)

    Decker, S.K.; Mercereau, J.E.

    1975-01-01

    Audio frequency noise density measurements were performed on weakly superconducting proximity effect bridges on using a cooled transformer and room temperature low noise preamplifier. The noise temperature of the measuring system is approximately 4 0 K for a 0.9 Ω resistor. Noise density was measured as a function of bias current and temperature for the bridges. Excess noise above that expected from Johnson noise for a resistor equal to the dynamic resistance of the bridges was observed in the region near the critical current of the device. At high currents compared to the critical current, the noise density closely approaches that given by Johnson noise

  1. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics.

    Science.gov (United States)

    Wilmes, Anja; Bielow, Chris; Ranninger, Christina; Bellwon, Patricia; Aschauer, Lydia; Limonciel, Alice; Chassaigne, Hubert; Kristl, Theresa; Aiche, Stephan; Huber, Christian G; Guillou, Claude; Hewitt, Philipp; Leonard, Martin O; Dekant, Wolfgang; Bois, Frederic; Jennings, Paul

    2015-12-25

    Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 μM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Little Leaguer's shoulder (proximal humeral epiphysiolysis): MRI findings in four boys

    International Nuclear Information System (INIS)

    Obembe, Olufolajimi O.; Gaskin, Cree M.; Anderson, Mark W.; Taffoni, Matthew J.

    2007-01-01

    Shoulder pain is a common problem among adolescent athletes. A possible cause of such pain that can be diagnosed on MRI is a stress injury to the proximal humerus known as Little Leaguer's shoulder (proximal humeral epiphysiolysis). Our objective was to describe the MRI appearance of Little Leaguer's shoulder. Four patients (all boys; age range 11-15 years; median 13 years) with clinical, plain radiographic, and MR imaging findings of Little Leaguer's shoulder were studied retrospectively. MRI demonstrated focal physeal widening in all four boys with extension of physeal signal intensity into the metaphysis on T1-weighted and gradient echo coronal and sagittal sequences. T2-weighted sequences were of limited use in demonstrating the physeal widening, which is critical to the diagnosis. Abnormal high T2-signal intensity was seen in the metaphysis adjacent to the focal physeal widening in all the boys. Focal extension of normal physeal T1-weighted and gradient echo signal intensity into the adjacent metaphysis is a sign of stress injury in the proximal humeral physis (Little Leaguer's shoulder). Children should suspend the offending sport to allow healing. (orig.)

  3. Congenital anomalies and proximity to landfill sites.

    LENUS (Irish Health Repository)

    Boyle, E

    2004-01-01

    The occurrence of congenital anomalies in proximity to municipal landfill sites in the Eastern Region (counties Dublin, Kildare, Wicklow) was examined by small area (district electoral division), distance and clustering tendancies in relation to 83 landfills, five of which were major sites. The study included 2136 cases of congenital anomaly, 37,487 births and 1423 controls between 1986 and 1990. For the more populous areas of the region 50% of the population lived within 2-3 km of a landfill and within 4-5 km for more rural areas. In the area-level analysis, the standardised prevalence ratios, empirical and full Bayesian modelling, and Kulldorff\\'s spatial scan statistic found no association between the residential area of cases and location of landfills. In the case control analysis, the mean distance of cases and controls from the nearest landfill was similar. The odds ratios of cases compared to controls for increasing distances from all landfills and major landfills showed no significant difference from the baseline value of 1. The kernel and K methods showed no tendency of cases to cluster in relationship to landfills. In conclusion, congenital anomalies were not found to occur more commonly in proximity to municipal landfills.

  4. Obesity and supermarket access: proximity or price?

    Science.gov (United States)

    Drewnowski, Adam; Aggarwal, Anju; Hurvitz, Philip M; Monsivais, Pablo; Moudon, Anne V

    2012-08-01

    We examined whether physical proximity to supermarkets or supermarket price was more strongly associated with obesity risk. The Seattle Obesity Study (SOS) collected and geocoded data on home addresses and food shopping destinations for a representative sample of adult residents of King County, Washington. Supermarkets were stratified into 3 price levels based on average cost of the market basket. Sociodemographic and health data were obtained from a telephone survey. Modified Poisson regression was used to test the associations between obesity and supermarket variables. Only 1 in 7 respondents reported shopping at the nearest supermarket. The risk of obesity was not associated with street network distances between home and the nearest supermarket or the supermarket that SOS participants reported as their primary food source. The type of supermarket, by price, was found to be inversely and significantly associated with obesity rates, even after adjusting for individual-level sociodemographic and lifestyle variables, and proximity measures (adjusted relative risk=0.34; 95% confidence interval=0.19, 0.63) Improving physical access to supermarkets may be one strategy to deal with the obesity epidemic; improving economic access to healthy foods is another.

  5. Amino-terminal domain of the v-fms oncogene product includes a functional signal peptide that directs synthesis of a transforming glycoprotein in the absence of feline leukemia virus gag sequences

    International Nuclear Information System (INIS)

    Wheeler, E.F.; Roussel, M.F.; Hampe, A.; Walker, M.H.; Fried, V.A.; Look, A.T.; Rettenmier, C.W.; Sherr, C.J.

    1986-01-01

    The nucleotide sequence of a 5' segment of the human genomic c-fms proto-oncogene suggested that recombination between feline leukemia virus and feline c-fms sequences might have occurred in a region encoding the 5' untranslated portion of c-fms mRNA. The polyprotein precursor gP180/sup gag-fms/ encoded by the McDonough strain of feline sarcoma virus was therefore predicted to contain 34 v-fms-coded amino acids derived from sequences of the c-fms gene that are not ordinarily translated from the proto-oncogene mRNA. The (gP180/sup gag-fms/) polyprotein was cotranslationally cleaved near the gag-fms junction to remove its gag gene-coded portion. Determination of the amino-terminal sequence of the resulting v-fms-coded glycoprotein, gp120/sup v-fms/, showed that the site of proteolysis corresponded to a predicted signal peptidase cleavage site within the c-fms gene product. Together, these analyses suggested that the linked gag sequences may not be necessary for expression of a biologically active v-fms gene product. The gag-fms sequences of feline sarcoma virus strain McDonough and the v-fms sequences alone were inserted into a murine retroviral vector containing a neomycin resistance gene. The authors conclude that a cryptic hydrophobic signal peptide sequence in v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms gene product within membranous organelles. It seems likely that the proteolytic cleavage of gP180/gag-fms/ is mediated by signal peptidase and that the amino termini of gp140/sup v-fms/ and the c-fms gene product are identical

  6. Amino-terminal domain of the v-fms oncogene product includes a functional signal peptide that directs synthesis of a transforming glycoprotein in the absence of feline leukemia virus gag sequences

    Energy Technology Data Exchange (ETDEWEB)

    Wheeler, E.F.; Roussel, M.F.; Hampe, A.; Walker, M.H.; Fried, V.A.; Look, A.T.; Rettenmier, C.W.; Sherr, C.J.

    1986-08-01

    The nucleotide sequence of a 5' segment of the human genomic c-fms proto-oncogene suggested that recombination between feline leukemia virus and feline c-fms sequences might have occurred in a region encoding the 5' untranslated portion of c-fms mRNA. The polyprotein precursor gP180/sup gag-fms/ encoded by the McDonough strain of feline sarcoma virus was therefore predicted to contain 34 v-fms-coded amino acids derived from sequences of the c-fms gene that are not ordinarily translated from the proto-oncogene mRNA. The (gP180/sup gag-fms/) polyprotein was cotranslationally cleaved near the gag-fms junction to remove its gag gene-coded portion. Determination of the amino-terminal sequence of the resulting v-fms-coded glycoprotein, gp120/sup v-fms/, showed that the site of proteolysis corresponded to a predicted signal peptidase cleavage site within the c-fms gene product. Together, these analyses suggested that the linked gag sequences may not be necessary for expression of a biologically active v-fms gene product. The gag-fms sequences of feline sarcoma virus strain McDonough and the v-fms sequences alone were inserted into a murine retroviral vector containing a neomycin resistance gene. The authors conclude that a cryptic hydrophobic signal peptide sequence in v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms gene product within membranous organelles. It seems likely that the proteolytic cleavage of gP180/gag-fms/ is mediated by signal peptidase and that the amino termini of gp140/sup v-fms/ and the c-fms gene product are identical.

  7. The N-methyl-D-aspartate receptor subunits NR2A and NR2B bind to the SH2 domains of phospholipase C-gamma.

    Science.gov (United States)

    Gurd, J W; Bissoon, N

    1997-08-01

    The NMDA receptor has recently been found to be phosphorylated on tyrosine. To assess the possible connection between tyrosine phosphorylation of the NMDA receptor and signaling pathways in the postsynaptic cell, we have investigated the relationship between tyrosine phosphorylation and the binding of NMDA receptor subunits to the SH2 domains of phospholipase C-gamma (PLC-gamma). A glutathione S-transferase (GST) fusion protein containing both the N- and the C-proximal SH2 domains of PLC-gamma was bound to glutathione-agarose and reacted with synaptic junctional proteins and glycoproteins. Tyrosine-phosphorylated PSD-GP180, which has been identified as the NR2B subunit of the NMDA receptor, bound to the SH2-agarose beads in a phosphorylation-dependent fashion. Immunoblot analysis with antibodies specific for individual NMDA receptor subunits showed that both NR2A and NR2B subunits bound to the SH2-agarose. No binding occurred to GST-agarose lacking an associated SH2 domain, indicating that binding was specific for the SH2 domains. The binding of receptor subunits increased after the incubation of synaptic junctions with ATP and decreased after treatment of synaptic junctions with exogenous protein tyrosine phosphatase. Immunoprecipitation experiments confirmed that NR2A and NR2B were phosphorylated on tyrosine and further that tyrosine phosphorylation of each of the subunits was increased after incubation with ATP. The results demonstrate that NMDA receptor subunits NR2A and NR2B will bind to the SH2 domains of PLC-gamma and that isolated synaptic junctions contain endogenous protein tyrosine kinase(s) that can phosphorylate both NR2A and NR2B receptor subunits, and suggest that interaction of the tyrosine-phosphorylated NMDA receptor with proteins that contain SH2 domains may serve to link it to signaling pathways in the postsynaptic cell.

  8. Frequency Domain Image Filtering Using CUDA

    Directory of Open Access Journals (Sweden)

    Muhammad Awais Rajput

    2014-10-01

    Full Text Available In this paper, we investigate the implementation of image filtering in frequency domain using NVIDIA?s CUDA (Compute Unified Device Architecture. In contrast to signal and image filtering in spatial domain which uses convolution operations and hence is more compute-intensive for filters having larger spatial extent, the frequency domain filtering uses FFT (Fast Fourier Transform which is much faster and significantly reduces the computational complexity of the filtering. We implement the frequency domain filtering on CPU and GPU respectively and analyze the speed-up obtained from the CUDA?s parallel processing paradigm. In order to demonstrate the efficiency of frequency domain filtering on CUDA, we implement three frequency domain filters, i.e., Butterworth, low-pass and Gaussian for processing different sizes of images on CPU and GPU respectively and perform the GPU vs. CPU benchmarks. The results presented in this paper show that the frequency domain filtering with CUDA achieves significant speed-up over the CPU processing in frequency domain with the same level of (output image quality on both the processing architectures

  9. Frequency domain image filtering using cuda

    International Nuclear Information System (INIS)

    Rajput, M.A.; Khan, U.A.

    2014-01-01

    In this paper, we investigate the implementation of image filtering in frequency domain using NVIDIA's CUDA (Compute Unified Device Architecture). In contrast to signal and image filtering in spatial domain which uses convolution operations and hence is more compute-intensive for filters having larger spatial extent, the frequency domain filtering uses FFT (Fast Fourier Transform) which is much faster and significantly reduces the computational complexity of the filtering. We implement the frequency domain filtering on CPU and GPU respectively and analyze the speed-up obtained from the CUDA's parallel processing paradigm. In order to demonstrate the efficiency of frequency domain filtering on CUDA, we implement three frequency domain filters, i.e., Butter worth, low-pass and Gaussian for processing different sizes of images on CPU and GPU respectively and perform the GPU vs. CPU benchmarks. The results presented in this paper show that the frequency domain filtering with CUDA achieves significant speed-up over the CPU processing in frequency domain with the same level of (output) image quality on both the processing architectures. (author)

  10. Structure of a conserved hypothetical protein SA1388 from S. aureus reveals a capped hexameric toroid with two PII domain lids and a dinuclear metal center

    Directory of Open Access Journals (Sweden)

    Leybourne Matthew

    2006-12-01

    Full Text Available Abstract Background The protein encoded by the SA1388 gene from Staphylococcus aureus was chosen for structure determination to elucidate its domain organization and confirm our earlier remote homology based prediction that it housed a nitrogen regulatory PII protein-like domain. SA1388 was predicted to contain a central PII-like domain and two flanking regions, which together belong to the NIF3-like protein family. Proteins like SA1388 remain a poorly studied group and their structural characterization could guide future investigations aimed at understanding their function. Results The structure of SA1388 has been solved to 2.0Å resolution by single wavelength anomalous dispersion phasing method using selenium anomalous signals. It reveals a canonical NIF3-like fold containing two domains with a PII-like domain inserted in the middle of the polypeptide. The N and C terminal halves of the NIF3-like domains are involved in dimerization, while the PII domain forms trimeric contacts with symmetry related monomers. Overall, the NIF3-like domains of SA1388 are organized as a hexameric toroid similar to its homologs, E. coli ybgI and the hypothetical protein SP1609 from Streptococcus pneumoniae. The openings on either side of the toroid are partially covered by trimeric "lids" formed by the PII domains. The junction of the two NIF3 domains has two zinc ions bound at what appears to be a histidine rich active site. A well-defined electron density corresponding to an endogenously bound ligand of unknown identity is observed in close proximity to the metal site. Conclusion SA1388 is the third member of the NIF3-like family of proteins to be structurally characterized, the other two also being hypothetical proteins of unknown function. The structure of SA1388 confirms our earlier prediction that the inserted domain that separates the two NIF3 domains adopts a PII-like fold and reveals an overall capped toroidal arrangement for the protein hexamer. The

  11. The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity

    International Nuclear Information System (INIS)

    Meissner, Torsten B.; Li, Amy; Liu, Yuen-Joyce; Gagnon, Etienne; Kobayashi, Koichi S.

    2012-01-01

    Highlights: ► NLRC5 requires an intact NLS for its function as MHC class I transactivator. ► Nuclear presence of NLRC5 is required for MHC class I induction. ► Nucleotide-binding controls nuclear import and transactivation activity of NLRC5. -- Abstract: Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. A member of the NLR (nucleotide-binding domain, leucine-rich repeat) protein family, NLRC5, has recently been identified as a transcriptional regulator of MHC class I and related genes. While a ‘master regulator’ of MHC class II genes, CIITA, has long been known, NLRC5 specifically associates with and transactivates the proximal promoters of MHC class I genes. In this study, we analyzed the molecular requirements of NLRC5 nuclear import and transactivation activity. We show that NLRC5-mediated MHC class I gene induction requires an intact nuclear localization signal and nuclear distribution of NLRC5. In addition, we find that the nucleotide-binding domain (NBD) of NLRC5 is critical not only for nuclear translocation but also for the transactivation of MHC class I genes. Changing the cellular localization of NLRC5 is likely to immediately impact MHC class I expression as well as MHC class I-mediated antigen presentation. NLRC5 may thus provide a promising target for the modulation of MHC class I antigen presentation, especially in the setting of transplant medicine.

  12. Promoter proximal polyadenylation sites reduce transcription activity

    DEFF Research Database (Denmark)

    Andersen, Pia Kjølhede; Lykke-Andersen, Søren; Jensen, Torben Heick

    2012-01-01

    Gene expression relies on the functional communication between mRNA processing and transcription. We previously described the negative impact of a point-mutated splice donor (SD) site on transcription. Here we demonstrate that this mutation activates an upstream cryptic polyadenylation (CpA) site......, which in turn causes reduced transcription. Functional depletion of U1 snRNP in the context of the wild-type SD triggers the same CpA event accompanied by decreased RNA levels. Thus, in accordance with recent findings, U1 snRNP can shield premature pA sites. The negative impact of unshielded pA sites...... on transcription requires promoter proximity, as demonstrated using artificial constructs and supported by a genome-wide data set. Importantly, transcription down-regulation can be recapitulated in a gene context devoid of splice sites by placing a functional bona fide pA site/transcription terminator within ∼500...

