NO Metabolites Levels in Human Red Blood Cells are Affected by Palytoxin, an Inhibitor of Na(+)/K(+)-ATPase Pump.

PubMed

Carelli-Alinovi, Cristiana; Tellone, Ester; Russo, Anna Maria; Ficarra, Silvana; Pirolli, Davide; Galtieri, Antonio; Giardina, Bruno; Misiti, Francesco

2014-01-01

Palytoxin (PTX), a marine toxin, represents an increasing hazard for human health. Despite its high toxicity for biological systems, the mechanisms triggered by PTX, are not well understood. The high affinity of PTX for erythrocyte Na(+)/K(+)-ATPase pump is largely known, and it indicates PTX as a sensitive tool to characterize the signal transducer role for Na(+)/K(+)-ATPase pump. Previously, it has been reported that in red blood cells (RBC), probably via a signal transduction generated by the formation of a PTX-Na(+)/K(+)-ATPase complex, PTX alters band 3 functions and glucose metabolism. The present study addresses the question of which other signaling pathways are regulated by Na(+)/K(+)-ATPase in RBC. Here it has been evidenced that PTX following its interaction with Na(+)/K(+)-ATPase pump, alters RBC morphology and this event is correlated to decreases by 30% in nitrites and nitrates levels, known as markers of plasma membrane eNOS activity. Orthovanadate (OV), an antagonist of PTX binding to Na(+)/K(+)-ATPase pump, was able to reverse the effects elicited by PTX. Finally, current investigation firstly suggests that Na(+)/K(+)-ATPase pump, following its interaction with PTX, triggers a signal transduction involved in NO metabolism regulation.

Human Monocytes Engage an Alternative Inflammasome Pathway.

PubMed

Gaidt, Moritz M; Ebert, Thomas S; Chauhan, Dhruv; Schmidt, Tobias; Schmid-Burgk, Jonathan L; Rapino, Francesca; Robertson, Avril A B; Cooper, Matthew A; Graf, Thomas; Hornung, Veit

2016-04-19

Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

MicroRNA-triggered, cascaded and catalytic self-assembly of functional ``DNAzyme ferris wheel'' nanostructures for highly sensitive colorimetric detection of cancer cells

NASA Astrophysics Data System (ADS)

Zhou, Wenjiao; Liang, Wenbin; Li, Xin; Chai, Yaqin; Yuan, Ruo; Xiang, Yun

2015-05-01

The construction of DNA nanostructures with various sizes and shapes has significantly advanced during the past three decades, yet the application of these DNA nanostructures for solving real problems is still in the early stage. On the basis of microRNA-triggered, catalytic self-assembly formation of the functional ``DNAzyme ferris wheel'' nanostructures, we show here a new signal amplification platform for highly sensitive, label-free and non-enzyme colorimetric detection of a small number of human prostate cancer cells. The microRNA (miR-141), which is catalytically recycled and reused, triggers isothermal self-assembly of a pre-designed, G-quadruplex sequence containing hairpin DNAs into ``DNAzyme ferris wheel''-like nanostructures (in association with hemin) with horseradish peroxidase mimicking activity. These DNAzyme nanostructures catalyze an intensified color transition of the probe solution for highly sensitive detection of miR-141 down to 0.5 pM with the naked eye, and the monitoring of as low as 283 human prostate cancer cells can also, theoretically, be achieved in a colorimetric approach. The work demonstrated here thus offers new opportunities for the construction of functional DNA nanostructures and for the application of these DNA nanostructures as an effective signal amplification means in the sensitive detection of nucleic acid biomarkers.

Conflicts as Aversive Signals

ERIC Educational Resources Information Center

Dreisbach, Gesine; Fischer, Rico

2012-01-01

Theories of human action control deal with the question of how cognitive control is dynamically adjusted to task demands. The conflict monitoring theory of anterior cingulate (ACC) function suggests that the ACC monitors for response conflicts in the ongoing processing stream thereby triggering the mobilization of cognitive control. Alternatively,…

Dissociable brain mechanisms underlying the conscious and unconscious control of behavior.

PubMed

van Gaal, Simon; Lamme, Victor A F; Fahrenfort, Johannes J; Ridderinkhof, K Richard

2011-01-01

Cognitive control allows humans to overrule and inhibit habitual responses to optimize performance in challenging situations. Contradicting traditional views, recent studies suggest that cognitive control processes can be initiated unconsciously. To further capture the relation between consciousness and cognitive control, we studied the dynamics of inhibitory control processes when triggered consciously versus unconsciously in a modified version of the stop task. Attempts to inhibit an imminent response were often successful after unmasked (visible) stop signals. Masked (invisible) stop signals rarely succeeded in instigating overt inhibition but did trigger slowing down of response times. Masked stop signals elicited a sequence of distinct ERP components that were also observed on unmasked stop signals. The N2 component correlated with the efficiency of inhibitory control when elicited by unmasked stop signals and with the magnitude of slowdown when elicited by masked stop signals. Thus, the N2 likely reflects the initiation of inhibitory control, irrespective of conscious awareness. The P3 component was much reduced in amplitude and duration on masked versus unmasked stop trials. These patterns of differences and similarities between conscious and unconscious cognitive control processes are discussed in a framework that differentiates between feedforward and feedback connections in yielding conscious experience.

Airborne polycyclic aromatic hydrocarbons trigger human skin cells aging through aryl hydrocarbon receptor.

PubMed

Qiao, Yuan; Li, Qiang; Du, Hong-Yang; Wang, Qiao-Wei; Huang, Ye; Liu, Wei

2017-07-01

Accumulating evidence suggests that polycyclic aromatic hydrocarbons (PAH) which adsorbed on the surface of ambient air particulate matters (PM), are the major toxic compound to cause cardiovascular and respiratory diseases, even cancer. However, its detrimental effects on human skin cell remain unclear. Here, we demonstrated that SRM1649b, a reference urban dust material of PAH, triggers human skin cells aging through cell cycle arrest, cell growth inhibition and apoptosis. Principally, SRM1649b facilitated Aryl hydrocarbon receptor (AhR) translocated into nucleus, subsequently activated ERK/MAPK signaling pathway, and upregulated aging-related genes expression. Most important, we found that AhR antagonist efficiently revert the aging of skin cells. Thus our novel findings firstly revealed the mechanism of skin aging under PAH contamination and provided potential strategy for clinical application. Copyright © 2017. Published by Elsevier Inc.

Mitochondrial dysfunction as a trigger of innate immune responses and inflammation.

PubMed

West, A Phillip

2017-11-01

A growing literature indicates that mitochondria are key participants in innate immune pathways, functioning as both signaling platforms and contributing to effector responses. In addition to regulating antiviral signaling and antibacterial immunity, mitochondria are also important drivers of inflammation caused by sterile injury. Much research on mitochondrial control of immunity now centers on understanding how mitochondrial constituents released during cellular damage simulate the innate immune system. When mitochondrial integrity is compromised, mitochondrial damage-associated molecular patterns engage pattern recognition receptors, trigger inflammation, and promote pathology in an expanding list of diseases. Here, I review the emerging knowledge of mitochondrial dysfunction in innate immune responses and discuss how environmental exposures may induce mitochondrial damage to potentiate inflammation and human disease. Copyright © 2017 Elsevier B.V. All rights reserved.

A role for oxalic acid generation in ozone-induced signallization in Arabidopis cells.

PubMed

Tran, Daniel; Kadono, Takashi; Molas, Maria Lia; Errakhi, Rafik; Briand, Joël; Biligui, Bernadette; Kawano, Tomonori; Bouteau, François

2013-03-01

Ozone (O(3) ) is an air pollutant with an impact increasingly important in our industrialized world. It affects human health and productivity in various crops. We provide the evidences that treatment of Arabidopsis thaliana with O(3) results in ascorbate-derived oxalic acid production. Using cultured cells of A. thaliana as a model, here we further showed that oxalic acid induces activation of anion channels that trigger depolarization of the cell, increase in cytosolic Ca(2+) concentration, generation of reactive oxygen species and cell death. We confirmed that O(3) reacts with ascorbate in the culture, thus resulting in production of oxalic acid and this could be part of the O(3) -induced signalling pathways that trigger programmed cell death. © 2012 Blackwell Publishing Ltd.

VISA is an adapter protein required for virus-triggered IFN-beta signaling.

PubMed

Xu, Liang-Guo; Wang, Yan-Yi; Han, Ke-Jun; Li, Lian-Yun; Zhai, Zhonghe; Shu, Hong-Bing

2005-09-16

Viral infection or stimulation of TLR3 triggers signaling cascades, leading to activation of the transcription factors IRF-3 and NF-kappaB, which collaborate to induce transcription of type I interferon (IFN) genes. In this study, we identified a protein termed VISA (for virus-induced signaling adaptor) as a critical component in the IFN-beta signaling pathways. VISA recruits IRF-3 to the cytoplasmic viral dsRNA sensor RIG-I. Depletion of VISA inhibits virus-triggered and RIG-I-mediated activation of IRF-3, NF-kappaB, and the IFN-beta promoter, suggesting that VISA plays a central role in virus-triggered TLR3-independent IFN-beta signaling. Our data also indicate that VISA interacts with TRIF and TRAF6 and mediates bifurcation of the TLR3-triggered NF-kappaB and IRF-3 activation pathways. These findings suggest that VISA is critically involved in both virus-triggered TLR3-independent and TLR3-mediated antiviral IFN signaling.

Biological Motion Cues Trigger Reflexive Attentional Orienting

ERIC Educational Resources Information Center

Shi, Jinfu; Weng, Xuchu; He, Sheng; Jiang, Yi

2010-01-01

The human visual system is extremely sensitive to biological signals around us. In the current study, we demonstrate that biological motion walking direction can induce robust reflexive attentional orienting. Following a brief presentation of a central point-light walker walking towards either the left or right direction, observers' performance…

A plant effector-triggered immunity signaling sector is inhibited by pattern-triggered immunity.

PubMed

Hatsugai, Noriyuki; Igarashi, Daisuke; Mase, Keisuke; Lu, You; Tsuda, Yayoi; Chakravarthy, Suma; Wei, Hai-Lei; Foley, Joseph W; Collmer, Alan; Glazebrook, Jane; Katagiri, Fumiaki

2017-09-15

Since signaling machineries for two modes of plant-induced immunity, pattern-triggered immunity (PTI) and effector-triggered immunity (ETI), extensively overlap, PTI and ETI signaling likely interact. In an Arabidopsis quadruple mutant, in which four major sectors of the signaling network, jasmonate, ethylene, PAD4, and salicylate, are disabled, the hypersensitive response (HR) typical of ETI is abolished when the Pseudomonas syringae effector AvrRpt2 is bacterially delivered but is intact when AvrRpt2 is directly expressed in planta These observations led us to discovery of a network-buffered signaling mechanism that mediates HR signaling and is strongly inhibited by PTI signaling. We named this mechanism the ETI-Mediating and PTI-Inhibited Sector (EMPIS). The signaling kinetics of EMPIS explain apparently different plant genetic requirements for ETI triggered by different effectors without postulating different signaling machineries. The properties of EMPIS suggest that information about efficacy of the early immune response is fed back to the immune signaling network, modulating its activity and limiting the fitness cost of unnecessary immune responses. © 2017 The Authors.

Control of Aβ release from human neurons by differentiation status and RET signaling.

PubMed

Scholz, Diana; Chernyshova, Yana; Leist, Marcel

2013-01-01

Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid β (Aβ) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Aβ secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Aβ release was associated with rapid upregulation of the GDNF coreceptor "rearranged during transfection" (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Aβ, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Aβ increase. This suggests that RET signaling affects Aβ release from aging neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

Echicetin Coated Polystyrene Beads: A Novel Tool to Investigate GPIb-Specific Platelet Activation and Aggregation

PubMed Central

Petunin, Alexey; Clemetson, Kenneth J.; Gambaryan, Stepan; Walter, Ulrich

2014-01-01

von Willebrand factor/ristocetin (vWF/R) induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin, which also binds vWF. These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets. Here, we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads, which specifically activate GPIb. We compared platelet activation induced by echicetin beads to vWF/R. Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling. Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets, while under the same conditions vWF/R treatment led only to αIIbβ3-independent platelet agglutination. The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation, while the total amount of echicetin used for activation is not critical. Echicetin beads induced strong phosphorylation of several proteins including p38, ERK and PKB. Synergistic signaling via P2Y12 and thromboxane receptor through secreted ADP and TxA2, respectively, were important for echicetin bead triggered platelet activation. Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation. Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways. PMID:24705415

Switch device having a non-linear transmission line

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

Elizondo-Decanini, Juan M.