  13. Children’s proximal societal conditions

    DEFF Research Database (Denmark)

    Stanek, Anja Hvidtfeldt

    or the children’s everyday life, but something that is represented through societal structures and actual persons participating (in political ways) within the institutional settings, in ways that has meaning to children’s possibilities to participate, learn and develop. Understanding school or daycare as (part of......) the children’s proximal societal conditions for development and learning, means for instance that considerations about an inclusive agenda in a (Danish) welfare state with well-developed school- and daycare system, are no longer simply thoughts about the school having space for as many pupils as possible...... (schools for all). Such thoughts can or should be supplemented by reflections about which version of ‘the societal’ we wish to present our children with, and which version of ‘the societal’ we wish to set up as the condition for children’s participation and development. These questions require an ethical...

  14. One-Time URL: A Proximity Security Mechanism between Internet of Things and Mobile Devices.

    Science.gov (United States)

    Solano, Antonio; Dormido, Raquel; Duro, Natividad; González, Víctor

    2016-10-13

    The aim of this paper is to determine the physical proximity of connected things when they are accessed from a smartphone. Links between connected things and mobile communication devices are temporarily created by means of dynamic URLs (uniform resource locators) which may be easily discovered with pervasive short-range radio frequency technologies available on smartphones. In addition, a multi cross domain silent logging mechanism to allow people to interact with their surrounding connected things from their mobile communication devices is presented. The proposed mechanisms are based in web standards technologies, evolving our social network of Internet of Things towards the so-called Web of Things.

  15. Parametric time-frequency domain spatial audio

    CERN Document Server

    Delikaris-Manias, Symeon; Politis, Archontis

    2018-01-01

    This book provides readers with the principles and best practices in spatial audio signal processing. It describes how sound fields and their perceptual attributes are captured and analyzed within the time-frequency domain, how essential representation parameters are coded, and how such signals are efficiently reproduced for practical applications. The book is split into four parts starting with an overview of the fundamentals. It then goes on to explain the reproduction of spatial sound before offering an examination of signal-dependent spatial filtering. The book finishes with coverage of both current and future applications and the direction that spatial audio research is heading in. Parametric Time-frequency Domain Spatial Audio focuses on applications in entertainment audio, including music, home cinema, and gaming--covering the capturing and reproduction of spatial sound as well as its generation, transduction, representation, transmission, and perception. This book will teach readers the tools needed...

  16. Engineering of kinase-based protein interacting devices: active expression of tyrosine kinase domains

    KAUST Repository

    Diaz Galicia, Miriam Escarlet

    2018-01-01

    is then translated into a FRET (Fluorescence Resonance Energy Transfer) signal is here proposed. To this end, DNA constructs for interaction amplification (split kinases), positive controls (intact kinase domains), scaffolding proteins and phosphopeptide - SH2-domain

  17. Supersymmetric domain walls

    NARCIS (Netherlands)

    Bergshoeff, Eric A.; Kleinschmidt, Axel; Riccioni, Fabio

    2012-01-01

    We classify the half-supersymmetric "domain walls," i.e., branes of codimension one, in toroidally compactified IIA/IIB string theory and show to which gauged supergravity theory each of these domain walls belong. We use as input the requirement of supersymmetric Wess-Zumino terms, the properties of

  18. Structure function relations in PDZ-domain-containing proteins ...

    Indian Academy of Sciences (India)

    G P Manjunath

    2017-12-30

    Dec 30, 2017 ... Implications for protein networks in cellular signalling ..... However, surface plasmon resonance .... entiate between conformation changes in the PDZ domain or .... NHERF1, through long-range electrostatic and hydrophobic.

  19. Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

    Directory of Open Access Journals (Sweden)

    Andrew D. Nelson

    2017-05-01

    Full Text Available Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of

  20. A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.

    Science.gov (United States)

    Courtney, Adam H; Amacher, Jeanine F; Kadlecek, Theresa A; Mollenauer, Marianne N; Au-Yeung, Byron B; Kuriyan, John; Weiss, Arthur

    2017-08-03

    The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck, which prevents its adoption of an active open conformation. These results suggest a negative feedback loop that responds to signaling events that tune active Lck amounts and TCR sensitivity. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Distributed Autonomous Control of Multiple Spacecraft During Close Proximity Operations

    National Research Council Canada - National Science Library

    McCamish, Shawn B

    2007-01-01

    This research contributes to multiple spacecraft control by developing an autonomous distributed control algorithm for close proximity operations of multiple spacecraft systems, including rendezvous...

  2. Proximal design for a multimodality endoscope with multiphoton microscopy, optical coherence microscopy and visual modalities

    Science.gov (United States)

    Kiekens, Kelli C.; Talarico, Olivia; Barton, Jennifer K.

    2018-02-01

    A multimodality endoscope system has been designed for early detection of ovarian cancer. Multiple illumination and detection systems must be integrated in a compact, stable, transportable configuration to meet the requirements of a clinical setting. The proximal configuration presented here supports visible light navigation with a large field of view and low resolution, high resolution multiphoton microscopy (MPM), and high resolution optical coherence microscopy (OCM). All modalities are integrated into a single optical system in the endoscope. The system requires two light sources: a green laser for visible light navigation and a compact fiber based femtosecond laser for MPM and OCM. Using an inline wavelength division multiplexer, the two sources are combined into a single mode fiber. To accomplish OCM, a fiber coupler is used to separate the femtosecond laser into a reference arm and signal arm. The reflected reference arm and the signal from the sample are interfered and wavelength separated by a reflection grating and detected using a linear array. The MPM signal is collimated and goes through a series of filters to separate the 2nd and 3rd harmonics as well as twophoton excitation florescence (2PEF) and 3PEF. Each signal is independently detected on a photo multiplier tube and amplified. The visible light is collected by multiple high numerical aperture fibers at the endoscope tip which are bundled into one SMA adapter at the proximal end and connected to a photodetector. This integrated system design is compact, efficient and meets both optical and mechanical requirements for clinical applications.

  3. ATP signals

    DEFF Research Database (Denmark)

    Novak, Ivana

    2016-01-01

    The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas......The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas...

  4. PROXIMAL DISABILITY AND SPINAL DEFORMITY INDEX IN PATIENTS WITH PROXIMAL FEMUR FRACTURES

    Directory of Open Access Journals (Sweden)

    Sylvio Mistro Neto

    2015-12-01

    Full Text Available Objective : To evaluate the quality of life related to the spine in patients with proximal femoral fractures. Methods : Study conducted in a tertiary public hospital in patients with proximal femoral fractures caused by low-energy trauma, through the Oswestry Disability Index questionnaire to asses complaints related to the spine at the time of life prior to the femoral fracture. The thoracic and lumbar spine of patients were also evaluated applying the radiographic index described by Gennant (Spinal Deformity Index, which assesses the number and severity of fractures. Results : Seventeen subjects completed the study. All had some degree of vertebral fracture. Patients were classified in the categories of severe and very severe disability in the questionnaire about quality of life. It was found that the higher SDI, the better the quality of life. Conclusion : There is a strong association of disability related to the spine in patients with proximal femoral fracture, and this complaint must be systematically evaluated in patients with appendicular fracture.

  5. Initial outcome and efficacy of S3 proximal humerus locking plate in the treatment of proximal humerus fractures

    International Nuclear Information System (INIS)

    Zhang Zhiming; Zhu Xuesong; Bao Zhaohua; Yang Huilin

    2012-01-01

    Objective: to explore the initial outcome and efficacy of S 3 proximal humerus locking plate in the treatment of proximal humerus fractures. Methods: Twenty-two patients with proximal humerus fracture were treated with the S 3 proximal humerus locking plate. Most of the fractures were complex, two-part (n=4), three-part (n=11) and four-part (n=7) fractures according to the Neer classification of the proximal humerus fractures. Results: All patients were followed up for 3∼15 months. There were no complications related to the implant including loosening or breakage of the plate. Good and excellent results were documented in 17 patients fair results in 4 patients according the Neer scores of shoulder. Conclusion: New design concepts of S 3 proximal humerus plate provide the subchondral support and the internal fixation support. With the addition of the proper exercise of the shoulder joint, the outcomes would be satisfied. (authors)

  6. Low-dose cone-beam CT via raw counts domain low-signal correction schemes: Performance assessment and task-based parameter optimization (Part II. Task-based parameter optimization).

    Science.gov (United States)

    Gomez-Cardona, Daniel; Hayes, John W; Zhang, Ran; Li, Ke; Cruz-Bastida, Juan Pablo; Chen, Guang-Hong

    2018-05-01

    Different low-signal correction (LSC) methods have been shown to efficiently reduce noise streaks and noise level in CT to provide acceptable images at low-radiation dose levels. These methods usually result in CT images with highly shift-variant and anisotropic spatial resolution and noise, which makes the parameter optimization process highly nontrivial. The purpose of this work was to develop a local task-based parameter optimization framework for LSC methods. Two well-known LSC methods, the adaptive trimmed mean (ATM) filter and the anisotropic diffusion (AD) filter, were used as examples to demonstrate how to use the task-based framework to optimize filter parameter selection. Two parameters, denoted by the set P, for each LSC method were included in the optimization problem. For the ATM filter, these parameters are the low- and high-signal threshold levels p l and p h ; for the AD filter, the parameters are the exponents δ and γ in the brightness gradient function. The detectability index d' under the non-prewhitening (NPW) mathematical observer model was selected as the metric for parameter optimization. The optimization problem was formulated as an unconstrained optimization problem that consisted of maximizing an objective function d'(P), where i and j correspond to the i-th imaging task and j-th spatial location, respectively. Since there is no explicit mathematical function to describe the dependence of d' on the set of parameters P for each LSC method, the optimization problem was solved via an experimentally measured d' map over a densely sampled parameter space. In this work, three high-contrast-high-frequency discrimination imaging tasks were defined to explore the parameter space of each of the LSC methods: a vertical bar pattern (task I), a horizontal bar pattern (task II), and a multidirectional feature (task III). Two spatial locations were considered for the analysis, a posterior region-of-interest (ROI) located within the noise streaks region

  7. Wavelet analysis for nonstationary signals

    International Nuclear Information System (INIS)

    Penha, Rosani Maria Libardi da

    1999-01-01

    Mechanical vibration signals play an important role in anomalies identification resulting of equipment malfunctioning. Traditionally, Fourier spectral analysis is used where the signals are assumed to be stationary. However, occasional transient impulses and start-up process are examples of nonstationary signals that can be found in mechanical vibrations. These signals can provide important information about the equipment condition, as early fault detection. The Fourier analysis can not adequately be applied to nonstationary signals because the results provide data about the frequency composition averaged over the duration of the signal. In this work, two methods for nonstationary signal analysis are used: Short Time Fourier Transform (STFT) and wavelet transform. The STFT is a method of adapting Fourier spectral analysis for nonstationary application to time-frequency domain. To have a unique resolution throughout the entire time-frequency domain is its main limitation. The wavelet transform is a new analysis technique suitable to nonstationary signals, which handles the STFT drawbacks, providing multi-resolution frequency analysis and time localization in a unique time-scale graphic. The multiple frequency resolutions are obtained by scaling (dilatation/compression) the wavelet function. A comparison of the conventional Fourier transform, STFT and wavelet transform is made applying these techniques to: simulated signals, arrangement rotor rig vibration signal and rotate machine vibration signal Hanning window was used to STFT analysis. Daubechies and harmonic wavelets were used to continuos, discrete and multi-resolution wavelet analysis. The results show the Fourier analysis was not able to detect changes in the signal frequencies or discontinuities. The STFT analysis detected the changes in the signal frequencies, but with time-frequency resolution problems. The wavelet continuos and discrete transform demonstrated to be a high efficient tool to detect

  8. Proximity Operations and Docking Sensor Development

    Science.gov (United States)

    Howard, Richard T.; Bryan, Thomas C.; Brewster, Linda L.; Lee, James E.

    2009-01-01

    The Next Generation Advanced Video Guidance Sensor (NGAVGS) has been under development for the last three years as a long-range proximity operations and docking sensor for use in an Automated Rendezvous and Docking (AR&D) system. The first autonomous rendezvous and docking in the history of the U.S. Space Program was successfully accomplished by Orbital Express, using the Advanced Video Guidance Sensor (AVGS) as the primary docking sensor. That flight proved that the United States now has a mature and flight proven sensor technology for supporting Crew Exploration Vehicles (CEV) and Commercial Orbital Transport Systems (COTS) Automated Rendezvous and Docking (AR&D). NASA video sensors have worked well in the past: the AVGS used on the Demonstration of Autonomous Rendezvous Technology (DART) mission operated successfully in spot mode out to 2 km, and the first generation rendezvous and docking sensor, the Video Guidance Sensor (VGS), was developed and successfully flown on Space Shuttle flights in 1997 and 1998. 12 Parts obsolescence issues prevent the construction of more AVGS units, and the next generation sensor was updated to allow it to support the CEV and COTS programs. The flight proven AR&D sensor has been redesigned to update parts and add additional capabilities for CEV and COTS with the development of the Next Generation AVGS at the Marshall Space Flight Center. The obsolete imager and processor are being replaced with new radiation tolerant parts. In addition, new capabilities include greater sensor range, auto ranging capability, and real-time video output. This paper presents some sensor hardware trades, use of highly integrated laser components, and addresses the needs of future vehicles that may rendezvous and dock with the International Space Station (ISS) and other Constellation vehicles. It also discusses approaches for upgrading AVGS to address parts obsolescence, and concepts for minimizing the sensor footprint, weight, and power requirements

  9. Videosensor for the detection of unsafe driving behavior in the proximity of black spots.

    Science.gov (United States)

    Fuentes, Andres; Fuentes, Ricardo; Cabello, Enrique; Conde, Cristina; Martin, Isaac

    2014-10-24

    This paper discusses the overall design and implementation of a video sensor for the detection of risky behaviors of car drivers near previously identified and georeferenced black spots. The main goal is to provide the driver with a visual audio alert that informs of the proximity of an area of high incidence of highway accidents only if their driving behavior could result in a risky situation. It proposes a video sensor for detecting and supervising driver behavior, its main objective being manual distractions, so hand driver supervision is performed. A GPS signal is also considered, the GPS information is compared with a database of global positioning Black Spots to determine the relative proximity of a risky area. The outputs of the video sensor and GPS sensor are combined to evaluate a possible risky behavior. The results are promising in terms of risk analysis in order to be validated for use in the context of the automotive industry as future work.

  10. Videosensor for the Detection of Unsafe Driving Behavior in the Proximity of Black Spots

    Directory of Open Access Journals (Sweden)

    Andres Fuentes

    2014-10-01

    Full Text Available This paper discusses the overall design and implementation of a video sensor for the detection of risky behaviors of car drivers near previously identified and georeferenced black spots. The main goal is to provide the driver with a visual audio alert that informs of the proximity of an area of high incidence of highway accidents only if their driving behavior could result in a risky situation. It proposes a video sensor for detecting and supervising driver behavior, its main objective being manual distractions, so hand driver supervision is performed. A GPS signal is also considered, the GPS information is compared with a database of global positioning Black Spots to determine the relative proximity of a risky area. The outputs of the video sensor and GPS sensor are combined to evaluate a possible risky behavior. The results are promising in terms of risk analysis in order to be validated for use in the context of the automotive industry as future work.

  11. 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.

  12. 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.

  13. Structure and Function of an Actin-Based Filter in the Proximal Axon

    Directory of Open Access Journals (Sweden)

    Varuzhan Balasanyan

    2017-12-01

    Full Text Available Summary: The essential organization of microtubules within neurons has been described; however, less is known about how neuronal actin is arranged and the functional implications of its arrangement. Here, we describe, in live cells, an actin-based structure in the proximal axon that selectively prevents some proteins from entering the axon while allowing the passage of others. Concentrated patches of actin in proximal axons are present shortly after axonal specification in rat and zebrafish neurons imaged live, and they mark positions where anterogradely traveling vesicles carrying dendritic proteins halt and reverse. Patches colocalize with the ARP2/3 complex, and when ARP2/3-mediated nucleation is blocked, a dendritic protein mislocalizes to the axon. Patches are highly dynamic, with few persisting longer than 30 min. In neurons in culture and in vivo, actin appears to form a contiguous, semipermeable barrier, despite its apparently sparse distribution, preventing axonal localization of constitutively active myosin Va but not myosin VI. : Balasanyan et al. find dynamic patches of actin in proximal axons of live neurons, mature and newly differentiated, in culture and in vivo. Patches contribute to a filter that sequesters some proteins within the somatodendritic domain while allowing others to pass into the axon, leading to polarized localization of proteins.