Switching devices are provided. The switching devices include an input electrode, having a main electrode and a trigger electrode, and an output electrode. The main electrode and the trigger electrode are separated from the output electrode by a main gap and a trigger gap, respectively. During operation, the trigger electrode compresses and amplifies a trigger voltage signal causing the trigger electrode to emit a pulse of energy. This pulse of energy form plasma near the trigger electrode, either by arcing across the trigger gap, or by arcing from the trigger electrode to the main electrode. This plasma decreases the breakdownmore » voltage of the main gap. Simultaneously, or near simultaneously, a main voltage signal propagates through the main electrode. The main voltage signal emits a main pulse of energy that arcs across the main gap while the plasma formed by the trigger pulse is still present.« less

Electronics design of the RPC system for the OPERA muon spectrometer

NASA Astrophysics Data System (ADS)

Acquafredda, R.; Ambrosio, M.; Balsamo, E.; Barichello, G.; Bergnoli, A.; Consiglio, L.; Corradi, G.; dal Corso, F.; Felici, G.; Manea, C.; Masone, V.; Parascandolo, P.; Sorrentino, G.

2004-09-01

The present document describes the front-end electronics of the RPC system that instruments the magnet muon spectrometer of the OPERA experiment. The main task of the OPERA spectrometer is to provide particle tracking information for muon identification and simplify the matching between the Precision Trackers. As no trigger has been foreseen for the experiment, the spectrometer electronics must be self-triggered with single-plane readout capability. Moreover, precision time information must be added within each event frame for off-line reconstruction. The read-out electronics is made of three different stages: the Front-End Boards (FEBs) system, the Controller Boards (CBs) system and the Trigger Boards (TBs) system. The FEB system provides discrimination of the strip incoming signals; a FAST-OR output of the input signals is also available for trigger plane signal generation. FEB signals are acquired by the CB system that provides the zero suppression and manages the communication to the DAQ and Slow Control. A Trigger Board allows to operate in both self-trigger mode (the FEB's FAST-OR signal starts the plane acquisition) or in external-trigger mode (different conditions can be set on the FAST-OR signals generated from different planes).

Investigation of Potential Triggered Tremor in Latin America and the Caribbean

NASA Astrophysics Data System (ADS)

Gonzalez-Huizar, H.; Velasco, A. A.; Peng, Z.

2012-12-01

Recent observations have shown that seismic waves generate transient stresses capable of triggering earthquakes and tectonic (or non-volcanic) tremor far away from the original earthquake source. However, the mechanisms behind remotely triggered seismicity still remain unclear. Triggered tremor signals can be particularly useful in investigating remote triggering processes, since in many cases, the tremor pulses are very clearly modulated by the passing surface waves. The temporal stress changes (magnitude and orientation) caused by seismic waves at the tremor source region can be calculated and correlated with tremor pulses, which allows for exploring the stresses involved in the triggering process. Some observations suggest that triggered and ambient tremor signals are generated under similar physical conditions; thus, investigating triggered tremor might also provide important clues on how and under what conditions ambient tremor signals generate. In this work we present some of the results and techniques we employ in the research of potential cases of triggered tectonic tremor in Latin America and the Caribbean. This investigation includes: (1) the triggered tremor detection, with the use of specific signal filters; (2) localization of the sources, using uncommon techniques like time reversal signals; (3) and the analysis of the stress conditions under which they are generated, by modeling the triggering waves related dynamic stress. Our results suggest that tremor can be dynamically triggered by both Love and Rayleigh waves and in broad variety of tectonic environments depending strongly on the dynamic stress amplitude and orientation. Investigating remotely triggered seismicity offers the opportunity to improve our knowledge about deformation mechanisms and the physics of rupture.

Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial stromal cell responsiveness to interleukin 1: a new possible mechanism underlying embryo implantation.

PubMed

Bourdiec, Amélie; Shao, Rong; Rao, C V; Akoum, Ali

2012-09-01

Deep functional changes occurring within the endometrium during implantation are orchestrated by embryonic and maternal signals. Human chorionic gonadotropin (hCG), a major embryonic signal, plays a critical role in the initiation and maintenance of pregnancy. Interleukin (IL) 1, one of the earliest embryonic signals, appears to exert a direct impact on the receptive endometrium and to induce major molecular changes that are essential for embryo implantation. Herein we investigate whether hCG can modulate endometrial stromal cell (ESC) receptivity to IL1 during the implantation window and assess the impact on angiogenesis in vitro. Primary cultures of ESCs from normal fertile women during the implantation window were treated for 24 h with different concentrations of hCG (0-100 ng/ml) and stimulated for 24 h with IL1B (0-0.1 ng/ml). IL1 receptors (IL1Rs), IL1R antagonist (IL1RA), and monocyte chemotactic protein (MCP) 1 were analyzed by real-time PCR, ELISA, and Western blotting. The angiogenic activity in vitro was studied using human microvascular endothelial cell line, scratch wound assay, and cell proliferation via BrdU incorporation into DNA. Human CG induced a dose-dependent imbalance in ESC receptivity to IL1 by significantly upregulating the functional signaling IL1R1 and concomitantly downregulating the decoy inhibitory IL1R2 and IL1RA upon subsequent exposure to IL1B. Prior exposure to hCG amplified MCP1 secretion by ESCs in response to IL1B and triggered the release of angiogenic activity in vitro in which MCP1 appeared to play a significant role. Overexpression of IL1R2 using cell transfection inhibited IL1 and hCG/IL1B-mediated MCP1 secretion. These findings suggest that hCG coordinates embryonic signal interaction with the maternal endometrium, and point to a new possible pathway by which it may promote embryonic growth.

Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion.

PubMed

Romero, Damian G; Zhou, Ming Yi; Yanes, Licy L; Plonczynski, Maria W; Washington, Tanganika R; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P

2007-08-01

Regulators of G-protein signaling (RGS proteins) interact with Galpha subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)-ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

Altered PKR signalling and C/EBPβ expression is associated with HLA-B27 expression in monocytic cells

PubMed Central

Sahlberg, Anna S.; Ruuska, Marja; Colbert, Robert A.; Granfors, Kaisa; Penttinen, Markus A.

2011-01-01

Infection caused by certain gram negative bacteria, e.g. Salmonella, can trigger inflammatory joint disease reactive arthritis (ReA). It is suggested that the disease-triggering bacteria or bacterial components persist in patients for an abnormally long time. Development of ReA is strongly associated with tissue antigen HLA-B27. Previously, we reported an enhanced replication of S. enteritidis and altered p38 MAP kinase signalling in HLA-B27-expressing monocytic cells. Here we aimed to investigate the role of HLA-B27 in regulation of double-stranded RNA activated kinase (PKR)-related signalling in Salmonella-infected or Salmonella LPS-stimulated human U937 monocytic cells, since PKR has been reported to modify p38 signalling in Salmonella-infected cells. In cells expressing HLA-B27, PKR is overexpressed and hypophosphorylated, and the expression of transcription factor CCAAT enhancer binding protein beta (C/EBPβ) is increased upon Salmonella infection and LPS stimulation. The expression of C/EBPβ is PKR-dependent in LPS-stimulated mock cells whereas in LPS-stimulated B27 cells the majority of C/EBPβ is expressed in a PKR-independent manner. Our results show that the expression of HLA-B27 disturbs the PKR-mediated signalling pathway. Moreover, altered signalling is related to misfolding-linked Glu45 in the B pocket of the HLA-B27 heavy chain. We suggest that the expression of HLA-B27 HCs modulates the intracellular environment of monocyte/macrophages and the mechanisms that are important in eliminating intracellular S. enteritidis by altering the intracellular signalling. This phenomenon is at least partly dependent on the misfolding featureof the B27 molecule. These observations offer a novel mechanism by which HLA-B27 may modulate inflammatory response induced by ReA-triggering bacteria. PMID:21988375

Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha11-dependent, PLC-beta-mediated pathway.

PubMed

Bueno, Clara; Lemke, Caitlin D; Criado, Gabriel; Baroja, Miren L; Ferguson, Stephen S G; Rahman, A K M Nur-Ur; Tsoukas, Constantine D; McCormick, John K; Madrenas, Joaquin

2006-07-01

The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.

Implement an adjustable delay time digital trigger for an NI data acquisition card in a high-speed demodulation system

NASA Astrophysics Data System (ADS)

Zhang, Hongtao; Fan, Lingling; Wang, Pengfei; Park, Seong-Wook

2012-06-01

A National Instruments (NI) DAQ card PCI 5105 is installed in a high-speed demodulation system based on Fiber Fabry-Pérot Tunable Filter. The instability of the spectra of Fiber Bragg Grating sensors caused by intrinsic drifts of FFP-TF needs an appropriate, flexible trigger. However, the driver of the DAQ card in the current development environment does not provide the functions of analog trigger but digital trigger type. Moreover, the high level of the trigger signal from the tuning voltage of FFP-TF is larger than the maximum input overload voltage of PCI 5105 card. To resolve this incompatibility, a novel converter to change an analog trigger signal into a digital trigger signal has been reported previously. However, the obvious delay time between input and output signals limits the function of demodulation system. Accordingly, we report an improved low-cost, small-size converter with an adjustable delay time. This new scheme can decline the delay time to or close to zero when the frequency of trigger signal is less than 3,000 Hz. This method might be employed to resolve similar problems or to be applied in semiconductor integrated circuits.

Review of first trial responses in balance control: influence of vestibular loss and Parkinson's disease.

PubMed

Allum, J H J; Tang, K-S; Carpenter, M G; Oude Nijhuis, L B; Bloem, B R

2011-04-01

The reaction to an unexpected balance disturbance is unpracticed, often startling and frequently associated with falls. This everyday situation can be reproduced in an experimental setting by exposing standing humans to sudden, unexpected and controlled movements of a support surface. In this review, we focus on the responses to the very first balance perturbation, the so-called first trial reactions (FTRs). Detailed analysis of FTRs may have important implications, both for clinical practice (providing new insights into the pathophysiological mechanisms underlying accidental falls in real life) and for understanding human physiology (what triggers and mediates these FTRs, and what is the relation to startle responses?). Several aspects of the FTRs have become clear. FTRs are characterized by an exaggerated postural reaction, with large EMG responses and co-contracting muscles in multiple body segments. This balance reaction is associated with marked postural instability (greater body sway to the perturbation). When the same perturbation is repeated, the size of the postural response habituates and the instability disappears. Other issues about FTRs remain largely unresolved, and these are addressed here. First, the functional role of FTRs is discussed. It appears that FTRs produce primarily increased trunk flexion during the multi-segmental response to postural perturbations, thus producing instability. Second, we consider which sensory signals trigger and modulate FTRs, placing specific emphasis on the role of vestibular signals. Surprisingly, vestibular signals appear to have no triggering role, but vestibular loss leads to excessive upper body FTRs due to loss of the normal modulatory influence. Third, we address the question whether startle-like responses are contributing to FTRs triggered by proprioceptive signals. We explain why this issue is still unresolved, mainly because of methodological difficulties involved in separating FTRs from 'pure' startle responses. Fourth, we review new work about the influence of perturbation direction on FTRs. Recent work from our group shows that the largest FTRs are obtained for toe-up support surface rotations which perturb the COM in the posterior direction. This direction corresponds to the directional preponderance for falls seen both in the balance laboratory and in daily life. Finally, we briefly touch upon clinical diagnostic issues, addressing whether FTRs (as opposed to habituated responses) could provide a more ecologically valid perspective of postural instability in patients compared to healthy subjects. We conclude that FTRs are an important source of information about human balance performance, both in health and disease. Future studies should no longer discard FTRs, but routinely include these in their analyses. Particular emphasis should be placed on the link between FTRs and everyday balance performance (including falls), and on the possible role played by startle reactions in triggering or modulating FTRs. Copyright © 2011 Elsevier B.V. All rights reserved.