  14. Proximity coupling in superconductor-graphene heterostructures

    Science.gov (United States)

    Lee, Gil-Ho; Lee, Hu-Jong

    2018-05-01

    This review discusses the electronic properties and the prospective research directions of superconductor-graphene heterostructures. The basic electronic properties of graphene are introduced to highlight the unique possibility of combining two seemingly unrelated physics, superconductivity and relativity. We then focus on graphene-based Josephson junctions, one of the most versatile superconducting quantum devices. The various theoretical methods that have been developed to describe graphene Josephson junctions are examined, together with their advantages and limitations, followed by a discussion on the advances in device fabrication and the relevant length scales. The phase-sensitive properties and phase-particle dynamics of graphene Josephson junctions are examined to provide an understanding of the underlying mechanisms of Josephson coupling via graphene. Thereafter, microscopic transport of correlated quasiparticles produced by Andreev reflections at superconducting interfaces and their phase-coherent behaviors are discussed. Quantum phase transitions studied with graphene as an electrostatically tunable 2D platform are reviewed. The interplay between proximity-induced superconductivity and the quantum-Hall phase is discussed as a possible route to study topological superconductivity and non-Abelian physics. Finally, a brief summary on the prospective future research directions is given.

  15. [Ophthalmologists in the proximity of Adolf Hitler].

    Science.gov (United States)

    Rohrbach, J M

    2012-10-01

    Adolf Hitler met or at least knew about 5 ophthalmologists. The chair of ophthalmology in Berlin, Walther Löhlein, personally examined Hitler's eyes at least two times. The chair of ophthalmology in Breslau, Walter Dieter, developed "air raid protection spectacles" with the aid of high representatives of the NS-system and probably Adolf Hitler himself. Heinrich Wilhelm Kranz became rector of the universities of Giessen and Frankfurt/Main. He was known as a very strict advocate of the NS-race hygiene. Werner Zabel made plans for Hitler's diet and tried to interfere with Hitler's medical treatment. Finally, Hellmuth Unger was an influential representative of the medical press and a famous writer. Three of his novels with medical topics were made into a film which Hitler probably saw. Hitler had, so to say, a small "ophthalmological proximity" which, however, did not play a significant role for himself or the NS-state. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Imaging of rectus femoris proximal tendinopathies

    International Nuclear Information System (INIS)

    Pesquer, Lionel; Poussange, Nicolas; Meyer, Philippe; Dallaudiere, Benjamin; Feldis, Matthieu; Sonnery-Cottet, Bertrand; Graveleau, Nicolas

    2016-01-01

    The rectus femoris is the most commonly injured muscle of the anterior thigh among athletes, especially soccer players. Although the injury pattern of the muscle belly is well documented, less is known about the anatomy and specific lesions of the proximal tendons. For each head, three distinctive patterns may be encountered according to the location of the injury, which can be at the enthesis, within the tendon, or at the musculotendinous junction. In children, injuries correspond most commonly to avulsion of the anteroinferior iliac spine from the direct head and can lead to subspine impingement. Calcific tendinitis and traumatic tears may be encountered in adults. Recent studies have shown that traumatic injuries of the indirect head may be underdiagnosed and that injuries of both heads may have a surgical issue. Finally, in the case of tears, functional outcome and treatment may vary if the rupture involves one or both tendons and if the tear is partial or complete. Thus, it is mandatory for the radiologist to know the different ultrasound and magnetic resonance imaging (MRI) patterns of these lesions in order to provide accurate diagnosis and treatment. The purpose of this article is to recall the anatomy of the two heads of rectus femoris, describe a reliable method of assessment with ultrasound and MRI and know the main injury patterns, through our own experience and literature review. (orig.)

  17. Proximal spinal muscular atrophy: current orthopedic perspective

    Directory of Open Access Journals (Sweden)

    Haaker G

    2013-11-01

    Full Text Available Gerrit Haaker, Albert Fujak Department of Orthopaedic Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Abstract: Spinal muscular atrophy (SMA is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective "survival motor neuron" (SMN protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach. Keywords: spinal muscular atrophy, scoliosis, contractures, fractures, lung function, treatment, rehabilitation, surgery, ventilation, nutrition, perioperative management

  18. Imaging of rectus femoris proximal tendinopathies

    Energy Technology Data Exchange (ETDEWEB)

    Pesquer, Lionel; Poussange, Nicolas; Meyer, Philippe; Dallaudiere, Benjamin; Feldis, Matthieu [Clinique du Sport de Bordeaux, Centre d' Imagerie Osteo-articulaire, Merignac (France); Sonnery-Cottet, Bertrand [Groupe Ramsay Generale de Sante - Hopital Prive Jean Mermoz, Centre Orthopedique Santy, Lyon (France); Graveleau, Nicolas [Clinique du Sport de Bordeaux, Centre de Chirurgie Orthopedique et Sportive, Merignac (France)

    2016-07-15

    The rectus femoris is the most commonly injured muscle of the anterior thigh among athletes, especially soccer players. Although the injury pattern of the muscle belly is well documented, less is known about the anatomy and specific lesions of the proximal tendons. For each head, three distinctive patterns may be encountered according to the location of the injury, which can be at the enthesis, within the tendon, or at the musculotendinous junction. In children, injuries correspond most commonly to avulsion of the anteroinferior iliac spine from the direct head and can lead to subspine impingement. Calcific tendinitis and traumatic tears may be encountered in adults. Recent studies have shown that traumatic injuries of the indirect head may be underdiagnosed and that injuries of both heads may have a surgical issue. Finally, in the case of tears, functional outcome and treatment may vary if the rupture involves one or both tendons and if the tear is partial or complete. Thus, it is mandatory for the radiologist to know the different ultrasound and magnetic resonance imaging (MRI) patterns of these lesions in order to provide accurate diagnosis and treatment. The purpose of this article is to recall the anatomy of the two heads of rectus femoris, describe a reliable method of assessment with ultrasound and MRI and know the main injury patterns, through our own experience and literature review. (orig.)

  19. Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells.

    Science.gov (United States)

    Schramek, Herbert; Sarközi, Rita; Lauterberg, Christina; Kronbichler, Andreas; Pirklbauer, Markus; Albrecht, Rudolf; Noppert, Susie-Jane; Perco, Paul; Rudnicki, Michael; Strutz, Frank M; Mayer, Gert

    2009-11-01

    Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins with large extracellular domains that interact with class 3 semaphorins, vascular endothelial growth factor (VEGF) family members, and ligands, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-beta1 (TGF-beta1), and fibroblast growth factor2 (FGF2). Neuropilins (NRPs) have been implicated in tumor growth and vascularization, as novel mediators of the primary immune response and in regeneration and repair; however, their role in renal pathophysiology is largely unknown. Here, we report upregulation of tubular and interstitial NRP2 protein expression in patients with focal segmental glomerulosclerosis (FSGS). In an additional cohort of patients with minimal change disease (MCD), membranous nephropathy (MN), and FSGS, elevated NRP2 mRNA expression in kidney biopsies inversely correlated with estimated glomerular filtration rate (eGFR) at the time of biopsy. Furthermore, upregulation of NRP2 mRNA correlated with post-bioptic decline of kidney function. Expression of NRP1 and NRP2 in human proximal tubular cells (PTCs) was differentially affected after stimulation with TGF-beta1, interleukin-1beta (IL-1beta), and oncostatin M (OSM). Although the pro-fibrotic mediators, TGF-beta1 and IL-1beta, induced upregulation of NRP2 expression but downregulation of NRP1 expression, OSM stimulated the expression of both NRP1 and NRP2. Basal and OSM-induced NRP1 mRNA expression, as well as TGF-beta1-induced NRP2 mRNA and protein expression were partially mediated by MEK1/2-ERK1/2 signaling. This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis, and TGF-beta1, IL-1beta, and OSM represent the first ligands known to stimulate NRP2 expression in mammalian cells.

  20. Wavelet-Based Signal Processing of Electromagnetic Pulse Generated Waveforms

    National Research Council Canada - National Science Library

    Ardolino, Richard S

    2007-01-01

    This thesis investigated and compared alternative signal processing techniques that used wavelet-based methods instead of traditional frequency domain methods for processing measured electromagnetic pulse (EMP) waveforms...

  1. Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.

    Science.gov (United States)

    Zhao, Li-Hua; Yin, Yanting; Yang, Dehua; Liu, Bo; Hou, Li; Wang, Xiaoxi; Pal, Kuntal; Jiang, Yi; Feng, Yang; Cai, Xiaoqing; Dai, Antao; Liu, Mingyao; Wang, Ming-Wei; Melcher, Karsten; Xu, H Eric

    2016-07-15

    G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain.

    Science.gov (United States)

    Huber, Roland G; Fan, Hao; Bond, Peter J

    2015-10-01

    ZAP-70 (Zeta-chain-associated protein kinase 70) is a tyrosine kinase that interacts directly with the activated T-cell receptor to transduce downstream signals, and is hence a major player in the regulation of the adaptive immune response. Dysfunction of ZAP-70 causes selective T cell deficiency that in turn results in persistent infections. ZAP-70 is activated by a variety of signals including phosphorylation of the kinase domain (KD), and binding of its regulatory tandem Src homology 2 (SH2) domains to the T cell receptor. The present study investigates molecular mechanisms of activation and inhibition of ZAP-70 via atomically detailed molecular dynamics simulation approaches. We report microsecond timescale simulations of five distinct states of the ZAP-70 KD, comprising apo, inhibited and three phosphorylated variants. Extensive analysis of local flexibility and correlated motions reveal crucial transitions between the states, thus elucidating crucial steps in the activation mechanism of the ZAP-70 KD. Furthermore, we rationalize previously observed staurosporine-bound crystal structures, suggesting that whilst the KD superficially resembles an "active-like" conformation, the inhibitor modulates the underlying protein dynamics and restricts it in a compact, rigid state inaccessible to ligands or cofactors. Finally, our analysis reveals a novel, potentially druggable pocket in close proximity to the activation loop of the kinase, and we subsequently use its structure in fragment-based virtual screening to develop a pharmacophore model. The pocket is distinct from classical type I or type II kinase pockets, and its discovery offers promise in future design of specific kinase inhibitors, whilst mutations in residues associated with this pocket are implicated in immunodeficiency in humans.

  3. The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain.

    Directory of Open Access Journals (Sweden)

    Roland G Huber

    2015-10-01

    Full Text Available ZAP-70 (Zeta-chain-associated protein kinase 70 is a tyrosine kinase that interacts directly with the activated T-cell receptor to transduce downstream signals, and is hence a major player in the regulation of the adaptive immune response. Dysfunction of ZAP-70 causes selective T cell deficiency that in turn results in persistent infections. ZAP-70 is activated by a variety of signals including phosphorylation of the kinase domain (KD, and binding of its regulatory tandem Src homology 2 (SH2 domains to the T cell receptor. The present study investigates molecular mechanisms of activation and inhibition of ZAP-70 via atomically detailed molecular dynamics simulation approaches. We report microsecond timescale simulations of five distinct states of the ZAP-70 KD, comprising apo, inhibited and three phosphorylated variants. Extensive analysis of local flexibility and correlated motions reveal crucial transitions between the states, thus elucidating crucial steps in the activation mechanism of the ZAP-70 KD. Furthermore, we rationalize previously observed staurosporine-bound crystal structures, suggesting that whilst the KD superficially resembles an "active-like" conformation, the inhibitor modulates the underlying protein dynamics and restricts it in a compact, rigid state inaccessible to ligands or cofactors. Finally, our analysis reveals a novel, potentially druggable pocket in close proximity to the activation loop of the kinase, and we subsequently use its structure in fragment-based virtual screening to develop a pharmacophore model. The pocket is distinct from classical type I or type II kinase pockets, and its discovery offers promise in future design of specific kinase inhibitors, whilst mutations in residues associated with this pocket are implicated in immunodeficiency in humans.

  4. Conserved Domain Database (CDD)

    Data.gov (United States)

    U.S. Department of Health & Human Services — CDD is a protein annotation resource that consists of a collection of well-annotated multiple sequence alignment models for ancient domains and full-length proteins.

  5. Proximate analysis of female population of wild feather back fish ...

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... Key words: Body composition, Notopterus notopterus, condition factor, wild fish. INTRODUCTION. Proximate body composition is the analysis of water, fat, protein and ash contents of the fish (Love, 1980). Proximate composition is a good indicator of physiology which is needed for routine analysis of ...

  6. Proximate analysis of Lentinus squarrosulus (Mont.) Singer and ...

    African Journals Online (AJOL)

    Each of the mushroom species was separated into its stipe and pileus and used for proximate analysis. There was a highly significant difference (p<0.01) in the proximate composition of the two species. P. atroumbonata had significantly higher crude protein, crude fibre and moisture content than L. squarrosulus while the ...

  7. Proximal Focal Femoral Deficiency in Ibadan a Developing ...

    African Journals Online (AJOL)

    The cultural aversion to amputation in our environment makes it difficult to employ that option of treatment. Proximal focal femoral deficiency in Ibadan a developing country's perspective and a review of the literature. Keywords: Proximal focal femoral deficiency , congenital malformations , limb malformations , lower limb ...

  8. Proximity approach to problems in topology and analysis

    CERN Document Server

    Naimpally, Somashekhar

    2009-01-01

    Dieses Buch konzentriert das aktuelle Gesamtwissen zum Proximity-Konzept und stellt es dem Leser in gut strukturierter Form dar. Hauptaugenmerk liegt auf den vielfältigen Möglichkeiten, die sich aus dem Proximity-Konzept der räumlichen Nähe und seiner Verallgemeinerung im Nearness-Konzept ergeben.

  9. Systemic calciphylaxis presenting as a painful, proximal myopathy.

    OpenAIRE

    Edelstein, C. L.; Wickham, M. K.; Kirby, P. A.

    1992-01-01

    A renal transplant patient who presented with a painful, proximal myopathy due to systemic calciphylaxis is described. The myopathy preceded the characteristic skin and soft tissue necrosis. Systemic calciphylaxis should be considered in a dialysis or a renal transplant patient presenting with a painful proximal myopathy even in the absence of necrotic skin lesions.

  10. Genetics Home Reference: proximal 18q deletion syndrome

    Science.gov (United States)

    ... characteristic features. Most cases of proximal 18q deletion syndrome are the result of a new (de novo) deletion and are not inherited from a ... J, Fox PT, Stratton RF, Perry B, Hale DE. Recurrent interstitial deletions of proximal 18q: a new syndrome involving expressive speech delay. Am J Med Genet ...

  11. Proximal soil sensors and data fusion for precision agriculture

    NARCIS (Netherlands)

    Mahmood, H.S.

    2013-01-01

    different remote and proximal soil sensors are available today that can scan entire fields and give detailed information on various physical, chemical, mechanical and biological soil properties. The first objective of this thesis was to evaluate different proximal soil sensors available today and to

  12. Two Stages repair of proximal hypospadias: Review of 33 cases

    African Journals Online (AJOL)

    HussamHassan

    Background/Purpose: Proximal hypospadias with chordee is the most challenging variant of hypospadias to reconstruct. During the last 10 years, the approach to sever hypospadias has been controversial. Materials & Methods: During the period from June 2002 to December 2009, I performed 33 cases with proximal.

  13. Proximity correction of high-dosed frame with PROXECCO

    Science.gov (United States)

    Eisenmann, Hans; Waas, Thomas; Hartmann, Hans

    1994-05-01

    Usefulness of electron beam lithography is strongly related to the efficiency and quality of methods used for proximity correction. This paper addresses the above issue by proposing an extension to the new proximity correction program PROXECCO. The combination of a framing step with PROXECCO produces a pattern with a very high edge accuracy and still allows usage of the fast correction procedure. Making a frame with a higher dose imitates a fine resolution correction where the coarse part is disregarded. So after handling the high resolution effect by means of framing, an additional coarse correction is still needed. Higher doses have a higher contribution to the proximity effect. This additional proximity effect is taken into account with the help of the multi-dose input of PROXECCO. The dose of the frame is variable, depending on the deposited energy coming from backscattering of the proximity. Simulation proves the very high edge accuracy of the applied method.

  14. Auditory signal design for automatic number plate recognition system

    NARCIS (Netherlands)

    Heydra, C.G.; Jansen, R.J.; Van Egmond, R.

    2014-01-01

    This paper focuses on the design of an auditory signal for the Automatic Number Plate Recognition system of Dutch national police. The auditory signal is designed to alert police officers of suspicious cars in their proximity, communicating priority level and location of the suspicious car and

  15. Image averaging of flexible fibrous macromolecules: the clathrin triskelion has an elastic proximal segment.

    Science.gov (United States)

    Kocsis, E; Trus, B L; Steer, C J; Bisher, M E; Steven, A C

    1991-08-01

    We have developed computational techniques that allow image averaging to be applied to electron micrographs of filamentous molecules that exhibit tight and variable curvature. These techniques, which involve straightening by cubic-spline interpolation, image classification, and statistical analysis of the molecules' curvature properties, have been applied to purified brain clathrin. This trimeric filamentous protein polymerizes, both in vivo and in vitro, into a wide range of polyhedral structures. Contrasted by low-angle rotary shadowing, dissociated clathrin molecules appear as distinctive three-legged structures, called "triskelions" (E. Ungewickell and D. Branton (1981) Nature 289, 420). We find triskelion legs to vary from 35 to 62 nm in total length, according to an approximately bell-shaped distribution (mu = 51.6 nm). Peaks in averaged curvature profiles mark hinges or sites of enhanced flexibility. Such profiles, calculated for each length class, show that triskelion legs are flexible over their entire lengths. However, three curvature peaks are observed in every case: their locations define a proximal segment of systematically increasing length (14.0-19.0 nm), a mid-segment of fixed length (approximately 12 nm), and a rather variable end-segment (11.6-19.5 nm), terminating in a hinge just before the globular terminal domain (approximately 7.3 nm diameter). Thus, two major factors contribute to the overall variability in leg length: (1) stretching of the proximal segment and (2) stretching of the end-segment and/or scrolling of the terminal domain. The observed elasticity of the proximal segment may reflect phosphorylation of the clathrin light chains.

  16. Interactive orbital proximity operations planning system

    Science.gov (United States)

    Grunwald, Arthur J.; Ellis, Stephen R.

    1990-01-01

    An interactive graphical planning system for on-site planning of proximity operations in the congested multispacecraft environment about the space station is presented. The system shows the astronaut a bird's eye perspective of the space station, the orbital plane, and the co-orbiting spacecraft. The system operates in two operational modes: (1) a viewpoint mode, in which the astronaut is able to move the viewpoint around in the orbital plane to range in on areas of interest; and (2) a trajectory design mode, in which the trajectory is planned. Trajectory design involves the composition of a set of waypoints which result in a fuel-optimal trajectory which satisfies all operational constraints, such as departure and arrival constraints, plume impingement constraints, and structural constraints. The main purpose of the system is to present the trajectory and the constraints in an easily interpretable graphical format. Through a graphical interactive process, the trajectory waypoints are edited until all operational constraints are satisfied. A series of experiments was conducted to evaluate the system. Eight airline pilots with no prior background in orbital mechanics participated in the experiments. Subject training included a stand-alone training session of about 6 hours duration, in which the subjects became familiar with orbital mechanics concepts and performed a series of exercises to familiarize themselves with the control and display features of the system. They then carried out a series of production runs in which 90 different trajectory design situations were randomly addressed. The purpose of these experiments was to investigate how the planning time, planning efforts, and fuel expenditures were affected by the planning difficulty. Some results of these experiments are presented.

  17. Selective proximal vagotomy with and without pyloroplasty

    International Nuclear Information System (INIS)

    Brodersen, E.

    1984-01-01

    It was the aim of the study described here to gain information relevant to the well-being of patients subjected to selective proximal vagotomy with or without pyroloplasty as soon as possible after surgery. For this purpose, particular care was taken to ascertain the frequency of recidivation and the post-operative occurrence of disturbances in the emptying of gastric contents. In 35 patients solely undergoing SPV and a further 12 individuals, where both SPV and pyroloplasty had been performed, gastric emptying was monitored using a gamma camera and computer system. All patients were given a standardised test meal consisting of 500 ml ready-made milk labeled with 2 mCi 99mTc-HSA. After the patients had been assigned to different study groups according to the gastric emptying rates established in the individual cases, it became evident that there was a correlation between gastric emptying time (T/2) and the occurrence of post-operative discomfort. In the majority of patients the gastric emptying rate was found to be increased as compared to individuals with a healthy stomach. Among a total of 8 patients showing delayed gastric emptying only one, who solely underwent SPV, reported post-operative discomfort. Markedly increased rates of gastric emptying (T/2 ≤ 5 min) were predominantly determined in patients subjected to SPV in conjunction with pyroloplasty. A dumping syndrome and diarrhea were diagnosed in every third patient. Clinical follow-up studies and questionnaires distributed among the study patients showed relapses to occur with a frequency of 6.7%, the recidivation of ulcera being confined to the group of patients merely undergoing SPV. (TRV) [de

  18. Nanocrystal Bioassembly: Asymmetry, Proximity, and Enzymatic Manipulation

    Energy Technology Data Exchange (ETDEWEB)

    Claridge, Shelley A. [Univ. of California, Berkeley, CA (United States)

    2008-05-01

    Research at the interface between biomolecules and inorganic nanocrystals has resulted in a great number of new discoveries. In part this arises from the synergistic duality of the system: biomolecules may act as self-assembly agents for organizing inorganic nanocrystals into functional materials; alternatively, nanocrystals may act as microscopic or spectroscopic labels for elucidating the behavior of complex biomolecular systems. However, success in either of these functions relies heavily uponthe ability to control the conjugation and assembly processes.In the work presented here, we first design a branched DNA scaffold which allows hybridization of DNA-nanocrystal monoconjugates to form discrete assemblies. Importantly, the asymmetry of the branched scaffold allows the formation of asymmetric2assemblies of nanocrystals. In the context of a self-assembled device, this can be considered a step toward the ability to engineer functionally distinct inputs and outputs.Next we develop an anion-exchange high performance liquid chromatography purification method which allows large gold nanocrystals attached to single strands of very short DNA to be purified. When two such complementary conjugates are hybridized, the large nanocrystals are brought into close proximity, allowing their plasmon resonances to couple. Such plasmon-coupled constructs are of interest both as optical interconnects for nanoscale devices and as `plasmon ruler? biomolecular probes.We then present an enzymatic ligation strategy for creating multi-nanoparticle building blocks for self-assembly. In constructing a nanoscale device, such a strategy would allow pre-assembly and purification of components; these constructs can also act as multi-label probes of single-stranded DNA conformational dynamics. Finally we demonstrate a simple proof-of-concept of a nanoparticle analog of the polymerase chain reaction.

  19. Proximally exposed A-bomb survivors. 2

    International Nuclear Information System (INIS)

    Kamada, Nanao

    1992-01-01

    Methods for observing chromosomes can be chronologically divided into the era of non-differential staining technique (1962-1975) and the era of differential staining method (since 1976). This paper reviews the literature of chromosomal aberrations in bone marrow cells found in the two eras. Findings during the era of 1962-1975 include the frequency of chromosomal aberrations in bone marrow cells, comparison of chromosomal aberrations in bone marrow cells and T lymphocytes, and annual variation of chromosomal aberrations. The frequency of chromosomal aberrations was high in proximally exposed A-bomb survivors (90.5% and 52.6% in A-bomb survivors exposed within 500 m and at 501-1,000 m, respectively); on the contrary, it was low in those exposed far from 1,000 m (6.2% or less). The frequency of chromosomal aberrations in bone marrow cells was lower than that in T lymphocytes (21.5% vs 27.1% in those exposed within 500 m and 14.1% vs 23% in those exposed at 501-1,000 m). Annual analysis for chromosomal aberrations has shown the somewhat dependence upon medullary hematopoiesis and virus infection. The advent of differential staining technique since 1976 has made it possible to clarify the type of chromosomal aberrations and site of breakage. Of 710 bone marrow cells taken from 13 A-bomb survivors exposed within 1,000 m, 121 cells (from 11 A-bomb survivors) exhibited chromosomal aberrations. In differential staining analysis, all 121 cells but one were found to be of stable type, such as translocation and inversion. Furthermore, the site of breakage was found to be non-randomly distributed. Analysis of chromosomal aberrations in bone marrow cells has advantages of reflecting dynamic condition of these cells and determining gradual progression into leukemia. (N.K.)

  20. Hypospadias and residential proximity to pesticide applications.

    Science.gov (United States)

    Carmichael, Suzan L; Yang, Wei; Roberts, Eric M; Kegley, Susan E; Wolff, Craig; Guo, Liang; Lammer, Edward J; English, Paul; Shaw, Gary M

    2013-11-01

    Experimental evidence suggests pesticides may be associated with hypospadias. Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications. The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year. Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9. Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  1. SH2 domains: modulators of nonreceptor tyrosine kinase activity.

    Science.gov (United States)

    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.

  2. Ligament augmentation for prevention of proximal junctional kyphosis and proximal junctional failure in adult spinal deformity.

    Science.gov (United States)

    Safaee, Michael M; Deviren, Vedat; Dalle Ore, Cecilia; Scheer, Justin K; Lau, Darryl; Osorio, Joseph A; Nicholls, Fred; Ames, Christopher P

    2018-05-01

    OBJECTIVE Proximal junctional kyphosis (PJK) is a well-recognized, yet incompletely defined, complication of adult spinal deformity surgery. There is no standardized definition for PJK, but most studies describe PJK as an increase in the proximal junctional angle (PJA) of greater than 10°-20°. Ligament augmentation is a novel strategy for PJK reduction that provides strength to the upper instrumented vertebra (UIV) and adjacent segments while also reducing junctional stress at those levels. METHODS In this study, ligament augmentation was used in a consecutive series of adult spinal deformity patients at a single institution. Patient demographics, including age; sex; indication for surgery; revision surgery; surgical approach; and use of 3-column osteotomies, vertebroplasty, or hook fixation at the UIV, were collected. The PJA was measured preoperatively and at last follow-up using 36-inch radiographs. Data on change in PJA and need for revision surgery were collected. Univariate and multivariate analyses were performed to identify factors associated with change in PJA and proximal junctional failure (PJF), defined as PJK requiring surgical correction. RESULTS A total of 200 consecutive patients were included: 100 patients before implementation of ligament augmentation and 100 patients after implementation of this technique. The mean age of the ligament augmentation cohort was 66 years, and 67% of patients were women. Over half of these cases (51%) were revision surgeries, with 38% involving a combined anterior or lateral and posterior approach. The mean change in PJA was 6° in the ligament augmentation group compared with 14° in the control group (p historical cohort, ligament augmentation is associated with a significant decrease in PJK and PJF. These data support the implementation of ligament augmentation in surgery for adult spinal deformity, particularly in patients with a high risk of developing PJK and PJF.

  3. Signaling aggression.

    Science.gov (United States)

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Domain configuration and magnetization switching in arrays of permalloy nanostripes

    International Nuclear Information System (INIS)

    Iglesias-Freire, Ó.; Jaafar, M.; Pérez, L.; Abril, O. de; Vázquez, M.; Asenjo, A.

    2014-01-01

    The proximity effect in the collective behavior of arrays of magnetic nanostripes is currently a subject of intensive research. The imperative of reducing the size and distances between elements in order to achieve higher storage capacity, faster access to the information as well as low energy consumption, brings consequences about the isolated behavior of the elements and devices. Parallel to each other permalloy nanostripes with high aspect ratio have been prepared by the nanolithography technique. The evolution of the closure domains and the magnetization direction in individual nanostructures has been imaged under applied magnetic fields using Variable Field Magnetic Force Microscopy. Moreover, the magnetostatic interactions between neighboring elements and the proximity effects in arrays of such nanostructures have been quantitatively analyzed by Magnetic Force Microscopy and micromagnetic simulations. The agreement between simulations and the experimental results allows us to conclude the relevance of those interactions depending on the geometry characteristics. In particular, results suggest that the magnetostatic coupling between adjacent nanostripes vanishes for separation distances higher than 500 nm. - Highlights: • A shape anisotropy-induced single domain remanent state is present in the stripes. Closure domains are formed under external fields. • Separation distances between neighboring stripes (500 nm) are enough to overcome the magnetostatic coupling and avoid a multi-stripe character. • Micromagnetic simulations predict critical distances of around 500 nm for the onset of magnetostatic coupling between neighboring elements. • Simulations predict stripes with a small longitudinal separation to behave as single elements, with domain walls “jumping” between them

  5. Domain configuration and magnetization switching in arrays of permalloy nanostripes

    Energy Technology Data Exchange (ETDEWEB)

    Iglesias-Freire, Ó., E-mail: aasenjo@icmm.csic.es [Instituto de Ciencia de Materiales de Madrid, CSIC, Sor Juana Inés de la Cruz 3, Madrid 28049 (Spain); Jaafar, M. [Instituto de Ciencia de Materiales de Madrid, CSIC, Sor Juana Inés de la Cruz 3, Madrid 28049 (Spain); Dpto. Física de la Materia Condensada, Universidad Autónoma de Madrid, Cantoblanco 28049 (Spain); Pérez, L. [Dpto. Física de Materiales, Universidad Complutense de Madrid, Madrid 28040 (Spain); Abril, O. de [Dpto. Física e Instalaciones Aplicadas a la Edificación, al Medio Ambiente y al Urbanismo, Universidad Politécnica de Madrid, Madrid 28040 (Spain); Vázquez, M.; Asenjo, A. [Instituto de Ciencia de Materiales de Madrid, CSIC, Sor Juana Inés de la Cruz 3, Madrid 28049 (Spain)

    2014-04-15

    The proximity effect in the collective behavior of arrays of magnetic nanostripes is currently a subject of intensive research. The imperative of reducing the size and distances between elements in order to achieve higher storage capacity, faster access to the information as well as low energy consumption, brings consequences about the isolated behavior of the elements and devices. Parallel to each other permalloy nanostripes with high aspect ratio have been prepared by the nanolithography technique. The evolution of the closure domains and the magnetization direction in individual nanostructures has been imaged under applied magnetic fields using Variable Field Magnetic Force Microscopy. Moreover, the magnetostatic interactions between neighboring elements and the proximity effects in arrays of such nanostructures have been quantitatively analyzed by Magnetic Force Microscopy and micromagnetic simulations. The agreement between simulations and the experimental results allows us to conclude the relevance of those interactions depending on the geometry characteristics. In particular, results suggest that the magnetostatic coupling between adjacent nanostripes vanishes for separation distances higher than 500 nm. - Highlights: • A shape anisotropy-induced single domain remanent state is present in the stripes. Closure domains are formed under external fields. • Separation distances between neighboring stripes (500 nm) are enough to overcome the magnetostatic coupling and avoid a multi-stripe character. • Micromagnetic simulations predict critical distances of around 500 nm for the onset of magnetostatic coupling between neighboring elements. • Simulations predict stripes with a small longitudinal separation to behave as single elements, with domain walls “jumping” between them.

  6. Treatment of Unstable Trochanteric Femur Fractures: Proximal Femur Nail Versus Proximal Femur Locking Compression Plate.

    Science.gov (United States)

    Singh, Ashutosh Kumar; Narsaria, Nidi; G R, Arun; Srivastava, Vivek

    Unstable trochanteric femur fractures are common fractures that are difficult to manage. We conducted a prospective study to compare functional outcomes and complications of 2 different implant designs, proximal femur nail (PFN) and proximal femur locking compression plate (PFLCP), used in internal fixation of unstable trochanteric femur fractures. On hospital admission, 48 patients with unstable trochanteric fractures were randomly assigned (using a sealed envelope method) to treatment with either PFN (24 patients) or PFLCP (24 patients). Perioperative data and complications were recorded. All cases were followed up for 2 years. The groups did not differ significantly (P > .05) in operative time, reduction quality, complications, hospital length of stay, union rate, or time to union. Compared with the PFLCP group, the PFN group had shorter incisions and less blood loss. Regarding functional outcomes, there was no significant difference in mean Harris Hip Score (P = .48) or Palmer and Parker mobility score (P = .58). Both PFN and PFLCP are effective in internal fixation of unstable trochanteric femur fractures.

  7. Dual pathology proximal median nerve compression of the forearm.

    LENUS (Irish Health Repository)

    Murphy, Siun M

    2013-12-01

    We report an unusual case of synchronous pathology in the forearm- the coexistence of a large lipoma of the median nerve together with an osteochondroma of the proximal ulna, giving rise to a dual proximal median nerve compression. Proximal median nerve compression neuropathies in the forearm are uncommon compared to the prevalence of distal compression neuropathies (eg Carpal Tunnel Syndrome). Both neural fibrolipomas (Refs. 1,2) and osteochondromas of the proximal ulna (Ref. 3) in isolation are rare but well documented. Unlike that of a distal compression, a proximal compression of the median nerve will often have a definite cause. Neural fibrolipoma, also called fibrolipomatous hamartoma are rare, slow-growing, benign tumours of peripheral nerves, most often occurring in the median nerve of younger patients. To our knowledge, this is the first report of such dual pathology in the same forearm, giving rise to a severe proximal compression of the median nerve. In this case, the nerve was being pushed anteriorly by the osteochondroma, and was being compressed from within by the intraneural lipoma. This unusual case highlights the advantage of preoperative imaging as part of the workup of proximal median nerve compression.