Nuclear calcium is required for human T cell activation

PubMed Central

Samstag, Yvonne

2016-01-01

Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show that the “T cell calcium signal” is a composite signal harboring two distinct components that antagonistically control genomic programs underlying the immune response. Using human T cells from healthy individuals, we establish nuclear calcium as a key signal in human T cell adaptogenomics that drives T cell activation and is required for signaling to cyclic adenosine monophosphate response element–binding protein and the induction of CD25, CD69, interleukin-2, and γ-interferon. In the absence of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calcium–driven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy. PMID:27810914

The social brain: allowing humans to boldly go where no other species has been

PubMed Central

Frith, Uta; Frith, Chris

2010-01-01

The biological basis of complex human social interaction and communication has been illuminated through a coming together of various methods and disciplines. Among these are comparative studies of other species, studies of disorders of social cognition and developmental psychology. The use of neuroimaging and computational models has given weight to speculations about the evolution of social behaviour and culture in human societies. We highlight some networks of the social brain relevant to two-person interactions and consider the social signals between interacting partners that activate these networks. We make a case for distinguishing between signals that automatically trigger interaction and cooperation and ostensive signals that are used deliberately. We suggest that this ostensive signalling is needed for ‘closing the loop’ in two-person interactions, where the partners each know that they have the intention to communicate. The use of deliberate social signals can serve to increase reputation and trust and facilitates teaching. This is likely to be a critical factor in the steep cultural ascent of mankind. PMID:20008394

Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation

PubMed Central

Sivori, Simona; Falco, Michela; Marcenaro, Emanuela; Parolini, Silvia; Biassoni, Roberto; Bottino, Cristina; Moretta, Lorenzo; Moretta, Alessandro

2002-01-01

In this study we analyzed the progression of cell surface receptor expression during the in vitro-induced human natural killer (NK) cell maturation from CD34+ Lin− cell precursors. NKp46 and NKp30, two major triggering receptors that play a central role in natural cytotoxicity, were expressed before the HLA class I-specific inhibitory receptors. Moreover, their appearance at the cell surface correlated with the acquisition of cytolytic activity by developing NK cells. Although the early expression of triggering receptors may provide activating signals required for inducing further cell differentiation, it may also affect the self-tolerance of developing NK cells. Our data show that a fail-safe mechanism preventing killing of normal autologous cells may be provided by the 2B4 surface molecule, which, at early stages of NK cell differentiation, functions as an inhibitory rather than as an activating receptor. PMID:11917118

The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44.

PubMed

Allcock, Richard J N; Barrow, Alexander D; Forbes, Simon; Beck, Stephan; Trowsdale, John

2003-02-01

We have characterized a cluster of single immunoglobulin variable (IgV) domain receptors centromeric of the major histocompatibility complex (MHC) on human chromosome 6. In addition to triggering receptor expressed on myeloid cells (TREM)-1 and TREM2, the cluster contains NKp44, a triggering receptor whose expression is limited to NK cells. We identified three new related genes and two gene fragments within a cluster of approximately 200 kb. Two of the three new genes lack charged residues in their transmembrane domain tails. Further, one of the genes contains two potential immunotyrosine Inhibitory motifs in its cytoplasmic tail, suggesting that it delivers inhibitory signals. The human and mouse TREM clusters appear to have diverged such that there are unique sequences in each species. Finally, each gene in the TREM cluster was expressed in a different range of cell types.

Raft-dependent endocytic movement and intracellular cluster formation during T cell activation triggered by concanavalin A.

PubMed

Yabuuchi, Satomi; Endo, Satoshi; Baek, KeangOk; Hoshino, Kunihide; Tsujino, Yoshio; Vestergaard, Mun'delanji C; Takagi, Masahiro

2017-12-01

Certain food ingredients can stimulate the human immune system. A lectin, concanavalin A (ConA), from Canavalia ensiformis (jack bean) is one of the most well-known food-derived immunostimulants and mediates activation of cell-mediated immunity through T cell proliferation. Generally, T cell activation is known to be triggered by the interaction between T cells and antigen-presenting cells (APCs) via a juxtacrine (contact-dependent) signaling pathway. The mechanism has been well characterized and is referred to as formation of the immunological synapse (IS). We were interested in the mechanism behind the T cell activation by food-derived ConA which might be different from that of T cell activation by APCs. The purpose of this study was to characterize T cell activation by ConA with regard to (i) movement of raft domain, (ii) endocytic vesicular transport, (iii) the cytoskeleton (actin and microtubules), and (iv) cholesterol composition. We found that raft-dependent endocytic movement was important for T cell activation by ConA and this movement was dependent on actin, microtubules, and cholesterol. The T cell signaling mechanism triggered by ConA can be defined as endocrine signaling which is distinct from the activation process triggered by interaction between T cells and APCs by juxtacrine signaling. Therefore, we hypothesized that T cell activation by ConA includes both two-dimensional superficial raft movement on the membrane surface along actin filaments and three-dimensional endocytic movement toward the inside of the cell along microtubules. These findings are important for developing new methods for immune stimulation and cancer therapy based on the function of ConA. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

M. tuberculosis-Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1.

PubMed

Rajaram, Murugesan V S; Arnett, Eusondia; Azad, Abul K; Guirado, Evelyn; Ni, Bin; Gerberick, Abigail D; He, Li-Zhen; Keler, Tibor; Thomas, Lawrence J; Lafuse, William P; Schlesinger, Larry S

2017-10-03

Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides. We found that MR binds FcRγ-chain, which is required for MR plasma membrane localization and M.tb cell association. Additionally, we discovered that MR-mediated M.tb association triggers immediate MR tyrosine residue phosphorylation and Grb2 recruitment, activating the Rac/Pak/Cdc-42 signaling cascade important for M.tb uptake. MR activation subsequently recruits SHP-1 to the M.tb-containing phagosome, where its activity limits PI(3)P generation at the phagosome and M.tb P-L fusion and promotes M.tb growth. In sum, we identify human MR signaling pathways that temporally regulate phagocytosis and P-L fusion during M.tb infection. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Innate signaling by mycobacterial cell wall components and relevance for development of adjuvants for subunit vaccines.

PubMed

Tima, Hermann Giresse; Huygen, Kris; Romano, Marta

2016-11-01

Pathogen recognition receptors (PRRs) recognize pathogen-associated molecular patterns, triggering the induction of inflammatory innate responses and contributing to the development of specific adaptive immune responses. Novel adjuvants have been developed based on agonists of PRRs. Areas covered: Lipid pathogen-associated molecular patterns (PAMPs) present in the cell wall of mycobacteria are revised, with emphasis on agonists of C-type lectin receptors, signaling pathways, and preclinical data supporting their use as novel adjuvants inducing cell-mediated immune responses. Their potential use as lipid antigens in novel tuberculosis subunit vaccines is also discussed. Expert commentary: Few adjuvants are licensed for human use and mainly favour antibody-mediated protective immunity. Use of lipid PAMPs that trigger cell-mediated immune responses could lead to the development of adjuvants for vaccines against intracellular pathogens and cancer.

Electromagnetic signals are produced by aqueous nanostructures derived from bacterial DNA sequences.

PubMed

Montagnier, Luc; Aïssa, Jamal; Ferris, Stéphane; Montagnier, Jean-Luc; Lavallée, Claude

2009-06-01

A novel property of DNA is described: the capacity of some bacterial DNA sequences to induce electromagnetic waves at high aqueous dilutions. It appears to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. The genomic DNA of most pathogenic bacteria contains sequences which are able to generate such signals. This opens the way to the development of highly sensitive detection system for chronic bacterial infections in human and animal diseases.

Methods for automatic trigger threshold adjustment

DOEpatents

Welch, Benjamin J; Partridge, Michael E

2014-03-18

Methods are presented for adjusting trigger threshold values to compensate for drift in the quiescent level of a signal monitored for initiating a data recording event, thereby avoiding false triggering conditions. Initial threshold values are periodically adjusted by re-measuring the quiescent signal level, and adjusting the threshold values by an offset computation based upon the measured quiescent signal level drift. Re-computation of the trigger threshold values can be implemented on time based or counter based criteria. Additionally, a qualification width counter can be utilized to implement a requirement that a trigger threshold criterion be met a given number of times prior to initiating a data recording event, further reducing the possibility of a false triggering situation.

RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells.

PubMed

Romero, Damian G; Plonczynski, Maria W; Gomez-Sanchez, Elise P; Yanes, Licy L; Gomez-Sanchez, Celso E

2006-08-01

Regulator of G protein signaling (RGS) proteins interact with Galpha-subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. Angiotensin (Ang) II interacts with its G protein-coupled receptor in zona glomerulosa adrenal cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. We studied Ang II-mediated regulation of RGS2, the role of RGS2 in steroidogenesis, and the intracellular signal events involved in H295R human adrenal cells. We report that both H295R cells and human adrenal gland express RGS2 mRNA. In H295R cells, Ang II caused a rapid and transient increase in RGS2 mRNA levels quantified by real-time RT-PCR. Ang II effects were mimicked by calcium ionophore A23187 and blocked by calcium channel blocker nifedipine. Ang II effects also were blocked by calmodulin antagonists (W-7 and calmidazolium) and calcium/calmodulin-dependent kinase antagonist KN-93. RGS2 overexpression by retroviral infection in H295R cells caused a decrease in Ang II-stimulated aldosterone secretion but did not modify cortisol secretion. In reporter assays, RGS2 decreased Ang II-mediated aldosterone synthase up-regulation. These results suggest that Ang II up-regulates RGS2 mRNA by the calcium/calmodulin-dependent kinase pathway in H295R cells. RGS2 overexpression specifically decreases aldosterone secretion through a decrease in Ang II-mediated aldosterone synthase-induced expression. In conclusion, RGS2 expression is induced by Ang II to terminate the intracellular signaling cascade generated by Ang II. RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland.

Transdifferentiation from cornea to lens in Xenopus laevis depends on BMP signalling and involves upregulation of Wnt signalling

PubMed Central

2011-01-01

Background Surgical removal of the lens from larval Xenopus laevis results in a rapid transdifferention of central corneal cells to form a new lens. The trigger for this process is understood to be an induction event arising from the unprecedented exposure of the cornea to the vitreous humour that occurs following lens removal. The molecular identity of this trigger is unknown. Results Here, we have used a functional transgenic approach to show that BMP signalling is required for lens regeneration and a microarray approach to identify genes that are upregulated specifically during this process. Analysis of the array data strongly implicates Wnt signalling and the Pitx family of transcription factors in the process of cornea to lens transdifferentiation. Our analysis also captured several genes associated with congenital cataract in humans. Pluripotency genes, in contrast, were not upregulated, supporting the idea that corneal cells transdifferentiate without returning to a stem cell state. Several genes from the array were expressed in the forming lens during embryogenesis. One of these, Nipsnap1, is a known direct target of BMP signalling. Conclusions Our results strongly implicate the developmental Wnt and BMP signalling pathways in the process of cornea to lens transdifferentiation (CLT) in Xenopus, and suggest direct transdifferentiation between these two anterior eye tissues. PMID:21896182

The OPERA muon spectrometer tracking electronics

NASA Astrophysics Data System (ADS)

Ambrosio, M.; Barichello, G.; Brugnera, R.; Carrara, E.; Consiglio, L.; Corradi, A.; Dal Corso, F.; Dusini, S.; Felici, G.; Garfagnini, A.; Manea, C.; Masone, V.; Paoloni, A.; Paoluzzi, G.; Papalino, G.; Parascandolo, P.; Sorrentino, G.; Spinetti, M.; Stanco, L.; Terranova, F.; Votano, L.

2004-11-01

The document describes the front-end electronics that instrument the spectrometer of the OPERA experiment. The spectrometer is made of two separate modules. Each module consists of 22 RPC planes equipped with horizontal and vertical strips readout for a total amount of about 25,000 digital channels. The front end electronics is self-triggered and has single plane readout capability. It is made of three different stages: the Front End Boards (FEBs) system, the Controller Boards (CBs) system and the Timing Boards (TBs) system. The FEB system provides discrimination of the strip incoming signals; a FAST OR output of the input signals is also available for trigger plane signal generation. FEBs discriminated signals are acquired by the CBs system that manages also the communication to the experiment DAQ and Slow Control interface. A Trigger Board allows to operate in both self-trigger (the FEB FAST OR signal starts the plane acquisition) or external-trigger (different conditions can be set on the OR signals generated from different planes) modes.

UTP – Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells

PubMed Central

Liñán-Rico, Andromeda; Ochoa-Cortes, Fernando; Zuleta-Alarcon, Alix; Alhaj, Mazin; Tili, Esmerina; Enneking, Josh; Harzman, Alan; Grants, Iveta; Bergese, Sergio; Christofi, Fievos L.