  8. Dual pathology proximal median nerve compression of the forearm.

    Science.gov (United States)

    Murphy, Siun M; Browne, Katherine; Tuite, David J; O'Shaughnessy, Michael

    2013-12-01

    We report an unusual case of synchronous pathology in the forearm- the coexistence of a large lipoma of the median nerve together with an osteochondroma of the proximal ulna, giving rise to a dual proximal median nerve compression. Proximal median nerve compression neuropathies in the forearm are uncommon compared to the prevalence of distal compression neuropathies (eg Carpal Tunnel Syndrome). Both neural fibrolipomas (Refs. 1,2) and osteochondromas of the proximal ulna (Ref. 3) in isolation are rare but well documented. Unlike that of a distal compression, a proximal compression of the median nerve will often have a definite cause. Neural fibrolipoma, also called fibrolipomatous hamartoma are rare, slow-growing, benign tumours of peripheral nerves, most often occurring in the median nerve of younger patients. To our knowledge, this is the first report of such dual pathology in the same forearm, giving rise to a severe proximal compression of the median nerve. In this case, the nerve was being pushed anteriorly by the osteochondroma, and was being compressed from within by the intraneural lipoma. This unusual case highlights the advantage of preoperative imaging as part of the workup of proximal median nerve compression. Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  9. Digital contrast subtraction radiography for proximal caries diagnosis

    International Nuclear Information System (INIS)

    Kang, Byung Cheol; Yoon, Suk Ja

    2002-01-01

    To determine whether subtraction images utilizing contrast media can improve the diagnostic performance of proximal caries diagnosis compared to conventional periapical radiographic images. Thirty-six teeth with 57 proximal surfaces were radiographied using a size no.2 RVG-ui sensor (Trophy Radiology, Marne-la-Vallee, France). The teeth immersed in water-soluble contrast media and subtraction images were taken. Each tooth was then sectioned for histologic examination. The digital radiographic images and subtraction images were examined and interpreted by three dentists for proximal caries. The results of the proximal caries diagnosis were then verified with the results of the histologic examination. The proximal caries sensitivity using digital subtraction radiography was significantly higher than simply examining a single digital radiograph. The sensitivity of the proximal dentinal carious lesion when analyzed with the subtraction radiograph and the radiograph together was higher than with the subtraction radiograph or the radiograph alone. The use of subtraction radiography with contrast media may be useful for detecting proximal dentinal carious lesions.

  10. Effect of age on proximal esophageal response to swallowing

    Directory of Open Access Journals (Sweden)

    Roberto Oliveira Dantas

    2010-12-01

    Full Text Available CONTEXT: It has been demonstrated that the ageing process affects esophageal motility. OBJECTIVES: To evaluate the effect of the age on the proximal esophageal response to wet swallows. METHOD: We measured the proximal esophageal response to swallows of a 5 mL bolus of water in 69 healthy volunteers, 20 of them aged 18-30 years (group I, 27 aged 31-50 years (group II, and 22 aged 51-74 years (group III. We used the manometric method with continuous perfusion. The proximal esophageal contractions were recorded 5 cm from a pharyngeal recording site located 1 cm above the upper esophageal sphincter. The time between the onset of the pharyngeal and of the proximal esophageal recording (pharyngeal-esophageal time and the amplitude, duration and area under the curve of the proximal esophageal contraction were measured. RESULTS: The pharyngeal-esophageal time was shorter in group I subjects than in group II and III subjects (P<0.05. The duration of proximal esophageal contractions was longer in group I than in groups II and III (P<0.001. There was no differences between groups in the amplitude or area under the curve of contractions. There were no differences between groups II and III for any of the measurements. CONCLUSION: We conclude that the age may affects the response of the proximal esophagus to wet swallows.

  11. Giant proximity effect and critical opalescence in EuS

    Science.gov (United States)

    Charlton, Timothy; Ramos, Silvia; Quintanilla, Jorge; Suter, Andreas; Moodera, Jagadeesh

    2015-03-01

    The proximity effect is a type of wetting phenomenon where an ordered state, usually magnetism or superconductivity, ``leaks'' from one material into an adjacent one over some finite distance. For superconductors, the characteristic range is of the order of the coherence length, usually hundreds of nm. Nevertheless much longer, ``giant'' proximity effects have been observed in cuprate perovskite junctions. Such giant proximity effects can be understood by taking into account the divergence of the pairing susceptibility in the non-superconducting material when it is itself close to a superconducting instability: a superconducting version of critical opalescence. Since critical opalescence occurs in all second order phase transitions, giant proximity effects are expected to be general, therefor there must be a giant ferromagnetic proximity effect. Compared to its superconducting counterpart, the giant ferromagnetic proximity effect has the advantage that the order parameter (magnetization) can be observed directly. We have fabricated Co/EuS thin films and measured the magnetization profiles as a function of temperature using the complementary techniques of low energy muon relaxation and polarized neutron reflectivity. Details of the proximity effect near TCEuS will be presented.

  12. Conduction spectroscopy of a proximity induced superconducting topological insulator

    Science.gov (United States)

    Stehno, M. P.; Hendrickx, N. W.; Snelder, M.; Scholten, T.; Huang, Y. K.; Golden, M. S.; Brinkman, A.

    2017-09-01

    The combination of superconductivity and the helical spin-momentum locking at the surface state of a topological insulator (TI) has been predicted to give rise to p-wave superconductivity and Majorana bound states. The superconductivity can be induced by the proximity effect of a s-wave superconductor (S) into the TI. To probe the superconducting correlations inside the TI, dI/dV spectroscopy has been performed across such S-TI interfaces. Both the alloyed Bi1.5Sb0.5Te1.7Se1.3 and the stoichiometric BiSbTeSe2 have been used as three-dimensional TI. In the case of Bi1.5Sb0.5Te1.7Se1.3, the presence of disorder induced electron-electron interactions can give rise to an additional zero-bias resistance peak. For the stoichiometric BiSbTeSe2 with less disorder, tunnel barriers were employed in order to enhance the signal from the interface. The general observations in the spectra of a large variety of samples are conductance dips at the induced gap voltage, combined with an increased sub-gap conductance, consistent with p-wave predictions. The induced gap voltage is typically smaller than the gap of the Nb superconducting electrode, especially in the presence of an intentional tunnel barrier. Additional uncovered spectroscopic features are oscillations that are linearly spaced in energy, as well as a possible second order parameter component.

  13. Syndecans, signaling, and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Woods, A

    1996-01-01

    structures within the heparan sulfate chains, leaving the roles of chondroitin sulfate chains and extracellular portion of the core proteins to be elucidated. Evidence that syndecans are a class of receptor involved in cell adhesion is mounting, and their small cytoplasmic domains may link...... transmembrane signaling from matrix to cytoskeleton, as proposed for other classes of adhesion receptors....

  14. Cancer in proximity to TV towers

    International Nuclear Information System (INIS)

    Hocking, B.; Gordon, I.; Hatfield, G.

    1996-01-01

    Standard (AS2772.1). The few actual measurements available indicate even lower levels. The analysis shows no increased risk of brain cancer. An increased risk of childhood leukaemia is indicated in the municipalities close to the TV towers. The rate ratio for incidence is 1.6 (95% Cl: 1.08-2 41) and for mortality is 2.25 (95% Cl: 1.29-3.92), mainly due to lymphatic leukaemia (1.63 for incidence, 2.84 for mortality). An association between increased childhood leukaemia and proximity to TV towers is indicated. Further studies are needed to test this association and determine any dose-response relationship before firm conclusions may be reached

  15. Reoperations following proximal interphalangeal joint nonconstrained arthroplasties.

    Science.gov (United States)

    Pritsch, Tamir; Rizzo, Marco

    2011-09-01

    To retrospectively analyze the reasons for reoperations following primary nonconstrained proximal interphalangeal (PIP) joint arthroplasty and review clinical outcomes in this group of patients with 1 or more reoperations. Between 2001 and 2009, 294 nonconstrained (203 pyrocarbon and 91 metal-plastic) PIP joint replacements were performed in our institution. A total of 76 fingers (59 patients) required reoperation (50 pyrocarbon and 26 metal-plastic). There were 40 women and 19 men with an average age of 51 years (range, 19-83 y). Primary diagnoses included osteoarthritis in 35, posttraumatic arthritis in 24, and inflammatory arthritis in 17 patients. There were 21 index, 27 middle, 18 ring, and 10 small fingers. The average number of reoperations per PIP joint was 1.6 (range, 1-4). A total of 45 joints had 1 reoperation, 19 had 2, 11 had 3, and 1 had 4. Extensor mechanism dysfunction was the most common reason for reoperation; it involved 51 of 76 fingers and was associated with Chamay or tendon-reflecting surgical approaches. Additional etiologies included component loosening in 17, collateral ligament failure in 10, and volar plate contracture in 8 cases. Inflammatory arthritis was associated with collateral ligament failure. Six fingers were eventually amputated, 9 had PIP joint arthrodeses, and 2 had resection arthroplasties. The arthrodesis and amputation rates correlated with the increased number of reoperations per finger. Clinically, most patients had no or mild pain at the most recent follow-up, and the PIP joint range-of-motion was not significantly different from preoperative values. Pain levels improved with longer follow-up. Reoperations following primary nonconstrained PIP joint arthroplasties are common. Extensor mechanism dysfunction was the most common reason for reoperation. The average reoperation rate was 1.6, and arthrodesis and amputation are associated with an increasing number of operations. Overall clinical outcomes demonstrated no

  16. Transparent and flexible cellulose nanocrystal/reduced graphene oxide film for proximity sensing.

    Science.gov (United States)

    Sadasivuni, Kishor Kumar; Kafy, Abdullahil; Zhai, Lindong; Ko, Hyun-U; Mun, Seongcheol; Kim, Jaehwan

    2015-02-25

    The rapid development of touch screens as well as photoelectric sensors has stimulated the fabrication of reliable, convenient, and human-friendly devices. Other than sensors that detect physical touch or are based on pressure sensing, proximity sensors offer controlled sensibility without physical contact. In this work we present a transparent and eco-friendly sensor made through layer-by-layer spraying of modified graphene oxide filled cellulose nanocrystals on lithographic patterns of interdigitated electrodes on polymer substrates, which help to realize the precise location of approaching objects. Stable and reproducible signals generated by keeping the finger in close proximity to the sensor can be controlled by humidity, temperature, and the distance and number of sprayed layers. The chemical modification and reduction of the graphene oxide/cellulose crystal composite and its excellent nanostructure enable the development of proximity sensors with faster response and higher sensitivity, the integration of which resolves nearly all of the technological issues imposed on optoelectronic sensing devices. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Proximity hybridization-mediated isothermal exponential amplification for ultrasensitive electrochemical protein detection

    Directory of Open Access Journals (Sweden)

    Yu Y

    2017-08-01

    Full Text Available Yanyan Yu, Gaoxing Su, Hongyan Zhu, Qing Zhu, Yong Chen, Bohui Xu, Yuqin Li, Wei Zhang School of Pharmacy, Nantong University, Nantong, People’s Republic of China Abstract: In this study, we fabricated a novel electrochemical biosensing platform on the basis of target-triggered proximity hybridization-mediated isothermal exponential amplification reaction (EXPAR for ultrasensitive protein analysis. Through rational design, the aptamers for protein recognition were integrated within two DNA probes. Via proximity hybridization principle, the affinity protein-binding event was converted into DNA assembly process. The recognition of protein by aptamers can trigger the strand displacement through the increase of the local concentrations of the involved probes. As a consequence, the output DNA was displaced, which can hybridize with the duplex probes immobilized on the electrode surface subsequently, leading to the initiation of the EXPAR as well as the cleavage of duplex probes. Each cleavage will release the gold nanoparticles (AuNPs binding sequence. With the modification of G-quadruplex sequence, electrochemical signals were yielded by the AuNPs through oxidizing 3,3',5,5'-tetramethylbenzidine in the presence of H2O2. The study we proposed exhibited high sensitivity toward platelet-derived growth factor BB (PDGF-BB with the detection limit of 52 fM. And, this method also showed great selectivity among the PDGF isoforms and performed well in spiked human serum samples. Keywords: electrochemical biosensor, proximity hybridization, PDGF-BB, isothermal exponential amplification, G-quadruplex 

  18. Detection of avian influenza antigens in proximity fiber, droplet, and optical waveguide microfluidics

    Science.gov (United States)

    Yoon, Jeong-Yeol; Heinze, Brian C.; Gamboa, Jessica; You, David J.

    2009-05-01

    Virus antigens of avian influenza subtype H3N2 were detected on two different microfluidic platforms: microchannel and droplet. Latex immunoagglutination assays were performed using 920-nm highly carboxylated polystyrene beads that are conjugated with antibody to avian influenza virus. The bead suspension was merged with the solutions of avian influenza virus antigens in a Y-junction of a microchannel made by polydimethylsiloxane soft lithography. The resulting latex immunoagglutinations were measured with two optical fibers in proximity setup to detect 45° forward light scattering. Alternatively, 10 μL droplets of a bead suspension and an antigen solution were merged on a superhydrophobic surface (water contact angle = 155°), whose movement was guided by a metal wire, and 180° back light scattering is measured with a backscattering optical probe. Detection limits were 0.1 pg mL-1 for both microchannel with proximity fibers and droplet microfluidics, thanks to the use of micro-positioning stages to help generate reproducible optical signals. Additionally, optical waveguide was tested by constructing optical waveguide channels (filled with mineral oil) within a microfluidic device to detect the same light scattering. Detection limit was 0.1 ng mL-1 for an optical waveguide device, with a strong potential of improvement in the near future. The use of optical waveguide enabled smaller device setup, easier operation, smaller standard deviations and broader linear range of assay than proximity fiber microchannel and droplet microfluidics. Total assay time was less than 10 min.

  19. Signal detection

    International Nuclear Information System (INIS)

    Tholomier, M.

    1985-01-01

    In a scanning electron microscope, whatever is the measured signal, the same set is found: incident beam, sample, signal detection, signal amplification. The resulting signal is used to control the spot luminosity with the observer cathodoscope. This is synchronized with the beam scanning on the sample; on the cathodoscope, the image in secondary electrons, backscattered electrons,... of the sample surface is reconstituted. The best compromise must be found between a register time low enough to remove eventual variations (under the incident beam) of the nature of the observed phenomenon, and a good spatial resolution of the image and a signal-to-noise ratio high enough. The noise is one of the basic limitations of the scanning electron microscope performance. The whose measurement line must be optimized to reduce it [fr

  20. Proximal caries detection: Sirona Sidexis versus Kodak Ektaspeed Plus.

    Science.gov (United States)

    Khan, Emad A; Tyndall, Donald A; Ludlow, John B; Caplan, Daniel

    2005-01-01

    This study compared the accuracy of intraoral film and a charge-coupled device (CCD) receptor for proximal caries detection. Four observers evaluated images of the proximal surfaces of 40 extracted posterior teeth. The presence or absence of caries was scored using a five-point confidence scale. The actual status of each surface was determined from ground section histology. Responses were evaluated by means of receiver operating characteristic (ROC) analysis. Areas under ROC curves (Az) were assessed through a paired t-test. The performance of the CCD-based intraoral sensor was not different statistically from Ektaspeed Plus film in detecting proximal caries.

  1. [Avulsion of the Proximal Hamstring Insertion. Case Reports].

    Science.gov (United States)

    Mizera, R; Harcuba, R; Kratochvíl, J

    2016-01-01

    Proximal hamstring avulsion is an uncommon muscle injury with a lack of consensus on indications and the timing and technique of surgery. Poor clinical symptoms and difficulties in the diagnostic process can lead to a false diagnosis. The authors present three cases of proximal hamstring avulsion, two complete and one partial ruptures of the biceps femoris muscle. MRI and ultrasound scans were used for optimal treatment alignment. Acute surgery reconstruction (hamstring strength. Two interesting systematic reviews published on the treatment of proximal hamstring avulsion are discussed in the final part of the paper. Key words: hamstring, rupture, avulsion.

  2. A Signal-Interleaving Complex Bandpass Sigma-Delta Converter

    DEFF Research Database (Denmark)

    Wad, Paul Emmanuel

    1997-01-01

    Complex or quadrature Sigma-Delta converters operate on complex signals, i.e. signals consisting of a real and an imaginary component, whereas conventional converters operate only on real signals. The advantage of complex signal processing in the discrete-time domain is that the entire sampling...