2017-01-01

Background: Enterochromaffin cells (EC) synthesize and release 5-HT and ATP to trigger or modulate gut neural reflexes and transmit information about visceral/pain sensation. Alterations in 5-HT signaling mechanisms may contribute to the pathogenesis of IBD or IBS, but the pharmacologic or molecular mechanisms modulating Ca2+-dependent 5-HT release are not understood. Previous studies indicated that purinergic signaling via ATP and ADP is an important mechanism in modulation of 5-HT release. However, EC cells also respond to UTP and UDP suggesting uridine triphosphate receptor and signaling pathways are involved as well. We tested the hypothesis that UTP is a regulator of 5-HT release in human EC cells. Methods: UTP signaling mechanisms were studied in BON cells, a human EC model, using Fluo-4/Ca2+imaging, patch-clamp, pharmacological analysis, immunohistochemistry, western blots and qPCR. 5-HT release was monitored in BON or EC isolated from human gut surgical specimens (hEC). Results: UTP, UTPγS, UDP or ATP induced Ca2+oscillations in BON. UTP evoked a biphasic concentration-dependent Ca2+response. Cells responded in the order of UTP, ATP > UTPγS > UDP >> MRS2768, BzATP, α,β-MeATP > MRS2365, MRS2690, and NF546. Different proportions of cells activated by UTP and ATP also responded to UTPγS (P2Y4, 50% cells), UDP (P2Y6, 30%), UTPγS and UDP (14%) or MRS2768 (<3%). UTP Ca2+responses were blocked with inhibitors of PLC, IP3R, SERCA Ca2+pump, La3+sensitive Ca2+channels or chelation of intracellular free Ca2+ by BAPTA/AM. Inhibitors of L-type, TRPC, ryanodine-Ca2+pools, PI3-Kinase, PKC or SRC-Kinase had no effect. UTP stimulated voltage-sensitive Ca2+currents (ICa), Vm-depolarization and inhibited IK (not IA) currents. An IKv7.2/7.3 K+ channel blocker XE-991 mimicked UTP-induced Vm-depolarization and blocked UTP-responses. XE-991 blocked IK and UTP caused further reduction. La3+ or PLC inhibitors blocked UTP depolarization; PKC inhibitors, thapsigargin or zero Ca2+buffer did not. UTP stimulated 5-HT release in hEC expressing TPH1, 5-HT, P2Y4/P2Y6R. Zero-Ca2+buffer augmented Ca2+responses and 5-HT release. Conclusion: UTP activates a predominant P2Y4R pathway to trigger Ca2+oscillations via internal Ca2+mobilization through a PLC/IP3/IP3R/SERCA Ca2+signaling pathway to stimulate 5-HT release; Ca2+influx is inhibitory. UTP-induced Vm-depolarization depends on PLC signaling and an unidentified K channel (which appears independent of Ca2+oscillations or Ica/VOCC). UTP-gated signaling pathways triggered by activation of P2Y4R stimulate 5-HT release. PMID:28751862

UTP - Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells.

PubMed

Liñán-Rico, Andromeda; Ochoa-Cortes, Fernando; Zuleta-Alarcon, Alix; Alhaj, Mazin; Tili, Esmerina; Enneking, Josh; Harzman, Alan; Grants, Iveta; Bergese, Sergio; Christofi, Fievos L

2017-01-01

Background: Enterochromaffin cells (EC) synthesize and release 5-HT and ATP to trigger or modulate gut neural reflexes and transmit information about visceral/pain sensation. Alterations in 5-HT signaling mechanisms may contribute to the pathogenesis of IBD or IBS, but the pharmacologic or molecular mechanisms modulating Ca 2+ -dependent 5-HT release are not understood. Previous studies indicated that purinergic signaling via ATP and ADP is an important mechanism in modulation of 5-HT release. However, EC cells also respond to UTP and UDP suggesting uridine triphosphate receptor and signaling pathways are involved as well. We tested the hypothesis that UTP is a regulator of 5-HT release in human EC cells. Methods: UTP signaling mechanisms were studied in BON cells, a human EC model, using Fluo-4/Ca 2+ imaging, patch-clamp, pharmacological analysis, immunohistochemistry, western blots and qPCR. 5-HT release was monitored in BON or EC isolated from human gut surgical specimens (hEC). Results: UTP, UTPγS, UDP or ATP induced Ca 2+ oscillations in BON. UTP evoked a biphasic concentration-dependent Ca 2+ response. Cells responded in the order of UTP, ATP > UTPγS > UDP > MRS2768, BzATP, α,β-MeATP > MRS2365, MRS2690, and NF546. Different proportions of cells activated by UTP and ATP also responded to UTPγS (P2Y 4 , 50% cells), UDP (P2Y 6 , 30%), UTPγS and UDP (14%) or MRS2768 (<3%). UTP Ca 2+ responses were blocked with inhibitors of PLC, IP3R, SERCA Ca 2+ pump, La 3+ sensitive Ca 2+ channels or chelation of intracellular free Ca 2+ by BAPTA/AM. Inhibitors of L-type, TRPC, ryanodine-Ca 2+ pools, PI3-Kinase, PKC or SRC-Kinase had no effect. UTP stimulated voltage-sensitive Ca 2+ currents (I Ca ), V m -depolarization and inhibited I K (not I A ) currents. An I Kv 7.2/7.3 K + channel blocker XE-991 mimicked UTP-induced V m -depolarization and blocked UTP-responses. XE-991 blocked I K and UTP caused further reduction. La 3+ or PLC inhibitors blocked UTP depolarization; PKC inhibitors, thapsigargin or zero Ca 2+ buffer did not. UTP stimulated 5-HT release in hEC expressing TPH1, 5-HT, P2Y 4 /P2Y 6 R. Zero-Ca 2+ buffer augmented Ca 2+ responses and 5-HT release. Conclusion: UTP activates a predominant P2Y 4 R pathway to trigger Ca 2+ oscillations via internal Ca 2+ mobilization through a PLC/IP 3 /IP3R/SERCA Ca 2+ signaling pathway to stimulate 5-HT release; Ca 2+ influx is inhibitory. UTP-induced V m -depolarization depends on PLC signaling and an unidentified K channel (which appears independent of Ca 2+ oscillations or I ca /VOCC). UTP-gated signaling pathways triggered by activation of P2Y 4 R stimulate 5-HT release.

Deoxyelephantopin from Elephantopus scaber L. induces cell-cycle arrest and apoptosis in the human nasopharyngeal cancer CNE cells

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

Su, Miaoxian; Chung, Hau Yin, E-mail: anthonychung@cuhk.edu.hk; Food and Nutritional Sciences Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR

2011-07-29

Highlights: {yields} Deoxyelephantopin (ESD) inhibited cell proliferation in the human nasopharyngeal cancer CNE cells. {yields} ESD induced cell cycle arrest in S and G2/M phases via modulation of cell cycle regulatory proteins. {yields} ESD triggered apoptosis by dysfunction of mitochondria and induction of both intrinsic and extrinsic apoptotic signaling pathways. {yields} ESD also triggered Akt, ERK, and JNK signaling pathways. -- Abstract: Deoxyelephantopin (ESD), a naturally occurring sesquiterpene lactone present in the Chinese medicinal herb, Elephantopus scaber L. exerted anticancer effects on various cultured cancer cells. However, the cellular mechanisms by which it controls the development of the cancer cellsmore » are unavailable, particularly the human nasopharyngeal cancer CNE cells. In this study, we found that ESD inhibited the CNE cell proliferation. Cell cycle arrest in S and G2/M phases was also found. Western blotting analysis showed that modulation of cell cycle regulatory proteins was responsible for the ESD-induced cell cycle arrest. Besides, ESD also triggered apoptosis in CNE cells. Dysfunction in mitochondria was found to be associated with the ESD-induced apoptosis as evidenced by the loss of mitochondrial membrane potential ({Delta}{Psi}m), the translocation of cytochrome c, and the regulation of Bcl-2 family proteins. Despite the Western blotting analysis showed that both intrinsic and extrinsic apoptotic pathways (cleavage of caspases-3, -7, -8, -9, and -10) were triggered in the ESD-induced apoptosis, additional analysis also showed that the induction of apoptosis could be achieved by the caspase-independent manner. Besides, Akt, ERK and JNK pathways were found to involve in ESD-induced cell death. Overall, our findings provided the first evidence that ESD induced cell cycle arrest, and apoptosis in CNE cells. ESD could be a potential chemotherapeutic agent in the treatment of nasopharyngeal cancer (NPC).« less

Novel synthetic monoketone transmute radiation-triggered NFκB-dependent TNFα cross-signaling feedback maintained NFκB and favors neuroblastoma regression.

PubMed

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

PubMed Central

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S.; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion. PMID:23967300

Human emotions track changes in the acoustic environment.

PubMed

Ma, Weiyi; Thompson, William Forde

2015-11-24

Emotional responses to biologically significant events are essential for human survival. Do human emotions lawfully track changes in the acoustic environment? Here we report that changes in acoustic attributes that are well known to interact with human emotions in speech and music also trigger systematic emotional responses when they occur in environmental sounds, including sounds of human actions, animal calls, machinery, or natural phenomena, such as wind and rain. Three changes in acoustic attributes known to signal emotional states in speech and music were imposed upon 24 environmental sounds. Evaluations of stimuli indicated that human emotions track such changes in environmental sounds just as they do for speech and music. Such changes not only influenced evaluations of the sounds themselves, they also affected the way accompanying facial expressions were interpreted emotionally. The findings illustrate that human emotions are highly attuned to changes in the acoustic environment, and reignite a discussion of Charles Darwin's hypothesis that speech and music originated from a common emotional signal system based on the imitation and modification of environmental sounds.

Tumor dormancy and cell signaling: anti-mu-induced apoptosis in human B-lymphoma cells is not caused by an APO-1-APO-1 ligand interaction.

PubMed Central

Racila, E; Hsueh, R; Marches, R; Tucker, T F; Krammer, P H; Scheuermann, R H; Uhr, J W

1996-01-01

Signal transduction initiated by crosslinking of antigen-specific receptors on T- and B-lymphoma cells induces apoptosis. In T-lymphoma cells, such crosslinking results in upregulation of the APO-1 ligand, which then interacts with induced or constitutively expressed APO-1, thereby triggering apoptosis. Here we show that crosslinking the membrane immunoglobulin on human lymphoma cells (Daudi) (that constitutively express APO-1) does not induce synthesis of APO-1 ligand. Further, a noncytotoxic fragment of anti-APO-1 antibody that blocks T-cell-receptor-mediated apoptosis in T-lymphoma cells does not block anti-mu-induced apoptosis. Hence, in B-lymphoma cells, apoptosis induced by signaling via membrane IgM is not mediated by the APO-1 ligand. Images Fig. 2 Fig. 3 PMID:8700902

Universal fieldable assay with unassisted visual detection

NASA Technical Reports Server (NTRS)

Chelyapov, Nicolas (Inventor)

2012-01-01

A universal detection system based on allosteric aptamers, signal amplification cascade, and eye-detectable phrase transition. A broadly applicable homogeneous detection system is provided. It utilizes components of the blood coagulation cascade in the presence of polystyrene microspheres (MS) as a signal amplifier. Russell's viper venom factor X activator (RVV-X) triggers the cascade, which results in an eye-visible phase transition--precipitation of MS bound to clotted fibrin. An allosteric RNA aptamer, RNA132, with affinity for RVV-X and human vascular endothelial growth factor (VEGF.sub.165) was created. RNA132 inhibits enzymatic activity of RVV-X. The effector molecule, VEGF.sub.165, reverses the inhibitory activity of RNA132 on RVV-X and restores its enzymatic activity, thus triggering the cascade and enabling the phase transition. Similar results were obtained for another allosteric aptamer modulated by a protein tyrosine phosphatase. The assay is instrumentation-free for both processing and readout.

TRPM8, a Versatile Channel in Human Sperm

PubMed Central

Ocampo, Ana Y.; Serrano, Carmen J.; Castellano, Laura E.; Hernández-González, Enrique O.; Chirinos, Mayel; Larrea, Fernando; Beltrán, Carmen; Treviño, Claudia L.