  3. Domain fusion analysis by applying relational algebra to protein sequence and domain databases.

    Science.gov (United States)

    Truong, Kevin; Ikura, Mitsuhiko

    2003-05-06

    Domain fusion analysis is a useful method to predict functionally linked proteins that may be involved in direct protein-protein interactions or in the same metabolic or signaling pathway. As separate domain databases like BLOCKS, PROSITE, Pfam, SMART, PRINTS-S, ProDom, TIGRFAMs, and amalgamated domain databases like InterPro continue to grow in size and quality, a computational method to perform domain fusion analysis that leverages on these efforts will become increasingly powerful. This paper proposes a computational method employing relational algebra to find domain fusions in protein sequence databases. The feasibility of this method was illustrated on the SWISS-PROT+TrEMBL sequence database using domain predictions from the Pfam HMM (hidden Markov model) database. We identified 235 and 189 putative functionally linked protein partners in H. sapiens and S. cerevisiae, respectively. From scientific literature, we were able to confirm many of these functional linkages, while the remainder offer testable experimental hypothesis. Results can be viewed at http://calcium.uhnres.utoronto.ca/pi. As the analysis can be computed quickly on any relational database that supports standard SQL (structured query language), it can be dynamically updated along with the sequence and domain databases, thereby improving the quality of predictions over time.

  4. Src homology domain 2-containing protein-tyrosine phosphatase-1 (SHP-1) binds and dephosphorylates G(alpha)-interacting, vesicle-associated protein (GIV)/Girdin and attenuates the GIV-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway.

    Science.gov (United States)

    Mittal, Yash; Pavlova, Yelena; Garcia-Marcos, Mikel; Ghosh, Pradipta

    2011-09-16

    GIV (Gα-interacting vesicle-associated protein, also known as Girdin) is a bona fide enhancer of PI3K-Akt signals during a diverse set of biological processes, e.g. wound healing, macrophage chemotaxis, tumor angiogenesis, and cancer invasion/metastasis. We recently demonstrated that tyrosine phosphorylation of GIV by receptor and non-receptor-tyrosine kinases is a key step that is required for GIV to directly bind and enhance PI3K activity. Here we report the discovery that Src homology 2-containing phosphatase-1 (SHP-1) is the major protein-tyrosine phosphatase that targets two critical phosphotyrosines within GIV and antagonizes phospho-GIV-dependent PI3K enhancement in mammalian cells. Using phosphorylation-dephosphorylation assays, we demonstrate that SHP-1 is the major and specific protein-tyrosine phosphatase that catalyzes the dephosphorylation of tyrosine-phosphorylated GIV in vitro and inhibits ligand-dependent tyrosine phosphorylation of GIV downstream of both growth factor receptors and GPCRs in cells. In vitro binding and co-immunoprecipitation assays demonstrate that SHP-1 and GIV interact directly and constitutively and that this interaction occurs between the SH2 domain of SHP-1 and the C terminus of GIV. Overexpression of SHP-1 inhibits tyrosine phosphorylation of GIV and formation of phospho-GIV-PI3K complexes, and specifically suppresses GIV-dependent activation of Akt. Consistently, depletion of SHP-1 enhances peak tyrosine phosphorylation of GIV, which coincides with an increase in peak Akt activity. We conclude that SHP-1 antagonizes the action of receptor and non-receptor-tyrosine kinases on GIV and down-regulates the phospho-GIV-PI3K-Akt axis of signaling.

  5. The amino-terminal domain of human signal transducers and ...

    Indian Academy of Sciences (India)

    Unknown

    transferase (GST) moiety was cloned into the expression vector pGEX-2T ... containing 100 µg/ml of ampicillin to mid log phase as indicated by the .... equipped with pulsed field gradients. ... ferent algorithms like hidden Markov model (HMM).

  6. Domain: Labour market

    NARCIS (Netherlands)

    Oude Mulders, J.; Wadensjö, E.; Hasselhorn, H.M.; Apt, W.

    This domain chapter is dedicated to summarize research on the effects of labour market contextual factors on labour market participation of older workers (aged 50+) and identify research gaps. While employment participation and the timing of (early) retirement is often modelled as an individual

  7. Cellulose binding domain proteins

    Science.gov (United States)

    Shoseyov, Oded; Shpiegl, Itai; Goldstein, Marc; Doi, Roy

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  8. Domain-Specific Multimodeling

    DEFF Research Database (Denmark)

    Hessellund, Anders

    the overall level of abstraction. It does, however, also introduce a new problem of coordinating multiple different languages in a single system. We call this problem the coordination problem. In this thesis, we present the coordination method for domain-specific multimodeling that explicitly targets...

  9. GlycoDomainViewer

    DEFF Research Database (Denmark)

    Joshi, Hiren J; Jørgensen, Anja; Schjoldager, Katrine T

    2018-01-01

    features, which enhances visibility and accessibility of the wealth of glycoproteomic data being generated. The GlycoDomainViewer enables visual exploration of glycoproteomic data, incorporating information from recent N- and O-glycoproteome studies on human and animal cell lines and some organs and body...

  10. Bystander signaling via oxidative metabolism.

    Science.gov (United States)

    Sawal, Humaira Aziz; Asghar, Kashif; Bureik, Matthias; Jalal, Nasir

    2017-01-01

    The radiation-induced bystander effect (RIBE) is the initiation of biological end points in cells (bystander cells) that are not directly traversed by an incident-radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS) act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to pursue this field of science.

  11. Insulin Signaling and Heart Failure

    Science.gov (United States)

    Riehle, Christian; Abel, E. Dale

    2016-01-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral milieu leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead (FOXO) transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  12. Proximity effects of high voltage electric power transmission lines on ...

    African Journals Online (AJOL)

    Yomi

    2010-08-18

    Aug 18, 2010 ... transmission lines on ornamental plant growth. Zeki Demir ... The effects of proximity to power-line on specific leaf area and seedling dbh were tested .... during vegetation season is about 72% and common wind blow.

  13. Nutritive Value Assessment of Four Crop Residues by Proximate ...

    African Journals Online (AJOL)

    Dr Grace Tona

    Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Nigeria ... Abstract. This study estimated the proximate composition and in vitro gas production parameters of rice husk, bean ... farms and industries generate large quantities.

  14. Computational proximity excursions in the topology of digital images

    CERN Document Server

    Peters, James F

    2016-01-01

    This book introduces computational proximity (CP) as an algorithmic approach to finding nonempty sets of points that are either close to each other or far apart. Typically in computational proximity, the book starts with some form of proximity space (topological space equipped with a proximity relation) that has an inherent geometry. In CP, two types of near sets are considered, namely, spatially near sets and descriptivelynear sets. It is shown that connectedness, boundedness, mesh nerves, convexity, shapes and shape theory are principal topics in the study of nearness and separation of physical aswell as abstract sets. CP has a hefty visual content. Applications of CP in computer vision, multimedia, brain activity, biology, social networks, and cosmology are included. The book has been derived from the lectures of the author in a graduate course on the topology of digital images taught over the past several years. Many of the students have provided important insights and valuable suggestions. The topics in ...

  15. Population Exposure Estimates in Proximity to Nuclear Power Plants, Locations

    Data.gov (United States)

    National Aeronautics and Space Administration — The Population Exposure Estimates in Proximity to Nuclear Power Plants, Locations data set combines information from a global data set developed by Declan Butler of...

  16. Proximate composition and nutrient content of some wild and ...

    African Journals Online (AJOL)

    Proximate composition and nutrient content of some wild and cultivated ... Ca, P, K), one minor mineral (Fe) constituent and vitamin C content were determined. ... Mineral content (P and K) in the mushroom sporophores were found to be ...

  17. Effects of Fermentation and Extrusion on the Proximate Composition ...

    African Journals Online (AJOL)

    Prof. Ogunji

    protein malnutrition persists as a principal health problem among children .... Proximate analysis: Moisture content ... nitrogen by a factor of 6.25. Crude fat ... Statistical analysis: The data were ..... interaction of amino acid in maillard reactions.

  18. Proximate composition and mineral contents of Pebbly fish, Alestes ...

    African Journals Online (AJOL)

    ACSS

    /100 g) were significantly .... Proximate analysis of A. baremoze fillets according to sample sizes in a study in. Uganda .... present in the fish tissues in trace amounts. ... The zinc contents in fish samples of ..... (mercury, cadmium, lead, tin and.

  19. Effects of Planting Locations on the Proximate Compositions of ...

    African Journals Online (AJOL)

    ADOWIE PERE

    Ash, moisture, crude fat, crude fibre, carbohydrate and protein contents were determined according ... All fruits, vegetables, legumes (beans and peas), and the grains we eat ... isolate and quantify each proximate present in the plant material.

  20. Stalk-dependent and Stalk-independent Signaling by the Adhesion G Protein-coupled Receptors GPR56 (ADGRG1) and BAI1 (ADGRB1).

    Science.gov (United States)

    Kishore, Ayush; Purcell, Ryan H; Nassiri-Toosi, Zahra; Hall, Randy A

    2016-02-12

    The adhesion G protein-coupled receptors (aGPCRs) are a large yet poorly understood family of seven-transmembrane proteins. A defining characteristic of the aGPCR family is the conserved GAIN domain, which has autoproteolytic activity and can cleave the receptors near the first transmembrane domain. Several aGPCRs, including ADGRB1 (BAI1 or B1) and ADGRG1 (GPR56 or G1), have been found to exhibit significantly increased constitutive activity when truncated to mimic GAIN domain cleavage (ΔNT). Recent reports have suggested that the new N-terminal stalk, which is revealed by GAIN domain cleavage, can directly activate aGPCRs as a tethered agonist. We tested this hypothesis in studies on two distinct aGPCRs, B1 and G1, by engineering mutant receptors lacking the entire NT including the stalk (B1- and G1-SL, with "SL" indicating "stalkless"). These receptors were evaluated in a battery of signaling assays and compared with full-length wild-type and cleavage-mimicking (ΔNT) forms of the two receptors. We found that B1-SL, in multiple assays, exhibited robust signaling activity, suggesting that the membrane-proximal stalk region is not necessary for its activation. For G1, however, the results were mixed, with the SL mutant exhibiting robust activity in several signaling assays (including TGFα shedding, activation of NFAT luciferase, and β-arrestin recruitment) but reduced activity relative to ΔNT in a distinct assay (activation of SRF luciferase). These data support a model in which the activation of certain pathways downstream of aGPCRs is stalk-dependent, whereas signaling to other pathways is stalk-independent. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. The framing of scientific domains

    DEFF Research Database (Denmark)

    Dam Christensen, Hans

    2014-01-01

    domains, and UNISIST helps understanding this navigation. Design/methodology/approach The UNISIST models are tentatively applied to the domain of art history at three stages, respectively two modern, partially overlapping domains, as well as an outline of an art historical domain anno c1820...

  2. Inexact proximal Newton methods for self-concordant functions

    DEFF Research Database (Denmark)

    Li, Jinchao; Andersen, Martin Skovgaard; Vandenberghe, Lieven

    2016-01-01

    with an application to L1-regularized covariance selection, in which prior constraints on the sparsity pattern of the inverse covariance matrix are imposed. In the numerical experiments the proximal Newton steps are computed by an accelerated proximal gradient method, and multifrontal algorithms for positive definite...... matrices with chordal sparsity patterns are used to evaluate gradients and matrix-vector products with the Hessian of the smooth component of the objective....

  3. Hemiarthroplasty for proximal humeral fracture: restoration of the Gothic arch.

    Science.gov (United States)

    Krishnan, Sumant G; Bennion, Phillip W; Reineck, John R; Burkhead, Wayne Z

    2008-10-01

    Proximal humerus fractures are the most common fractures of the shoulder girdle, and initial management of these injuries often determines final outcome. When arthroplasty is used to manage proximal humeral fractures, surgery remains technically demanding, and outcomes have been unpredictable. Recent advances in both technique and prosthetic implants have led to more successful and reproducible results. Key technical points include restoration of the Gothic arch, anatomic tuberosity reconstruction, and minimal soft tissue dissection.

  4. Structure and dynamics of the human pleckstrin DEP domain: distinct molecular features of a novel DEP domain subfamily.

    Science.gov (United States)

    Civera, Concepcion; Simon, Bernd; Stier, Gunter; Sattler, Michael; Macias, Maria J

    2005-02-01

    Pleckstrin1 is a major substrate for protein kinase C in platelets and leukocytes, and comprises a central DEP (disheveled, Egl-10, pleckstrin) domain, which is flanked by two PH (pleckstrin homology) domains. DEP domains display a unique alpha/beta fold and have been implicated in membrane binding utilizing different mechanisms. Using multiple sequence alignments and phylogenetic tree reconstructions, we find that 6 subfamilies of the DEP domain exist, of which pleckstrin represents a novel and distinct subfamily. To clarify structural determinants of the DEP fold and to gain further insight into the role of the DEP domain, we determined the three-dimensional structure of the pleckstrin DEP domain using heteronuclear NMR spectroscopy. Pleckstrin DEP shares main structural features with the DEP domains of disheveled and Epac, which belong to different DEP subfamilies. However, the pleckstrin DEP fold is distinct from these structures and contains an additional, short helix alpha4 inserted in the beta4-beta5 loop that exhibits increased backbone mobility as judged by NMR relaxation measurements. Based on sequence conservation, the helix alpha4 may also be present in the DEP domains of regulator of G-protein signaling (RGS) proteins, which are members of the same DEP subfamily. In pleckstrin, the DEP domain is surrounded by two PH domains. Structural analysis and charge complementarity suggest that the DEP domain may interact with the N-terminal PH domain in pleckstrin. Phosphorylation of the PH-DEP linker, which is required for pleckstrin function, could regulate such an intramolecular interaction. This suggests a role of the pleckstrin DEP domain in intramolecular domain interactions, which is distinct from the functions of other DEP domain subfamilies found so far.

  5. The sooner, the better: exercise outcome proximity and intrinsic motivation.

    Science.gov (United States)

    Evans, M Blair; Cooke, Lisa M; Murray, Robyn A; Wilson, Anne E

    2014-11-01

    Despite evidence that outcomes are highly valued when they are expected sooner rather than further into the future (Ainslie, 1975), limited research effort has been devoted to understanding the role of exercise outcome proximity. The purpose of this study was to examine how temporal proximity to positive outcomes influences exercisers' intrinsic motivation. We expected that focusing people on temporally proximal exercise outcomes would increase intrinsic motivation, especially among low-frequency exercisers. This online experimental study was completed by 135 community exercisers (Mage  = 31.11, SD = 10.29; 62% female) who reported an average of 4.86 exercise bouts per week (SD = 2.12). Participants were randomly assigned to a condition that primed temporally proximal positive exercise outcomes (i.e. experienced during or directly following an exercise bout) or temporally distal outcomes (i.e. experienced after days, months, or years of regular exercise). Participants then reported perceptions of behavioral regulation in exercise. As expected, the proximal exercise outcome condition elicited increased intrinsic regulation among those participants who exercised less frequently (i.e. 1 SD below the mean). This study reveals the importance of considering proximity as an important dimension of exercise outcomes-particularly when promoting intrinsic motivation among relatively infrequent exercisers. © 2014 The International Association of Applied Psychology.

  6. Psychological responses to the proximity of climate change

    Science.gov (United States)

    Brügger, Adrian; Dessai, Suraje; Devine-Wright, Patrick; Morton, Thomas A.; Pidgeon, Nicholas F.

    2015-12-01

    A frequent suggestion to increase individuals' willingness to take action on climate change and to support relevant policies is to highlight its proximal consequences, that is, those that are close in space and time. But previous studies that have tested this proximizing approach have not revealed the expected positive effects on individual action and support for addressing climate change. We present three lines of psychological reasoning that provide compelling arguments as to why highlighting proximal impacts of climate change might not be as effective a way to increase individual mitigation and adaptation efforts as is often assumed. Our contextualization of the proximizing approach within established psychological research suggests that, depending on the particular theoretical perspective one takes on this issue, and on specific individual characteristics suggested by these perspectives, proximizing can bring about the intended positive effects, can have no (visible) effect or can even backfire. Thus, the effects of proximizing are much more complex than is commonly assumed. Revealing this complexity contributes to a refined theoretical understanding of the role that psychological distance plays in the context of climate change and opens up further avenues for future research and for interventions.