2009-01-01

Background The transient receptor potential channel (TRP) family includes more than 30 proteins; they participate in various Ca2+ dependent processes. TRPs are functionally diverse involving thermal, chemical and mechanical transducers which modulate the concentration of intracellular Ca2+ ([Ca2+]i). Ca2+ triggers and/or regulates principal sperm functions during fertilization such as motility, capacitation and the acrosome reaction. Nevertheless, the presence of the TRPM subfamily in sperm has not been explored. Principal Findings Here we document with RT-PCR, western blot and immunocitochemistry analysis the presence of TRPM8 in human sperm. We also examined the participation of this channel in sperm function using specific agonists (menthol and temperature) and antagonists (BCTC and capsazepine). Computer-aided sperm analysis revealed that menthol did not significantly alter human sperm motility. In contrast, menthol induced the acrosome reaction in human sperm. This induction was inhibited about 70% by capsazepine (20 µM) and 80% by BCTC (1.6 µM). Activation of TRPM8 either by temperature or menthol induced [Ca2+]i increases in human sperm measured by fluorescence in populations or individual sperm cells, effect that was also inhibited by capsazepine (20 µM) and BCTC (1.6 µM). However, the progesterone and ZP3-induced acrosome reaction was not inhibited by capsazepine or BCTC, suggesting that TRPM8 activation triggers this process by a different signaling pathway. Conclusions This is the first report dealing with the presence of a thermo sensitive channel (TRPM8) in human sperm. This channel could be involved in cell signaling events such as thermotaxis or chemotaxis. PMID:19582168

Investigating Neuromagnetic Brain Responses against Chromatic Flickering Stimuli by Wavelet Entropies

PubMed Central

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-01-01

Background Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Methodology/Principal Findings Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Conclusions/Significance Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations. PMID:19779630

Investigating neuromagnetic brain responses against chromatic flickering stimuli by wavelet entropies.

PubMed

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-09-25

Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations.

Detonation control

DOEpatents

Mace, Jonathan L.; Seitz, Gerald J.; Bronisz, Lawrence E.

2016-10-25

Detonation control modules and detonation control circuits are provided herein. A trigger input signal can cause a detonation control module to trigger a detonator. A detonation control module can include a timing circuit, a light-producing diode such as a laser diode, an optically triggered diode, and a high-voltage capacitor. The trigger input signal can activate the timing circuit. The timing circuit can control activation of the light-producing diode. Activation of the light-producing diode illuminates and activates the optically triggered diode. The optically triggered diode can be coupled between the high-voltage capacitor and the detonator. Activation of the optically triggered diode causes a power pulse to be released from the high-voltage capacitor that triggers the detonator.

X-ray irradiation activates K+ channels via H2O2 signaling.

PubMed

Gibhardt, Christine S; Roth, Bastian; Schroeder, Indra; Fuck, Sebastian; Becker, Patrick; Jakob, Burkhard; Fournier, Claudia; Moroni, Anna; Thiel, Gerhard

2015-09-09

Ionizing radiation is a universal tool in tumor therapy but may also cause secondary cancers or cell invasiveness. These negative side effects could be causally related to the human-intermediate-conductance Ca2+-activated-K+-channel (hIK), which is activated by X-ray irradiation and affects cell proliferation and migration. To analyze the signaling cascade downstream of ionizing radiation we use genetically encoded reporters for H2O2 (HyPer) and for the dominant redox-buffer glutathione (Grx1-roGFP2) to monitor with high spatial and temporal resolution, radiation-triggered excursions of H2O2 in A549 and HEK293 cells. The data show that challenging cells with ≥1 Gy X-rays or with UV-A laser micro-irradiation causes a rapid rise of H2O2 in the nucleus and in the cytosol. This rise, which is determined by the rate of H2O2 production and glutathione-buffering, is sufficient for triggering a signaling cascade that involves an elevation of cytosolic Ca2+ and eventually an activation of hIK channels.

X-ray irradiation activates K+ channels via H2O2 signaling

PubMed Central

Gibhardt, Christine S.; Roth, Bastian; Schroeder, Indra; Fuck, Sebastian; Becker, Patrick; Jakob, Burkhard; Fournier, Claudia; Moroni, Anna; Thiel, Gerhard

2015-01-01

Ionizing radiation is a universal tool in tumor therapy but may also cause secondary cancers or cell invasiveness. These negative side effects could be causally related to the human-intermediate-conductance Ca2+-activated-K+-channel (hIK), which is activated by X-ray irradiation and affects cell proliferation and migration. To analyze the signaling cascade downstream of ionizing radiation we use genetically encoded reporters for H2O2 (HyPer) and for the dominant redox-buffer glutathione (Grx1-roGFP2) to monitor with high spatial and temporal resolution, radiation-triggered excursions of H2O2 in A549 and HEK293 cells. The data show that challenging cells with ≥1 Gy X-rays or with UV-A laser micro-irradiation causes a rapid rise of H2O2 in the nucleus and in the cytosol. This rise, which is determined by the rate of H2O2 production and glutathione-buffering, is sufficient for triggering a signaling cascade that involves an elevation of cytosolic Ca2+ and eventually an activation of hIK channels. PMID:26350345

Method for triggering an action

DOEpatents

Hall, David R.; Bartholomew, David B.; Johnson, Monte L.; Moon, Justin; Koehler, Roger O.

2006-10-17

A method for triggering an action of at least one downhole device on a downhole network integrated into a downhole tool string synchronized to an event comprises determining latency, sending a latency adjusted signal, and performing the action. The latency is determined between a control device and the at least one downhole device. The latency adjusted signal for triggering an action is sent to the downhole device. The action is performed downhole synchronized to the event. A preferred method for determining latency comprises the steps: a control device sends a first signal to the downhole device; after receiving the signal, the downhole device sends a response signal to the control device; and the control device analyzes the time from sending the signal to receiving the response signal.

Multi-Inhibitory Effects of A2A Adenosine Receptor Signaling on Neutrophil Adhesion Under Flow.

PubMed

Yago, Tadayuki; Tsukamoto, Hiroki; Liu, Zhenghui; Wang, Ying; Thompson, Linda F; McEver, Rodger P

2015-10-15

A2A adenosine receptor (A2AAR) signaling negatively regulates inflammatory responses in many disease models, but the detailed mechanisms remain unclear. We used the selective A2AAR agonist, ATL313, to examine how A2AAR signaling affects human and murine neutrophil adhesion under flow. Treating neutrophils with ATL313 inhibited selectin-induced, β2 integrin-dependent slow rolling and chemokine-induced, β2 integrin-dependent arrest on ICAM-1. ATL313 inhibited selectin-induced β2 integrin extension, which supports slow rolling, and chemokine-induced hybrid domain "swing-out," which supports arrest. Furthermore, ATL313 inhibited integrin outside-in signaling as revealed by reduced neutrophil superoxide production and spreading on immobilized anti-β2 integrin Ab. ATL313 suppressed selectin-triggered activation of Src family kinases (SFKs) and p38 MAPK, chemokine-triggered activation of Ras-related protein 1, and β2 integrin-triggered activation of SFKs and Vav cytoskeletal regulatory proteins. ATL313 activated protein kinase A and its substrate C-terminal Src kinase, an inhibitor of SFKs. Treating neutrophils with a protein kinase A inhibitor blocked the actions of ATL313. In vivo, ATL313-treated neutrophils rolled faster and arrested much less frequently in postcapillary venules of the murine cremaster muscle after TNF-α challenge. Furthermore, ATL313 markedly suppressed neutrophil migration into the peritoneum challenged with thioglycollate. ATL313 did not affect A2AAR-deficient neutrophils, confirming its specificity. Our findings provide new insights into the anti-inflammatory mechanisms of A2AAR signaling and the potential utility of A2AAR agonists in inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.

Multi-inhibitory effects of A2A adenosine receptor signaling on neutrophil adhesion under flow**

PubMed Central

Yago, Tadayuki; Tsukamoto, Hiroki; Liu, Zhenghui; Wang, Ying; Thompson, Linda F.; McEver, Rodger P.

2015-01-01

A2A adenosine receptor (A2AAR) signaling negatively regulates inflammatory responses in many disease models, but the detailed mechanisms remain unclear. We used the selective A2AAR agonist, ATL313, to examine how A2AAR signaling affects human and murine neutrophil adhesion under flow. Treating neutrophils with ATL313 inhibited selectin-induced, β2 integrin-dependent slow rolling and chemokine-induced, β2 integrin-dependent arrest on ICAM-1. ATL313 inhibited selectin-induced β2 integrin extension, which supports slow rolling, and chemokine-induced hybrid domain “swing-out”, which supports arrest. Furthermore, ATL313 inhibited integrin outside-in signaling as revealed by reduced neutrophil superoxide production and spreading on immobilized anti-β2 integrin antibody. ATL313 suppressed selectin-triggered activation of Src family kinases (SFKs) and p38 MAPK, chemokine-triggered activation of Ras-related protein 1 (Rap1), and β2 integrin-triggered activation of SFKs and Vav cytoskeletal regulatory proteins. ATL313 activated protein kinase A (PKA) and its substrate C-terminal Src kinase (Csk), an inhibitor of SFKs. Treating neutrophils with a PKA inhibitor blocked the actions of ATL313. In vivo, ATL313-treated neutrophils rolled faster and arrested much less frequently in postcapillary venules of the murine cremaster muscle after TNF-α challenge. Furthermore, ATL313 markedly suppressed neutrophil migration into the peritoneum challenged with thioglycollate. ATL313 did not affect A2AAR-deficient neutrophils, confirming its specificity. Our findings provide new insights into the anti-inflammatory mechanisms of A2AAR signaling and the potential utility of A2AAR agonists in inflammatory diseases. PMID:26355151

Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement.

PubMed

Dinicola, Simona; Mariggiò, Maria Addolorata; Morabito, Caterina; Guarnieri, Simone; Cucina, Alessandra; Pasqualato, Alessia; D'Anselmi, Fabrizio; Proietti, Sara; Coluccia, Pierpaolo; Bizzarri, Mariano

2013-09-14

Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.

Hyaluronan and Layilin Mediate Loss of Airway Epithelial Barrier Function Induced by Cigarette Smoke by Decreasing E-cadherin*

PubMed Central

Forteza, Rosanna Malbran; Casalino-Matsuda, S. Marina; Falcon, Nieves S.; Valencia Gattas, Monica; Monzon, Maria E.

2012-01-01

Cigarette smoke (CigS) exposure is associated with increased bronchial epithelial permeability and impaired barrier function. Primary cultures of normal human bronchial epithelial cells exposed to CigS exhibit decreased E-cadherin expression and reduced transepithelial electrical resistance. These effects were mediated by hyaluronan (HA) because inhibition of its synthesis with 4-methylumbelliferone prevented these effects, and exposure to HA fragments of <70 kDa mimicked these effects. We show that the HA receptor layilin is expressed apically in human airway epithelium and that cells infected with lentivirus expressing layilin siRNAs were protected against increased permeability triggered by both CigS and HA. We identified RhoA/Rho-associated protein kinase (ROCK) as the signaling effectors downstream layilin. We conclude that HA fragments generated by CigS bind to layilin and signal through Rho/ROCK to inhibit the E-cadherin gene and protein expression, leading to a loss of epithelial cell-cell contact. These studies suggest that HA functions as a master switch protecting or disrupting the epithelial barrier in its high versus low molecular weight form and that its depolymerization is a first and necessary step triggering the inflammatory response to CigS. PMID:23048036

MyShake - A smartphone app to detect earthquake

NASA Astrophysics Data System (ADS)

Kong, Q.; Allen, R. M.; Schreier, L.; Kwon, Y. W.

2015-12-01

We designed an android app that harnesses the accelerometers in personal smartphones to record earthquake-shaking data for research, hazard information and warnings. The app has the function to distinguish earthquake shakings from daily human activities based on the different patterns behind the movements. It also can be triggered by the traditional earthquake early warning (EEW) system to record for a certain amount of time to collect earthquake data. When the app is triggered by the earthquake-like movements, it sends the trigger information back to our server which contains time and location of the trigger, at the same time, it stores the waveform data on local phone first, and upload to our server later. Trigger information from multiple phones will be processed in real time on the server to find the coherent signal to confirm the earthquakes. Therefore, the app provides the basis to form a smartphone seismic network that can detect earthquake and even provide warnings. A planned public roll-out of MyShake could collect millions of seismic recordings for large earthquakes in many regions around the world.

Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling.

PubMed

Sonoshita, Masahiro; Aoki, Masahiro; Fuwa, Haruhiko; Aoki, Koji; Hosogi, Hisahiro; Sakai, Yoshiharu; Hashida, Hiroki; Takabayashi, Arimichi; Sasaki, Makoto; Robine, Sylvie; Itoh, Kazuyuki; Yoshioka, Kiyoko; Kakizaki, Fumihiko; Kitamura, Takanori; Oshima, Masanobu; Taketo, Makoto Mark

2011-01-18

Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis. Copyright © 2011 Elsevier Inc. All rights reserved.

Single-cell analyses reveal that KISS1R-expressing cells undergo sustained kisspeptin-induced signaling that is dependent upon an influx of extracellular Ca2+.