  7. HEMATOMA OF THE PROXIMAL NAIL FOLD. REPORT OF 41 CASES

    Directory of Open Access Journals (Sweden)

    Chang Patricia

    2011-04-01

    Full Text Available Background: The proximal fold is an important part of the nail apparatus it contributes to the formation of the nail plate and through the cuticle acts as an impermeable barrier protecting it from any cause.Objective: To know the proximal nail fold hematoma caused by the use of pulse oximeter.Material and Methods: A descriptive study was conducted in 41 patients with proximal nail hematoma secondary to the use of oximetry in patients hospitalized in the Intermediate and Intensive Care Unit at the Hospital General de Enfermedades from December 1, 2007 to December 31, 2010.Results: We studied 41 patients with proximal nail fold hematoma secondary to the use of oximeter, 30 (73.1% were males and 11 (26.8% females. The numbers of fingers affected by pulse oximeter were in one digit. 30 (73.1% cases, in two digits 6 (14.6%, in three digits 3 (7.3%, in 4 digits 1 (2.4% and in 5 digits 1 (2.4% case. The most affected proximal nail fold was right index: 24 (58.5%, right middle 11 (26.8%, right ring 6 (14.6%, left index 12 (29.2%, and left middle 6 (14.6% cases.Conclusions: Hematomas of the proximal nail fold may be caused by different traumatisms. The use of pulse oximeter is one of them.

  8. Expression and Production of SH2 Domain Proteins.

    Science.gov (United States)

    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.

  9. Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration

    Directory of Open Access Journals (Sweden)

    Yvona Ward

    2018-04-01

    Full Text Available Summary: Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR, is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread. : Tumor-initiated platelet activation promotes tissue invasion of cancer cells and metastasis. Ward et al. demonstrate that a common tumor-associated antigen, CD97, accounts for platelet activation and participates directly in LPA-mediated signal transduction leading to tumor cell invasion. CD97 promotes vascular extravasation and metastasis in pre-clinical models. Keywords: platelets, metastasis, transendothelial migration, circulating tumor cells, CD97, adhesion GPCR, LPA

  10. High-resolution MR imaging of the proximal zone of the lunotriquetral ligament with a microscopy coil

    International Nuclear Information System (INIS)

    Yoshioka, Hiroshi; Carrino, John A.; Lang, Philipp; Winalski, Carl S.; Tanaka, Toshikazu; Ueno, Teruko; Shindo, Masashi

    2006-01-01

    To evaluate high-resolution MRI of the proximal zone of the lunotriquetral ligament (LTL) using a microscopy surface coil with a 1.5 T scanner. The proximal zone of the LTL was reviewed in 90 subjects (23 asymptomatic normal volunteers and 67 patients with suspicion of triangular fibrocartilage complex injury) with high-resolution MRI using a 47-mm microscopy surface coil. High-resolution MR images were obtained with gradient recalled echo (GRE) T2*-weighted sequence and short tau inversion recovery imaging, with a 1- to 1.5-mm slice thickness, a 50-mm field of view, an imaging matrix of 140-224 x 512 using zero fill interpolation, and 3-4 excitations. As a qualitative analysis, the LTL was classified in shape and signal intensity. The triangle-shaped low-signal-intensity LTL was identified in 77 of 90 subjects (85.6%) on GRE images. The triangle was classified as regular (41.1%), broad-based (20.0%), narrow-based (6.7%), or asymmetrical (17.8%). The bar-shaped ligament was seen in one patient, and unclassified ligaments were seen in 12 patients. All volunteers showed triangle-shaped LTL. The MR signal intensity of the proximal zone in the LTL was characterized as homogeneously low intensity (type 1; 33.8%). (orig.)

  11. High-resolution MR imaging of the proximal zone of the lunotriquetral ligament with a microscopy coil

    Energy Technology Data Exchange (ETDEWEB)

    Yoshioka, Hiroshi; Carrino, John A.; Lang, Philipp; Winalski, Carl S. [Brigham and Women' s Hospital, Department of Radiology, Boston, MA (United States); Tanaka, Toshikazu [Tsukuba Memorial Hospital, Department of Orthopedic Surgery, Tsukuba (Japan); Ueno, Teruko [University of Tsukuba, Department of Radiology, Tsukuba (Japan); Shindo, Masashi [Tsukuba University Hospital, Tsukuba (Japan)

    2006-05-15

    To evaluate high-resolution MRI of the proximal zone of the lunotriquetral ligament (LTL) using a microscopy surface coil with a 1.5 T scanner. The proximal zone of the LTL was reviewed in 90 subjects (23 asymptomatic normal volunteers and 67 patients with suspicion of triangular fibrocartilage complex injury) with high-resolution MRI using a 47-mm microscopy surface coil. High-resolution MR images were obtained with gradient recalled echo (GRE) T2*-weighted sequence and short tau inversion recovery imaging, with a 1- to 1.5-mm slice thickness, a 50-mm field of view, an imaging matrix of 140-224 x 512 using zero fill interpolation, and 3-4 excitations. As a qualitative analysis, the LTL was classified in shape and signal intensity. The triangle-shaped low-signal-intensity LTL was identified in 77 of 90 subjects (85.6%) on GRE images. The triangle was classified as regular (41.1%), broad-based (20.0%), narrow-based (6.7%), or asymmetrical (17.8%). The bar-shaped ligament was seen in one patient, and unclassified ligaments were seen in 12 patients. All volunteers showed triangle-shaped LTL. The MR signal intensity of the proximal zone in the LTL was characterized as homogeneously low intensity (type 1; 33.8%). (orig.)

  12. Signal Conditioning An Introduction to Continuous Wave Communication and Signal Processing

    CERN Document Server

    Das, Apurba

    2012-01-01

    "Signal Conditioning” is a comprehensive introduction to electronic signal processing. The book presents the mathematical basics including the implications of various transformed domain representations in signal synthesis and analysis in an understandable and lucid fashion and illustrates the theory through many applications and examples from communication systems. The ease to learn is supported by well-chosen exercises which give readers the flavor of the subject. Supplementary electronic materials available on http://extras.springer.com including MATLAB codes illuminating applications in the domain of one dimensional electrical signal processing, image processing and speech processing. The book is an introduction for students with a basic understanding in engineering or natural sciences.

  13. Music genre classification using temporal domain features

    Science.gov (United States)

    Shiu, Yu; Kuo, C.-C. Jay

    2004-10-01

    Music genre provides an efficient way to index songs in the music database, and can be used as an effective means to retrieval music of a similar type, i.e. content-based music retrieval. In addition to other features, the temporal domain features of a music signal are exploited so as to increase the classification rate in this research. Three temporal techniques are examined in depth. First, the hidden Markov model (HMM) is used to emulate the time-varying properties of music signals. Second, to further increase the classification rate, we propose another feature set that focuses on the residual part of music signals. Third, the overall classification rate is enhanced by classifying smaller segments from a test material individually and making decision via majority voting. Experimental results are given to demonstrate the performance of the proposed techniques.

  14. On-Demand Targeting: Investigating Biology with Proximity-Directed Chemistry.

    Science.gov (United States)

    Long, Marcus J C; Poganik, Jesse R; Aye, Yimon

    2016-03-23

    Proximity enhancement is a central chemical tenet underpinning an exciting suite of small-molecule toolsets that have allowed us to unravel many biological complexities. The leitmotif of this opus is "tethering"-a strategy in which a multifunctional small molecule serves as a template to bring proteins/biomolecules together. Scaffolding approaches have been powerfully applied to control diverse biological outcomes such as protein-protein association, protein stability, activity, and improve imaging capabilities. A new twist on this strategy has recently appeared, in which the small-molecule probe is engineered to unleash controlled amounts of reactive chemical signals within the microenvironment of a target protein. Modification of a specific target elicits a precisely timed and spatially controlled gain-of-function (or dominant loss-of-function) signaling response. Presented herein is a unique personal outlook conceptualizing the powerful proximity-enhanced chemical biology toolsets into two paradigms: "multifunctional scaffolding" versus "on-demand targeting". By addressing the latest advances and challenges in the established yet constantly evolving multifunctional scaffolding strategies as well as in the emerging on-demand precision targeting (and related) systems, this Perspective is aimed at choosing when it is best to employ each of the two strategies, with an emphasis toward further promoting novel applications and discoveries stemming from these innovative chemical biology platforms.

  15. SH2/SH3 signaling proteins.

    Science.gov (United States)

    Schlessinger, J

    1994-02-01

    SH2 and SH3 domains are small protein modules that mediate protein-protein interactions in signal transduction pathways that are activated by protein tyrosine kinases. SH2 domains bind to short phosphotyrosine-containing sequences in growth factor receptors and other phosphoproteins. SH3 domains bind to target proteins through sequences containing proline and hydrophobic amino acids. SH2 and SH3 domain containing proteins, such as Grb2 and phospholipase C gamma, utilize these modules in order to link receptor and cytoplasmic protein tyrosine kinases to the Ras signaling pathway and to phosphatidylinositol hydrolysis, respectively. The three-dimensional structures of several SH2 and SH3 domains have been determined by NMR and X-ray crystallography, and the molecular basis of their specificity is beginning to be unveiled.

  16. Signal Enhancement with Variable Span Linear Filters

    DEFF Research Database (Denmark)

    Benesty, Jacob; Christensen, Mads Græsbøll; Jensen, Jesper Rindom

    . Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal...... the time and STFT domains, and, lastly, in time-domain binaural enhancement. In these contexts, the properties of these filters are analyzed in terms of their noise reduction capabilities and desired signal distortion, and the analyses are validated and further explored in simulations....

  17. Inferring Person-to-person Proximity Using WiFi Signals

    OpenAIRE

    Sapiezynski, Piotr; Stopczynski, Arkadiusz; Wind, David Kofoed; Leskovec, Jure; Lehmann, Sune

    2016-01-01

    Today's societies are enveloped in an ever-growing telecommunication infrastructure. This infrastructure offers important opportunities for sensing and recording a multitude of human behaviors. Human mobility patterns are a prominent example of such a behavior which has been studied based on cell phone towers, Bluetooth beacons, and WiFi networks as proxies for location. However, while mobility is an important aspect of human behavior, understanding complex social systems requires studying no...

  18. TENCompetence Domain Model

    NARCIS (Netherlands)

    2006-01-01

    This is the version 1.1 of the TENCompetence Domain Model (version 1.0 released at 19-6-2006; version 1.1 at 9-11-2008). It contains several files: a) a pdf with the model description, b) three jpg files with class models (also in the pdf), c) a MagicDraw zip file with the model itself, d) a release

  19. Testin, a novel binding partner of the calcium-sensing receptor, enhances receptor-mediated Rho-kinase signalling

    International Nuclear Information System (INIS)

    Magno, Aaron L.; Ingley, Evan; Brown, Suzanne J.; Conigrave, Arthur D.; Ratajczak, Thomas; Ward, Bryan K.

    2011-01-01

    Highlights: → A yeast two-hybrid screen revealed testin bound to the calcium-sensing receptor. → The second zinc finger of LIM domain 1 of testin is critical for interaction. → Testin bound to a region of the receptor tail important for cell signalling. → Testin and receptor interaction was confirmed in mammalian (HEK293) cells. → Overexpression of testin enhanced receptor-mediated Rho signalling in HEK293 cells. -- Abstract: The calcium-sensing receptor (CaR) plays an integral role in calcium homeostasis and the regulation of other cellular functions including cell proliferation and cytoskeletal organisation. The multifunctional nature of the CaR is manifested through ligand-dependent stimulation of different signalling pathways that are also regulated by partner binding proteins. Following a yeast two-hybrid library screen using the intracellular tail of the CaR as bait, we identified several novel binding partners including the focal adhesion protein, testin. Testin has not previously been shown to interact with cell surface receptors. The sites of interaction between the CaR and testin were mapped to the membrane proximal region of the receptor tail and the second zinc-finger of LIM domain 1 of testin, the integrity of which was found to be critical for the CaR-testin interaction. The CaR-testin association was confirmed in HEK293 cells by coimmunoprecipitation and confocal microscopy studies. Ectopic expression of testin in HEK293 cells stably expressing the CaR enhanced CaR-stimulated Rho activity but had no effect on CaR-stimulated ERK signalling. These results suggest an interplay between the CaR and testin in the regulation of CaR-mediated Rho signalling with possible effects on the cytoskeleton.

  20. PROXIMAL: a method for Prediction of Xenobiotic Metabolism.

    Science.gov (United States)

    Yousofshahi, Mona; Manteiga, Sara; Wu, Charmian; Lee, Kyongbum; Hassoun, Soha

    2015-12-22

    Contamination of the environment with bioactive chemicals has emerged as a potential public health risk. These substances that may cause distress or disease in humans can be found in air, water and food supplies. An open question is whether these chemicals transform into potentially more active or toxic derivatives via xenobiotic metabolizing enzymes expressed in the body. We present a new prediction tool, which we call PROXIMAL (Prediction of Xenobiotic Metabolism) for identifying possible transformation products of xenobiotic chemicals in the liver. Using reaction data from DrugBank and KEGG, PROXIMAL builds look-up tables that catalog the sites and types of structural modifications performed by Phase I and Phase II enzymes. Given a compound of interest, PROXIMAL searches for substructures that match the sites cataloged in the look-up tables, applies the corresponding modifications to generate a panel of possible transformation products, and ranks the products based on the activity and abundance of the enzymes involved. PROXIMAL generates transformations that are specific for the chemical of interest by analyzing the chemical's substructures. We evaluate the accuracy of PROXIMAL's predictions through case studies on two environmental chemicals with suspected endocrine disrupting activity, bisphenol A (BPA) and 4-chlorobiphenyl (PCB3). Comparisons with published reports confirm 5 out of 7 and 17 out of 26 of the predicted derivatives for BPA and PCB3, respectively. We also compare biotransformation predictions generated by PROXIMAL with those generated by METEOR and Metaprint2D-react, two other prediction tools. PROXIMAL can predict transformations of chemicals that contain substructures recognizable by human liver enzymes. It also has the ability to rank the predicted metabolites based on the activity and abundance of enzymes involved in xenobiotic transformation.

  1. Correlations and coherence of monopolar EMG-currents of the medial gastrocnemius muscle in proximal and distal compartments

    Directory of Open Access Journals (Sweden)

    Vinzenz eVon Tscharner

    2014-06-01

    Full Text Available The penniform gastrocnemius muscle contains multiple heads in the proximal regions and the aponeuroses are attached to the Achilles tendon. The multiple head structure lead to the assumption that different regions of the muscle must be activated compartment wise. The purpose of this study was to compare the correlation and coherence of EMG-currents within and between proximal and distal compartments of the medial gastrocnemius muscle, which reflect underling synchronization of motor units. It was hypothesized and shown that phase-inverted signals represent a property that discriminates compartments. However, the phase-inverted and non-inverted signals showed values of correlations that were indicative for highly synchronized signals. The correlation increased with the complexity of the task and was higher for the calf-rising movement than while balancing in a tiptoe position. Because the muscle fibers do not span the whole length of the muscles one has to conclude that the MUs were synchronized by synchronizing the various motor nerves. This study shows that it is essential to measure monopolar signals and use non-isometric contractions to observe synchronization of the EMG-signals. One could speculate that compartmental differences can only be observed if more complex movements that generate rotational forces at the knee or ankle are used.

  2. Calculus Rules for V-Proximal Subdifferentials in Smooth Banach Spaces

    Directory of Open Access Journals (Sweden)

    Messaoud Bounkhel

    2016-01-01

    Full Text Available In 2010, Bounkhel et al. introduced new proximal concepts (analytic proximal subdifferential, geometric proximal subdifferential, and proximal normal cone in reflexive smooth Banach spaces. They proved, in p-uniformly convex and q-uniformly smooth Banach spaces, the density theorem for the new concepts of proximal subdifferential and various important properties for both proximal subdifferential concepts and the proximal normal cone concept. In this paper, we establish calculus rules (fuzzy sum rule and chain rule for both proximal subdifferentials and we prove the Bishop-Phelps theorem for the proximal normal cone. The limiting concept for both proximal subdifferentials and for the proximal normal cone is defined and studied. We prove that both limiting constructions coincide with the Mordukhovich constructions under some assumptions on the space. Applications to nonconvex minimisation problems and nonconvex variational inequalities are established.

  3. Domain decomposition method for solving elliptic problems in unbounded domains

    International Nuclear Information System (INIS)

    Khoromskij, B.N.; Mazurkevich, G.E.; Zhidkov, E.P.