PubMed

Babwah, Andy V; Pampillo, Macarena; Min, Le; Kaiser, Ursula B; Bhattacharya, Moshmi

2012-12-01

The kisspeptin receptor (KISS1R) is a Gα(q/11)-coupled seven-transmembrane receptor activated by a group of peptides referred to as kisspeptins (Kps). The Kp/KISS1R signaling system is a powerful regulator of GnRH secretion, and inactivating mutations in this system are associated with hypogonadotropic hypogonadism. A recent study revealed that Kp triggers prolonged signaling; not from the inability of the receptor to undergo rapid desensitization, but instead from the maintenance of a dynamic and active pool of KISS1R at the cell surface. To investigate this further, we hypothesized that if a dynamic pool of receptor is maintained at the cell surface for a protracted period, chronic Kp-10 treatment would trigger the sustained activation of Gα(q/11) as evidenced through the prolonged activation of phospholipase C, protein kinase C, and prolonged mobilization of intracellular Ca(2+). Through single-cell analyses, we tested our hypothesis in human embryonic kidney (HEK) 293 cells and found that was indeed the case. We subsequently determined that prolonged KISS1R signaling was not a phenomenon specific to HEK 293 cells but is likely a conserved property of KISS1R-expressing cells because evidence of sustained KISS1R signaling was also observed in the GT1-7 GnRH neuronal and Chinese hamster ovary cell lines. While exploring the regulation of prolonged KISS1R signaling, we identified a critical role for extracellular Ca(2+). We found that although free intracellular Ca(2+), primarily derived from intracellular stores, was sufficient to trigger the acute activation of a major KISS1R secondary effector, protein kinase C, it was insufficient to sustain chronic KISS1R signaling; instead extracellular Ca(2+) was absolutely required for this.

AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis

PubMed Central

Zhang, Jiqin; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

2016-01-01

AIP1 (encoded by the DAB2IP gene), a signaling scaffolding protein, is abundantly expressed in vascular endothelial cells (EC). While it was initially discovered as an ASK1-interacting protein, AIP1 broadly suppresses inflammatory responses triggered by cytokines and stresses such as TNF, LPS, VEGF and ER stress in EC (therefore AIP1 is an Anti-Inflammatory Protein). Human genome-wide association study (GWAS) has identified DAB2IP gene variants conferring susceptibility to cardiovascular diseases. Consistently, a global or vascular EC-specific deletion of DAB2IP in mice strongly enhances inflammatory responses and exacerbates atherosclerosis and graft arteriosclerosis progression in mouse models. Mechanisms for AIP1 function and regulation associated with human cardiovascular diseases need further investigations. PMID:25732743

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

PubMed Central

Le Ferrec, Eric; Podechard, Normand; Lagadic-Gossmann, Dominique; Shoji, Kenji F.; Kukowski, Klara; Holme, Jørn A.; Øvrevik, Johan

2018-01-01

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca2+]i increase. PMID:29748474

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling.

PubMed

Brinchmann, Bendik C; Le Ferrec, Eric; Podechard, Normand; Lagadic-Gossmann, Dominique; Shoji, Kenji F; Penna, Aubin; Kukowski, Klara; Kubátová, Alena; Holme, Jørn A; Øvrevik, Johan

2018-05-10

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca 2+ ] i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca 2+ ] i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n -hexane ( n -Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n -Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n -Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n -Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca 2+ ] i increases in HMEC-1. n -Hex-EOM triggered [Ca 2+ ] i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca 2+ ] i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca 2+ ] i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca 2+ ] i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n -hexane and DCM seem to induce rapid AhR-dependent [Ca 2+ ] i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca 2+ ] i increase.

Geologic fracturing method and resulting fractured geologic structure

DOEpatents

Mace, Jonathan L.; Bradley, Christopher R.; Greening, Doran R.; Steedman, David W.

2016-11-08

Detonation control modules and detonation control circuits are provided herein. A trigger input signal can cause a detonation control module to trigger a detonator. A detonation control module can include a timing circuit, a light-producing diode such as a laser diode, an optically triggered diode, and a high-voltage capacitor. The trigger input signal can activate the timing circuit. The timing circuit can control activation of the light-producing diode. Activation of the light-producing diode illuminates and activates the optically triggered diode. The optically triggered diode can be coupled between the high-voltage capacitor and the detonator. Activation of the optically triggered diode causes a power pulse to be released from the high-voltage capacitor that triggers the detonator.

Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

PubMed

Miranda, Benjamin H; Charlesworth, Matthew R; Tobin, Desmond J; Sharpe, David T; Randall, Valerie A

2018-02-01

Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs ( e.g., beard). Follicle response is epigenetically varied: some remain unaffected ( e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

Tidal Triggering of Microearthquakes Over an Eruption Cycle at 9°50'N East Pacific Rise

NASA Astrophysics Data System (ADS)

Tan, Yen Joe; Tolstoy, Maya; Waldhauser, Felix; Bohnenstiehl, DelWayne R.

2018-02-01

Studies have found that earthquake timing often correlates with tides at mid-ocean ridges and some terrestrial settings. Studies have also suggested that tidal triggering may preferentially happen when a region is critically stressed, making it a potential tool to forecast earthquakes and volcanic eruptions. We examine tidal triggering of ˜100,000 microearthquakes near 9°50'N East Pacific Rise recorded between October 2003 and January 2007, which encompasses an eruption in January 2006. This allows us to look at how tidal triggering signal varies over an eruption cycle to examine its utility as a forecasting tool. We find that tidal triggering signal is strong but does not vary systematically in the 2+ years leading up to the eruption. However, tidal triggering signal disappears immediately posteruption. Our findings suggest that tidal triggering variation may not be useful for forecasting mid-ocean ridge eruptions over a 2+ year timescale but might be useful over a longer timescale.

FPGA Based Wavelet Trigger in Radio Detection of Cosmic Rays

NASA Astrophysics Data System (ADS)

Szadkowski, Zbigniew; Szadkowska, Anna

2014-12-01

Experiments which show coherent radio emission from extensive air showers induced by ultra-high-energy cosmic rays are designed for a detailed study of the development of the electromagnetic part of air showers. Radio detectors can operate with 100 % up time as, e.g., surface detectors based on water-Cherenkov tanks. They are being developed for ground-based experiments (e.g., the Pierre Auger Observatory) as another type of air-shower detector in addition to fluorescence detectors, which operate with only ˜10 % of duty on dark nights. The radio signals from air showers are caused by coherent emission from geomagnetic radiation and charge-excess processes. The self-triggers in radio detectors currently in use often generate a dense stream of data, which is analyzed afterwards. Huge amounts of registered data require significant manpower for off-line analysis. Improvement of trigger efficiency is a relevant factor. The wavelet trigger, which investigates on-line the power of radio signals (˜ V2/ R), is promising; however, it requires some improvements with respect to current designs. In this work, Morlet wavelets with various scaling factors were used for an analysis of real data from the Auger Engineering Radio Array and for optimization of the utilization of the resources in an FPGA. The wavelet analysis showed that the power of events is concentrated mostly in a limited range of the frequency spectrum (consistent with a range imposed by the input analog band-pass filter). However, we found several events with suspicious spectral characteristics, where the signal power is spread over the full band-width sampled by a 200 MHz digitizer with significant contribution of very high and very low frequencies. These events may not originate from cosmic ray showers but could be the result of human contamination. The engine of the wavelet analysis can be implemented in the modern powerful FPGAs and can remove suspicious events on-line to reduce the trigger rate.

Implementation of a level 1 trigger system using high speed serial (VXS) techniques for the 12GeV high luminosity experimental programs at Thomas Jefferson National Accelerator Facility

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

C. Cuevas, B. Raydo, H. Dong, A. Gupta, F.J. Barbosa, J. Wilson, W.M. Taylor, E. Jastrzembski, D. Abbott

We will demonstrate a hardware and firmware solution for a complete fully pipelined multi-crate trigger system that takes advantage of the elegant high speed VXS serial extensions for VME. This trigger system includes three sections starting with the front end crate trigger processor (CTP), a global Sub-System Processor (SSP) and a Trigger Supervisor that manages the timing, synchronization and front end event readout. Within a front end crate, trigger information is gathered from each 16 Channel, 12 bit Flash ADC module at 4 nS intervals via the VXS backplane, to a Crate Trigger Processor (CTP). Each Crate Trigger Processor receivesmore » these 500 MB/S VXS links from the 16 FADC-250 modules, aligns skewed data inherent of Aurora protocol, and performs real time crate level trigger algorithms. The algorithm results are encoded using a Reed-Solomon technique and transmission of this Level 1 trigger data is sent to the SSP using a multi-fiber link. The multi-fiber link achieves an aggregate trigger data transfer rate to the global trigger at 8 Gb/s. The SSP receives and decodes Reed-Solomon error correcting transmission from each crate, aligns the data, and performs the global level trigger algorithms. The entire trigger system is synchronous and operates at 250 MHz with the Trigger Supervisor managing not only the front end event readout, but also the distribution of the critical timing clocks, synchronization signals, and the global trigger signals to each front end readout crate. These signals are distributed to the front end crates on a separate fiber link and each crate is synchronized using a unique encoding scheme to guarantee that each front end crate is synchronous with a fixed latency, independent of the distance between each crate. The overall trigger signal latency is <3 uS, and the proposed 12GeV experiments at Jefferson Lab require up to 200KHz Level 1 trigger rate.« less

Human emotions track changes in the acoustic environment

PubMed Central

Ma, Weiyi; Thompson, William Forde

2015-01-01

Emotional responses to biologically significant events are essential for human survival. Do human emotions lawfully track changes in the acoustic environment? Here we report that changes in acoustic attributes that are well known to interact with human emotions in speech and music also trigger systematic emotional responses when they occur in environmental sounds, including sounds of human actions, animal calls, machinery, or natural phenomena, such as wind and rain. Three changes in acoustic attributes known to signal emotional states in speech and music were imposed upon 24 environmental sounds. Evaluations of stimuli indicated that human emotions track such changes in environmental sounds just as they do for speech and music. Such changes not only influenced evaluations of the sounds themselves, they also affected the way accompanying facial expressions were interpreted emotionally. The findings illustrate that human emotions are highly attuned to changes in the acoustic environment, and reignite a discussion of Charles Darwin’s hypothesis that speech and music originated from a common emotional signal system based on the imitation and modification of environmental sounds. PMID:26553987

Clock and trigger distribution for CBM-TOF quality evaluation of RPC super module detector assemblies

NASA Astrophysics Data System (ADS)

Li, C.; Huang, X.; Cao, P.; Wang, J.; An, Q.

2018-03-01

RPC Super module (SM) detector assemblies are used for charged hadron identification in the Time-of-Flight (TOF) spectrometer at the Compressed Baryonic Matter (CBM) experiment. Each SM contains several multi-gap Resistive Plate Chambers (MRPCs) and provides up to 320 electronic channels in total for high-precision time measurements. Time resolution of the Time-to-Digital Converter (TDC) is required to be better than 20 ps. During mass production, the quality of each SM needs to be evaluated. In order to meet the requirements, the system clock signal as well as the trigger signal should be distributed precisely and synchronously to all electronics modules within the evaluation readout system. In this paper, a hierarchical clock and trigger distribution method is proposed for the quality evaluation of CBM-TOF SM detectors. In a first stage, the master clock and trigger module (CTM) allocated in a 6U PXI chassis distributes the clock and trigger signals to the slave CTM in the same chassis. In a second stage, the slave CTM transmits the clock and trigger signals to the TDC readout module (TRM) through one optical link. In a third stage, the TRM distributes the clock and trigger signals synchronously to 10 individual TDC boards. Laboratory test results show that the clock jitter at the third stage is less than 4 ps (RMS) and the trigger transmission latency from the master CTM to the TDC is about 272 ns with 11 ps (RMS) jitter. The overall performance complies well with the required specifications.

High-Quality T2-Weighted 4-Dimensional Magnetic Resonance Imaging for Radiation Therapy Applications

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

Du, Dongsu; Caruthers, Shelton D.; Glide-Hurst, Carri

2015-06-01

Purpose: The purpose of this study was to improve triggering efficiency of the prospective respiratory amplitude-triggered 4-dimensional magnetic resonance imaging (4DMRI) method and to develop a 4DMRI imaging protocol that could offer T2 weighting for better tumor visualization, good spatial coverage and spatial resolution, and respiratory motion sampling within a reasonable amount of time for radiation therapy applications. Methods and Materials: The respiratory state splitting (RSS) and multi-shot acquisition (MSA) methods were analytically compared and validated in a simulation study by using the respiratory signals from 10 healthy human subjects. The RSS method was more effective in improving triggering efficiency.more » It was implemented in prospective respiratory amplitude-triggered 4DMRI. 4DMRI image datasets were acquired from 5 healthy human subjects. Liver motion was estimated using the acquired 4DMRI image datasets. Results: The simulation study showed the RSS method was more effective for improving triggering efficiency than the MSA method. The average reductions in 4DMRI acquisition times were 36% and 10% for the RSS and MSA methods, respectively. The human subject study showed that T2-weighted 4DMRI with 10 respiratory states, 60 slices at a spatial resolution of 1.5 × 1.5 × 3.0 mm{sup 3} could be acquired in 9 to 18 minutes, depending on the individual's breath pattern. Based on the acquired 4DMRI image datasets, the ranges of peak-to-peak liver displacements among 5 human subjects were 9.0 to 12.9 mm, 2.5 to 3.9 mm, and 0.5 to 2.3 mm in superior-inferior, anterior-posterior, and left-right directions, respectively. Conclusions: We demonstrated that with the RSS method, it was feasible to acquire high-quality T2-weighted 4DMRI within a reasonable amount of time for radiation therapy applications.« less

Method and apparatus for signal processing in a sensor system for use in spectroscopy

DOEpatents

O'Connor, Paul [Bellport, NY; DeGeronimo, Gianluigi [Nesconset, NY; Grosholz, Joseph [Natrona Heights, PA

2008-05-27

A method for processing pulses arriving randomly in time on at least one channel using multiple peak detectors includes asynchronously selecting a non-busy peak detector (PD) in response to a pulse-generated trigger signal, connecting the channel to the selected PD in response to the trigger signal, and detecting a pulse peak amplitude. Amplitude and time of arrival data are output in first-in first-out (FIFO) sequence. An apparatus includes trigger comparators to generate the trigger signal for the pulse-receiving channel, PDs, a switch for connecting the channel to the selected PD, and logic circuitry which maintains the write pointer. Also included, time-to-amplitude converters (TACs) convert time of arrival to analog voltage and an analog multiplexer provides FIFO output. A multi-element sensor system for spectroscopy includes detector elements, channels, trigger comparators, PDs, a switch, and a logic circuit with asynchronous write pointer. The system includes TACs, a multiplexer and analog-to-digital converter.

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

PubMed Central

Deschênes-Simard, Xavier; Gaumont-Leclerc, Marie-France; Bourdeau, Véronique; Lessard, Frédéric; Moiseeva, Olga; Forest, Valérie; Igelmann, Sebastian; Mallette, Frédérick A.; Saba-El-Leil, Marc K.; Meloche, Sylvain; Saad, Fred; Mes-Masson, Anne-Marie; Ferbeyre, Gerardo

2013-01-01

Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. In primary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAP kinase signaling by genetic inactivation of Erk2, RNAi-mediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented the activation of the senescence mechanism, allowing oncogenic ras to transform primary cells. Mechanistically, ERK-mediated senescence involved the proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions, cell migration, RNA metabolism, and cell signaling. This senescence-associated protein degradation (SAPD) was observed not only in cells expressing ectopic ras, but also in cells that senesced due to short telomeres. Individual RNAi-mediated inactivation of SAPD targets was sufficient to restore senescence in cells transformed by oncogenic ras or trigger senescence in normal cells. Conversely, the anti-senescence viral oncoproteins E1A, E6, and E7 prevented SAPD. In human prostate neoplasms, high levels of phosphorylated ERK were found in benign lesions, correlating with other senescence markers and low levels of STAT3, one of the SAPD targets. We thus identified a mechanism that links aberrant activation of growth signaling pathways and short telomeres to protein degradation and cellular senescence. PMID:23599344

Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and FcγRIIIa-Triggered Responses.

PubMed

Wagner, Julia A; Berrien-Elliott, Melissa M; Rosario, Maximillian; Leong, Jeffrey W; Jewell, Brea A; Schappe, Timothy; Abdel-Latif, Sara; Fehniger, Todd A

2017-03-01

Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-γ production triggered by leukemia targets or FcγRIIIa ligation within licensed NK cells, which exhibited the highest functionality of the NK cell subsets interrogated. IFN-γ production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to FcγRIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NK cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The nanoscale organization of signaling domains at the plasma membrane.

PubMed

Griffié, Juliette; Burn, Garth; Owen, Dylan M

2015-01-01

In this chapter, we present an overview of the role of the nanoscale organization of signaling domains in regulating key cellular processes. In particular, we illustrate the importance of protein and lipid nanodomains as triggers and mediators of cell signaling. As particular examples, we summarize the state of the art of understanding the role of nanodomains in the mounting of an immune response, cellular adhesion, intercellular communication, and cell proliferation. Thus, this chapter underlines the essential role the nanoscale organization of key signaling proteins and lipid domains. We will also see how nanodomains play an important role in the lifecycle of many pathogens relevant to human disease and therefore illustrate how these structures may become future therapeutic targets. Copyright © 2015 Elsevier Inc. All rights reserved.

Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi.

PubMed

Parthasarathy, Geetha; Philipp, Mario T

2017-05-30

In previous studies, human oligodendrocytes were demonstrated to undergo apoptosis in the presence of Borrelia burgdorferi under an inflammatory milieu. Subsequently, we determined that the MEK/ERK pathway played a significant role in triggering downstream inflammation as well as apoptosis. However, the identity of receptors triggered by exposure to B. burgdorferi and initiating signaling events was unknown. In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR tyrosine kinase pathways in inducing inflammation in the presence of B. burgdorferi, using siRNA and/or inhibitors, in MO3.13 human oligodendrocytes. Cell death and apoptosis assays were also carried out in the presence or absence of specific receptor inhibitors along with the bacteria to determine the role of these receptors in apoptosis induction. The expression pattern of specific receptors with or without B. burgdorferi was also determined. TLRs 2 and 5 had a minimal role in inducing inflammation, particularly IL-6 production. Rather, their effect was mostly inhibitory, with TLR2 downregulation significantly upregulating CXCL8, and CXCL (1,2,3) levels, and TLR5 likely having a similar role in CXCL8, CXCL(1,2,3), and CCL5 levels. TLR4 contributed mostly towards CCL5 production. On the other hand, inhibition of all three EGF/FGF/PDGF receptors significantly downregulated all five of the inflammatory mediators tested even in the presence of B. burgdorferi. Their inhibition also downregulated overall cell death and apoptosis levels. The expression pattern of these receptors, as assessed by immunohistochemistry indicated that the PDGFRβ receptor was the most predominantly expressed receptor, followed by FGFR, although no significant differences were discernible between presence and absence of bacteria. Interestingly, inhibition of individual EGFR, FGFR, or PDGFR receptors did not indicate an individual role for any of these receptors in the overall downregulation of pathogenesis. Contrarily, suppression of FGFR signaling alone in the presence of bacteria significantly upregulated inflammatory mediator levels indicating that it might control an inhibitory pathway when triggered individually. Unlike TLRs, EGF/FGF/PDGF receptors collectively play a significant role in the inflammation and apoptosis of human oligodendrocytes as mediated by B. burgdorferi. It is likely that these three receptors need to be triggered simultaneously to achieve this effect.

Revisiting the fear of snakes in children: the role of aposematic signalling.

PubMed

Souchet, Jérémie; Aubret, Fabien

2016-11-25

Why humans fear snakes is an old, yet unresolved debate. Its innate origin from evolutionary causes is debated against the powerful influence early experience, culture, media and religion may have on people's aversion to snakes. Here we show that the aversion to snakes in human beings may have been mistaken for an aversion to aposematic signals that are commonly displayed by snakes. A total of 635 children were asked to rate single item images as "nice" or "mean". Snakes, pets and smiley emoticon items were not rated as "mean" unless they displayed subtle aposematic signals in the form of triangular (rather than round) shapes. Another 722 children were shown images featuring two items and asked which item was "nice" and which item was "mean". This context dependent comparison triggered even sharper responses to aposematic signals. We hypothesise that early primates evolved an aversion for aposematic signals in the form of potentially harmful triangular shapes such as teeth, claws or spikes, not for snakes per se. Further, we hypothesise that this adaptation was in turn exploited by snakes in their anti-predatory threat display as a triangular head or dorsal zig-zag pattern, and is currently the basis for efficient international road-danger signalling.

Signal-averaged P wave in patients with paroxysmal atrial fibrillation.

PubMed

Rosenheck, S

1997-10-01

The theoretical and experimental rational of atrial signal-averaged ECG in patients with AF is delay in the intra-atrial and interatrial conduction. Similar to the ventricular signal-averaged ECG, the atrial signal-averaged ECG is an averaging of a high number of consecutive P waves that match the template created earlier P wave triggering is preferred over QRS triggering because of more accurate aligning. However, the small amplitude of the atrial ECG and its gradual increase from the isoelectric line may create difficulties in defining the start point if P wave triggering is used. Studies using P wave triggering and those using QRS triggering demonstrate a prolonged P wave duration in patients with paroxysmal AF. The negative predictive value of this test is relatively high at 60%-80%. The positive predictive value of atrial signal-averaged ECGs in predicting the risk of AF is considerably lower than the negative predictive value. All the data accumulated prospectively on the predictive value of P wave signal-averaging was determined only in patients undergoing coronary bypass surgery or following MI; its value in other patients with paroxysmal AF is still not determined. The clinical role of frequency-domain analysis (alone or added to time-domain analysis) remains undefined. Because of this limited knowledge on the predictive value of P wave signal-averaging, it is still not clinical medicine, and further research is needed before atrial signal-averaged ECG will be part of clinical testing.

Human Papillomavirus Type 18 E6 Protein Binds the Cellular PDZ Protein TIP-2/GIPC, Which Is Involved in Transforming Growth Factor β Signaling and Triggers Its Degradation by the Proteasome

PubMed Central

Favre-Bonvin, Arnaud; Reynaud, Caroline; Kretz-Remy, Carole; Jalinot, Pierre

2005-01-01

Several viral proteins expressed by DNA or RNA transforming viruses have the particular property of binding via their C-terminal end to various cellular proteins with PDZ domains. This study is focused on the PDZ protein TIP-2/GIPC, which was originally identified in two-hybrid screens performed with two different baits: the human T-cell leukemia virus type 1 Tax oncoprotein and the regulator of G signaling RGS-GAIP. Further studies have shown that TIP-2/GIPC is also able to associate with the cytoplasmic domains of various transmembrane proteins. In this report we show that TIP-2/GIPC interacts with the E6 protein of human papillomavirus type 18 (HPV-18). This event triggers polyubiquitination and proteasome-mediated degradation of the cellular protein. In agreement with this observation, silencing of E6 by RNA interference in HeLa cells causes an increase in the intracellular TIP-2/GIPC level. This PDZ protein has been previously found to be involved in transforming growth factor β (TGF-β) signaling by favoring expression of the TGF-β type III receptor at the cell membrane. In line with this activity of TIP-2/GIPC, we observed that depletion of this protein in HeLa cells hampers induction of the Id3 gene by TGF-β treatment and also diminishes the antiproliferative effect of this cytokine. Conversely, silencing of E6 increases the expression of Id3 and blocks proliferation of HeLa cells. These results support the notion that HPV-18 E6 renders cells less sensitive to the cytostatic effect of TGF-β by lowering the intracellular amount of TIP-2/GIPC. PMID:15767424

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

PubMed Central

Lindquist, Jonathan A.; Arhel, Nathalie; Felder, Edward; Karl, Sabine; Haas, Tobias L.; Fulda, Simone; Walczak, Henning; Kirchhoff, Frank; Debatin, Klaus-Michael

2009-01-01

CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion. PMID:19487421

Getting to PTI of bacterial RNAs: Triggering plant innate immunity by extracellular RNAs from bacteria.

PubMed

Park, Yong-Soon; Lee, Boyoung; Ryu, Choong-Min

2016-07-02

Defense against diverse biotic and abiotic stresses requires the plant to distinguish between self and non-self signaling molecules. Pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) are pivotal for triggering innate immunity in plants. Unlike in animals and humans, the precise roles of nucleic acids in plant innate immunity are unclear. We therefore investigated the effects of infiltration of total Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) RNAs into Arabidopsis plants. The pathogen population was 10-fold lower in bacterial RNAs pre-treated Arabidopsis plants than in the control. Bacterial RNAs purity was confirmed by physical (sonication) and chemical (RNase A and proteinase K digestion) methods. The perception of bacterial RNAs, especially rRNAs, positively regulated mitogen-activated protein kinase (MAPK) and induced a reactive oxygen species burst, callose deposition, salicylic acid (SA) and jasmonic acid (JA) signaling, and defense-related genes. Therefore, bacterial RNAs function as a new MAMP that activates plant innate immunity, providing a new paradigm for plant-microbe interactions.