    1991-01-01

    Computational aspects of the box domain decomposition (DD) method for solving boundary value problems in an unbounded domain are discussed. A new variant of the DD-method for elliptic problems in unbounded domains is suggested. It is based on the partitioning of an unbounded domain adapted to the given asymptotic decay of an unknown function at infinity. The comparison of computational expenditures is given for boundary integral method and the suggested DD-algorithm. 29 refs.; 2 figs.; 2 tabs

  4. Sim3C: simulation of Hi-C and Meta3C proximity ligation sequencing technologies.

    Science.gov (United States)

    DeMaere, Matthew Z; Darling, Aaron E

    2018-02-01

    Chromosome conformation capture (3C) and Hi-C DNA sequencing methods have rapidly advanced our understanding of the spatial organization of genomes and metagenomes. Many variants of these protocols have been developed, each with their own strengths. Currently there is no systematic means for simulating sequence data from this family of sequencing protocols, potentially hindering the advancement of algorithms to exploit this new datatype. We describe a computational simulator that, given simple parameters and reference genome sequences, will simulate Hi-C sequencing on those sequences. The simulator models the basic spatial structure in genomes that is commonly observed in Hi-C and 3C datasets, including the distance-decay relationship in proximity ligation, differences in the frequency of interaction within and across chromosomes, and the structure imposed by cells. A means to model the 3D structure of randomly generated topologically associating domains is provided. The simulator considers several sources of error common to 3C and Hi-C library preparation and sequencing methods, including spurious proximity ligation events and sequencing error. We have introduced the first comprehensive simulator for 3C and Hi-C sequencing protocols. We expect the simulator to have use in testing of Hi-C data analysis algorithms, as well as more general value for experimental design, where questions such as the required depth of sequencing, enzyme choice, and other decisions can be made in advance in order to ensure adequate statistical power with respect to experimental hypothesis testing.

  5. An Analog Circuit Approximation of the Discrete Wavelet Transform for Ultra Low Power Signal Processing in Wearable Sensor Nodes

    OpenAIRE

    Casson, Alexander J.

    2015-01-01

    Ultra low power signal processing is an essential part of all sensor nodes, and particularly so in emerging wearable sensors for biomedical applications. Analog signal processing has an important role in these low power, low voltage, low frequency applications, and there is a key drive to decrease the power consumption of existing analog domain signal processing and to map more signal processing approaches into the analog domain. This paper presents an analog domain signal processing circuit ...

  6. Topology of digital images visual pattern discovery in proximity spaces

    CERN Document Server

    Peters, James F

    2014-01-01

    This book carries forward recent work on visual patterns and structures in digital images and introduces a near set-based a topology of digital images. Visual patterns arise naturally in digital images viewed as sets of non-abstract points endowed with some form of proximity (nearness) relation. Proximity relations make it possible to construct uniform topolo- gies on the sets of points that constitute a digital image. In keeping with an interest in gaining an understanding of digital images themselves as a rich source of patterns, this book introduces the basics of digital images from a computer vision perspective. In parallel with a computer vision perspective on digital images, this book also introduces the basics of prox- imity spaces. Not only the traditional view of spatial proximity relations but also the more recent descriptive proximity relations are considered. The beauty of the descriptive proximity approach is that it is possible to discover visual set patterns among sets that are non-overlapping ...

  7. Symmetry-based reciprocity: evolutionary constraints on a proximate mechanism.

    Science.gov (United States)

    Campennì, Marco; Schino, Gabriele

    2016-01-01

    Background. While the evolution of reciprocal cooperation has attracted an enormous attention, the proximate mechanisms underlying the ability of animals to cooperate reciprocally are comparatively neglected. Symmetry-based reciprocity is a hypothetical proximate mechanism that has been suggested to be widespread among cognitively unsophisticated animals. Methods. We developed two agent-based models of symmetry-based reciprocity (one relying on an arbitrary tag and the other on interindividual proximity) and tested their ability both to reproduce significant emergent features of cooperation in group living animals and to promote the evolution of cooperation. Results. Populations formed by agents adopting symmetry-based reciprocity showed differentiated "social relationships" and a positive correlation between cooperation given and received: two common aspects of animal cooperation. However, when reproduction and selection across multiple generations were added to the models, agents adopting symmetry-based reciprocity were outcompeted by selfish agents that never cooperated. Discussion. In order to evolve, hypothetical proximate mechanisms must be able to stand competition from alternative strategies. While the results of our simulations require confirmation using analytical methods, we provisionally suggest symmetry-based reciprocity is to be abandoned as a possible proximate mechanism underlying the ability of animals to reciprocate cooperative interactions.

  8. Biomechanical evaluation of straight antegrade nailing in proximal humeral fractures: the rationale of the "proximal anchoring point".

    Science.gov (United States)

    Euler, Simon A; Petri, Maximilian; Venderley, Melanie B; Dornan, Grant J; Schmoelz, Werner; Turnbull, Travis Lee; Plecko, Michael; Kralinger, Franz S; Millett, Peter J

    2017-09-01

    Varus failure is one of the most common failure modes following surgical treatment of proximal humeral fractures. Straight antegrade nails (SAN) theoretically provide increased stability by anchoring to the densest zone of the proximal humerus (subchondral zone) with the end of the nail. The aim of this study was to biomechanically investigate the characteristics of this "proximal anchoring point" (PAP). We hypothesized that the PAP would improve stability compared to the same construct without the PAP. Straight antegrade humeral nailing was performed in 20 matched pairs of human cadaveric humeri for a simulated unstable two-part fracture. Biomechanical testing, with stepwise increasing cyclic axial loading (50-N increments each 100 cycles) at an angle of 20° abduction revealed significantly higher median loads to failure for SAN constructs with the PAP (median, 450 N; range, 200-1.000 N) compared to those without the PAP (median, 325 N; range, 100-500 N; p = 0.009). SAN constructs with press-fit proximal extensions (endcaps) showed similar median loads to failure (median, 400 N; range, 200-650 N), when compared to the undersized, commercially available SAN endcaps (median, 450 N; range, 200-600 N; p = 0.240). The PAP provided significantly increased stability in SAN constructs compared to the same setup without this additional proximal anchoring point. Varus-displacing forces to the humeral head were superiorly reduced in this setting. This study provides biomechanical evidence for the "proximal anchoring point's" rationale. Straight antegrade humeral nailing may be beneficial for patients undergoing surgical treatment for unstable proximal humeral fractures to decrease secondary varus displacement and thus potentially reduce revision rates.

  9. Quantifying information transfer by protein domains: Analysis of the Fyn SH2 domain structure

    Directory of Open Access Journals (Sweden)

    Serrano Luis

    2008-10-01

    Full Text Available Abstract Background Efficient communication between distant sites within a protein is essential for cooperative biological response. Although often associated with large allosteric movements, more subtle changes in protein dynamics can also induce long-range correlations. However, an appropriate formalism that directly relates protein structural dynamics to information exchange between functional sites is still lacking. Results Here we introduce a method to analyze protein dynamics within the framework of information theory and show that signal transduction within proteins can be considered as a particular instance of communication over a noisy channel. In particular, we analyze the conformational correlations between protein residues and apply the concept of mutual information to quantify information exchange. Mapping out changes of mutual information on the protein structure then allows visualizing how distal communication is achieved. We illustrate the approach by analyzing information transfer by the SH2 domain of Fyn tyrosine kinase, obtained from Monte Carlo dynamics simulations. Our analysis reveals that the Fyn SH2 domain forms a noisy communication channel that couples residues located in the phosphopeptide and specificity binding sites and a number of residues at the other side of the domain near the linkers that connect the SH2 domain to the SH3 and kinase domains. We find that for this particular domain, communication is affected by a series of contiguous residues that connect distal sites by crossing the core of the SH2 domain. Conclusion As a result, our method provides a means to directly map the exchange of biological information on the structure of protein domains, making it clear how binding triggers conformational changes in the protein structure. As such it provides a structural road, next to the existing attempts at sequence level, to predict long-range interactions within protein structures.

  10. Signal Processing

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    Signal processing techniques, extensively used nowadays to maximize the performance of audio and video equipment, have been a key part in the design of hardware and software for high energy physics detectors since pioneering applications in the UA1 experiment at CERN in 1979

  11. Functional Domain Driven Design

    OpenAIRE

    Herrera Guzmán, Sergio

    2016-01-01

    Las tecnologías están en constante expansión y evolución, diseñando nuevas técnicas para cumplir con su fin. En el desarrollo de software, las herramientas y pautas para la elaboración de productos software constituyen una pieza en constante evolución, necesarias para la toma de decisiones sobre los proyectos a realizar. Uno de los arquetipos para el desarrollo de software es el denominado Domain Driven Design, donde es importante conocer ampliamente el negocio que se desea modelar en form...

  12. Feature-level domain adaptation

    DEFF Research Database (Denmark)

    Kouw, Wouter M.; Van Der Maaten, Laurens J P; Krijthe, Jesse H.

    2016-01-01

    -level domain adaptation (flda), that models the dependence between the two domains by means of a feature-level transfer model that is trained to describe the transfer from source to target domain. Subsequently, we train a domain-adapted classifier by minimizing the expected loss under the resulting transfer...... modeled via a dropout distribution, which allows the classiffier to adapt to differences in the marginal probability of features in the source and the target domain. Our experiments on several real-world problems show that flda performs on par with state-of-the-art domainadaptation techniques.......Domain adaptation is the supervised learning setting in which the training and test data are sampled from different distributions: training data is sampled from a source domain, whilst test data is sampled from a target domain. This paper proposes and studies an approach, called feature...

  13. Compensating for Incomplete Domain Knowledge

    National Research Council Canada - National Science Library

    Scott, Lynn M; Drezner, Steve; Rue, Rachel; Reyes, Jesse

    2007-01-01

    .... First, many senior leader positions require experience in more than one functional or operational domain, but it is difficult to develop a corps of senior leaders with all the required combinations of domain knowledge...

  14. Comparison of different proximity potentials for asymmetric colliding nuclei

    International Nuclear Information System (INIS)

    Dutt, Ishwar; Puri, Rajeev K.

    2010-01-01

    Using the different versions of phenomenological proximity potential as well as other parametrizations within the proximity concept, we perform a detailed comparative study of fusion barriers for asymmetric colliding nuclei with asymmetry parameter as high as 0.23. In all, 12 different proximity potentials are robust against the experimental data of 60 reactions. Our detailed study reveals that the surface energy coefficient as well as radius of the colliding nuclei depend significantly on the asymmetry parameter. All models are able to explain the fusion barrier heights within ±10% on the average. The potentials due to Bass 80, AW 95, and Denisov DP explain nicely the fusion cross sections at above- as well as below-barrier energies.

  15. Fractures of the proximal humerus involving the intertubercular groove

    International Nuclear Information System (INIS)

    Ahovuo, J.; Paavolainen, P.; Bjoerkenheim, J.M.; Helsinki Univ. Central Hospital

    1989-01-01

    The purpose of this study was to analyse the involvement of the gliding surface of the biceps tendon in fractures of the proximal humerus. Fifteen patients had a fracture of the proximal humerus verified with antero-posterior and axillary radiographs. Tangential radiographs of the intertubercular groove, obtained from the shoulder joint, showed involvement of the intertubercular groove in 13 patients (87%), which could not be shown with other projections. Groove radiographs revealed in 3 patients a dislocation of the fragments of the greater tuberosity large enough to require surgical treatment, but which had not been found using conventional techniques. Therefore, a groove radiograph should be used to precise fractures of the proximal humerus. (orig.)

  16. Structure and function of the TIR domain from the grape NLR protein RPV1

    Directory of Open Access Journals (Sweden)

    Simon John Williams

    2016-12-01

    Full Text Available The N-terminal Toll/interleukin-1 receptor/resistance protein (TIR domain has been shown to be both necessary and sufficient for defence signalling in the model plants flax and Arabidopsis. In examples from these organisms, TIR domain self-association is required for signalling function, albeit through distinct interfaces. Here, we investigate these properties in the TIR domain containing resistance protein RPV1 from the wild grapevine Muscadinia rotundifolia. The RPV1 TIR domain, without additional flanking sequence present, is autoactive when transiently expressed in tobacco, demonstrating that the TIR domain alone is capable of cell-death signalling. We determined the crystal structure of the RPV1 TIR domain at 2.3 Å resolution. In the crystals, the RPV1 TIR domain forms a dimer, mediated predominantly through residues in the αA and αE helices (AE interface. This interface is shared with the interface discovered in the dimeric complex of the TIR domains from the Arabidopsis RPS4/RRS1 resistance protein pair. We show that surface-exposed residues in the AE interface that mediate the dimer interaction in the crystals are highly conserved among plant TIR domain-containing proteins. While we were unable to demonstrate self-association of the RPV1 TIR domain in solution or using yeast 2-hybrid, mutations of surface-exposed residues in the AE interface prevent the cell-death autoactive phenotype. In addition, mutation of residues known to be important in the cell-death signalling function of the flax L6 TIR domain were also shown to be required for RPV1 TIR domain mediated cell-death. Our data demonstrate that multiple TIR domain surfaces control the cell-death function of the RPV1 TIR domain and we suggest that the conserved AE interface may have a general function in TIR-NLR signalling.

  17. Summarization by domain ontology navigation

    DEFF Research Database (Denmark)

    Andreasen, Troels; Bulskov, Henrik

    2013-01-01

    of the subject. In between these two extremes, conceptual summaries encompass selected concepts derived using background knowledge. We address in this paper an approach where conceptual summaries are provided through a conceptualization as given by an ontology. The ontology guiding the summarization can...... be a simple taxonomy or a generative domain ontology. A domain ontology can be provided by a preanalysis of a domain corpus and can be used to condense improved summaries that better reflects the conceptualization of a given domain....

  18. NMR and domain wall mobility in intermetallic compounds

    International Nuclear Information System (INIS)

    Guimaraes, A.P.; Sampaio, L.C.; Cunha, S.F.; Alves, K.M.B.

    1991-01-01

    The technique of pulsed NMR can be used to study the distribution of hyperfine fields in a magnetic matrix. The dynamics of the domain walls are relevant to the generation of NMR signals. In the present study on the (R x Y 1-x ) Fe 2 intermetallic compounds, the reduction in the signals is associated to increased propagation fields. This indicates that a smaller domain wall mobility is at the origin of these effects. NMR spectra in this system show the importance of direct and indirect (i.e., mediated by Fe atoms) terms in the transferred hyperfine field. (author)

  19. Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily

    Directory of Open Access Journals (Sweden)

    Marc Lenoir

    2015-10-01

    Full Text Available The human genome encodes about 285 proteins that contain at least one annotated pleckstrin homology (PH domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology (DH and Tec homology (TH domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. Here the Membrane Optimal Docking Area (MODA program is used at a genome-wide level to identify all membrane docking PH structures and map their lipid-binding determinants. In addition to the linear sequence motifs which are employed for phosphoinositide recognition, the three dimensional structural features that allow peripheral membrane domains to approach and insert into the bilayer are pinpointed and can be predicted ab initio. The analysis shows that conserved structural surfaces distinguish which PH domains associate with membrane from those that do not. Moreover, the results indicate that lipid-binding PH domains can be classified into different functional subgroups based on the type of membrane insertion elements they project towards the bilayer.

  20. Size and mobility of lipid domains tuned by geometrical constraints.

    Science.gov (United States)

    Schütte, Ole M; Mey, Ingo; Enderlein, Jörg; Savić, Filip; Geil, Burkhard; Janshoff, Andreas; Steinem, Claudia

    2017-07-25

    In the plasma membrane of eukaryotic cells, proteins and lipids are organized in clusters, the latter ones often called lipid domains or "lipid rafts." Recent findings highlight the dynamic nature of such domains and the key role of membrane geometry and spatial boundaries. In this study, we used porous substrates with different pore radii to address precisely the extent of the geometric constraint, permitting us to modulate and investigate the size and mobility of lipid domains in phase-separated continuous pore-spanning membranes (PSMs). Fluorescence video microscopy revealed two types of liquid-ordered ( l o ) domains in the freestanding parts of the PSMs: ( i ) immobile domains that were attached to the pore rims and ( ii ) mobile, round-shaped l o domains within the center of the PSMs. Analysis of the diffusion of the mobile l o domains by video microscopy and particle tracking showed that the domains' mobility is slowed down by orders of magnitude compared with the unrestricted case. We attribute the reduced mobility to the geometric confinement of the PSM, because the drag force is increased substantially due to hydrodynamic effects generated by the presence of these boundaries. Our system can serve as an experimental test bed for diffusion of 2D objects in confined geometry. The impact of hydrodynamics on the mobility of enclosed lipid domains can have great implications for the formation and lateral transport of signaling platforms.