Odorant Inhibition of the Olfactory Cyclic Nucleotide-gated Channel with a Native Molecular Assembly

PubMed Central

Chen, Tsung-Yu; Takeuchi, Hiroko; Kurahashi, Takashi

2006-01-01

Human olfaction comprises the opposing actions of excitation and inhibition triggered by odorant molecules. In olfactory receptor neurons, odorant molecules not only trigger a G-protein–coupled signaling cascade but also generate various mechanisms to fine tune the odorant-induced current, including a low-selective odorant inhibition of the olfactory signal. This wide-range olfactory inhibition has been suggested to be at the level of ion channels, but definitive evidence is not available. Here, we report that the cyclic nucleotide-gated (CNG) cation channel, which is a key element that converts odorant stimuli into electrical signals, is inhibited by structurally unrelated odorants, consistent with the expression of wide-range olfactory inhibition. Interestingly, the inhibitory effect was small in the homo-oligomeric CNG channel composed only of the principal channel subunit, CNGA2, but became larger in channels consisting of multiple types of subunits. However, even in the channel containing all native subunits, the potency of the suppression on the cloned CNG channel appeared to be smaller than that previously shown in native olfactory neurons. Nonetheless, our results further showed that odorant suppressions are small in native neurons if the subsequent molecular steps mediated by Ca2+ are removed. Thus, the present work also suggests that CNG channels switch on and off the olfactory signaling pathway, and that the on and off signals may both be amplified by the subsequent olfactory signaling steps. PMID:16940558

Specific analogues uncouple transport, signalling, oligo-ubiquitination and endocytosis in the yeast Gap1 amino acid transceptor

PubMed Central

Van Zeebroeck, Griet; Rubio-Texeira, Marta; Schothorst, Joep; Thevelein, Johan M

2014-01-01

The Saccharomyces cerevisiae amino acid transceptor Gap1 functions as receptor for signalling to the PKA pathway and concomitantly undergoes substrate-induced oligo-ubiquitination and endocytosis. We have identified specific amino acids and analogues that uncouple to certain extent signalling, transport, oligo-ubiquitination and endocytosis. l-lysine, l-histidine and l-tryptophan are transported by Gap1 but do not trigger signalling. Unlike l-histidine, l-lysine triggers Gap1 oligo-ubiquitination without substantial induction of endocytosis. Two transported, non-metabolizable signalling agonists, β-alanine and d-histidine, are strong and weak inducers of Gap1 endocytosis, respectively, but both causing Gap1 oligo-ubiquitination. The non-signalling agonist, non-transported competitive inhibitor of Gap1 transport, l-Asp-γ-l-Phe, induces oligo-ubiquitination but no discernible endocytosis. The Km of l-citrulline transport is much lower than the threshold concentration for signalling and endocytosis. These results show that molecules can be transported without triggering signalling or substantial endocytosis, and that oligo-ubiquitination and endocytosis do not require signalling nor metabolism. Oligo-ubiquitination is required, but apparently not sufficient to trigger endocytosis. In addition, we demonstrate intracellular cross-induction of endocytosis of transport-defective Gap1Y395C by ubiquitination- and endocytosis-deficient Gap1K9R,K16R. Our results support the concept that different substrates bind to partially overlapping binding sites in the same general substrate-binding pocket of Gap1, triggering divergent conformations, resulting in different conformation-induced downstream processes. PMID:24852066

Photolysis of Caged Ca2+ But Not Receptor-Mediated Ca2+ Signaling Triggers Astrocytic Glutamate Release

PubMed Central

Smith, Nathan A.; Xu, Qiwu; Goldman, Siri; Peng, Weiguo; Huang, Jason H.; Takano, Takahiro; Nedergaard, Maiken

2013-01-01

Astrocytes in hippocampal slices can dynamically regulate synaptic transmission in a process mediated by increases in intracellular Ca2+. However, it is debated whether astrocytic Ca2+ signals result in release of glutamate. We here compared astrocytic Ca2+ signaling triggered by agonist exposure versus photolysis side by side. Using transgenic mice in which astrocytes selectively express the MrgA1 receptor, we found that receptor-mediated astrocytic Ca2+ signaling consistently triggered neuronal hyperpolarization and decreased the frequency of miniature excitatory postsynaptic currents (EPSCs). In contrast, photolysis of caged Ca2+ (o-nitrophenyl–EGTA) in astrocytes led to neuronal depolarization and increased the frequency of mEPSCs through a metabotropic glutamate receptor-mediated pathway. Analysis of transgenic mice in which astrocytic vesicular release is suppressed (dominant-negative SNARE mice) and pharmacological manipulations suggested that glutamate is primarily released by opening of anion channels rather than exocytosis. Combined, these studies show that photolysis but not by agonists induced astrocytic Ca2+ signaling triggers glutamate release. PMID:24174673

Upgraded Readout Electronics for the ATLAS Liquid Argon Calorimeters at the High Luminosity LHC

NASA Astrophysics Data System (ADS)

Andeen, Timothy R.; ATLAS Liquid Argon Calorimeter Group

2012-12-01

The ATLAS liquid-argon calorimeters produce a total of 182,486 signals which are digitized and processed by the front-end and back-end electronics at every triggered event. In addition, the front-end electronics sum analog signals to provide coarsely grained energy sums, called trigger towers, to the first-level trigger system, which is optimized for nominal LHC luminosities. However, the pile-up background expected during the high luminosity phases of the LHC will be increased by factors of 3 to 7. An improved spatial granularity of the trigger primitives is therefore proposed in order to improve the identification performance for trigger signatures, like electrons or photons, at high background rejection rates. For the first upgrade phase in 2018, new Liquid Argon Trigger Digitizer Boards are being designed to receive higher granularity signals, digitize them on detector and send them via fast optical links to a new, off-detector digital processing system. The digital processing system applies digital filtering and identifies significant energy depositions. The refined trigger primitives are then transmitted to the first level trigger system to extract improved trigger signatures. The general concept of the upgraded liquid-argon calorimeter readout together with the various electronics components to be developed for such a complex system is presented. The research activities and architectural studies undertaken by the ATLAS Liquid Argon Calorimeter Group are described, particularly details of the on-going design of mixed-signal front-end electronics, of radiation tolerant optical-links, and of the high-speed off-detector digital processing system.

Apparatus for controlling the firing of rectifiers in polyphase rectifying circuits

DOEpatents

Yarema, R.J.

1979-09-18

A polyphase rectifier is controlled with precision by a circuit that filters and shifts a reference signal associated with each phase and that starts a ramp signal at a zero crossing of the shifted reference signal. The difference between the ramp signal and an external trigger signal is used to generate a pulse that switches power rectifiers into conduction. The circuit reduces effects of variations that introduce subharmonics into a rectified signal and it can be used for constant or time-varying external trigger signals.

Priming Endothelial Cells With a Melanoma-Derived Extracellular Matrix Triggers the Activation of αvβ3/VEGFR2 Axis.

PubMed

Helal-Neto, Edward; Brandão-Costa, Renata M; Saldanha-Gama, Roberta; Ribeiro-Pereira, Cristiane; Midlej, Victor; Benchimol, Marlene; Morandi, Verônica; Barja-Fidalgo, Christina

2016-11-01

The unique composition of tumor-produced extracellular matrix (ECM) can be a determining factor in changing the profile of endothelial cells in the tumor microenvironment. As the main receptor for ECM proteins, integrins can activate a series of signaling pathways related to cell adhesion, migration, and differentiation of endothelial cells that interact with ECM proteins. We studied the direct impact of the decellularized ECM produced by a highly metastatic human melanoma cell line (MV3) on the activation of endothelial cells and identified the intracellular signaling pathways associated with cell differentiation. Our data show that compared to the ECM derived from a human melanocyte cell line (NGM-ECM), ECM produced by a melanoma cell line (MV3-ECM) is considerably different in ultrastructural organization and composition and possesses a higher content of tenascin-C and laminin and a lower expression of fibronectin. When cultured directly on MV3-ECM, endothelial cells change morphology and show increased adhesion, migration, proliferation, and tubulogenesis. Interaction of endothelial cells with MV3-ECM induces the activation of integrin signaling, increasing FAK phosphorylation and its association with Src, which activates VEGFR2, potentiating the receptor response to VEGF. The blockage of αvβ3 integrin inhibited the FAK-Src association and VEGFR activation, thus reducing tubulogenesis. Together, our data suggest that the interaction of endothelial cells with the melanoma-ECM triggers integrin-dependent signaling, leading to Src pathway activation that may potentiate VEGFR2 activation and up-regulate angiogenesis. J. Cell. Physiol. 231: 2464-2473, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

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

Yuan, Xiaopeng; Du, Jie; Hua, Song

Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly,more » combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.« less

Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation*

PubMed Central

Weihs, Anna M.; Fuchs, Christiane; Teuschl, Andreas H.; Hartinger, Joachim; Slezak, Paul; Mittermayr, Rainer; Redl, Heinz; Junger, Wolfgang G.; Sitte, Harald H.; Rünzler, Dominik

2014-01-01

Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy- and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human Jurkat T cell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing. PMID:25118288

Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation.

PubMed

Weihs, Anna M; Fuchs, Christiane; Teuschl, Andreas H; Hartinger, Joachim; Slezak, Paul; Mittermayr, Rainer; Redl, Heinz; Junger, Wolfgang G; Sitte, Harald H; Rünzler, Dominik

2014-09-26

Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy- and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human Jurkat T cell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes.

PubMed

Schmidt, E; Reimer, S; Kruse, N; Jainta, S; Bröcker, E B; Marinkovich, M P; Giudice, G J; Zillikens, D

2000-11-01

Bullous pemphigoid is an inflammatory subepidermal blistering disease that is associated with auto- antibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.

Dissociating Consciousness from Inhibitory Control: Evidence for Unconsciously Triggered Response Inhibition in the Stop-Signal Task

ERIC Educational Resources Information Center

van Gaal, Simon; Ridderinkhof, K. Richard; van den Wildenberg, Wery P. M.; Lamme, Victor A. F.

2009-01-01

Theories about the functional relevance of consciousness commonly posit that higher order cognitive control functions, such as response inhibition, require consciousness. To test this assertion, the authors designed a masked stop-signal paradigm to examine whether response inhibition could be triggered and initiated by masked stop signals, which…

Non-immune cells equipped with T cell receptor-like signaling for cancer cell ablation

PubMed Central

Kojima, Ryosuke; Scheller, Leo; Fussenegger, Martin

2017-01-01

The ability to engineer custom cell-contact-sensing output devices into human non-immune cells would be useful for extending the applicability of cell-based cancer therapies and avoiding risks associated with engineered immune cells. Here, we have developed a new class of synthetic T-cell receptor-like signal-transduction device that functions efficiently in human non-immune cells and triggers release of output molecules specifically upon sensing contact with a target cell. This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal-inhibitory protein from the sensor cell/target cell interface. We further showed that designer non-immune cells equipped with this device driving expression of a membrane-penetrator/prodrug-activating enzyme construct could specifically kill target cells in the presence of the prodrug, indicating its potential usefulness for target-cell-specific, cell-based enzyme-prodrug cancer therapy. Our study also contributes to advancement of synthetic biology by extending available design principles to transmit extracellular information to cells. PMID:29131143

Crossed motor innervation of the base of human tongue

PubMed Central

Jordan, Amy S.; Nicholas, Christian L.; Cori, Jennifer M.; Semmler, John G.; Trinder, John

2015-01-01

Muscle fibers of the genioglossus (GG) form the bulk of the muscle mass at the base of the tongue. The motor control of the tongue is critical for vocalization, feeding, and breathing. Our goal was to assess the patterns of motor innervation of GG single motor units (SMUs) in humans. Simultaneous monopolar recordings were obtained from four sites in the base of the tongue bilaterally at two antero-posterior levels from 16 resting, awake, healthy adult males, who wore a face mask with airway pressure and airflow sensors. We analyzed 69 data segments in which at least one lead contained large action potentials generated by an SMU. Such potentials served as triggers for spike-triggered averaging (STA) of signals recorded from the other three sites. Spontaneous activity of the SMUs was classified as inspiratory modulated, expiratory modulated, or tonic. Consistent with the antero-posterior orientation of GG fibers, 44 STAs (77%) recorded ipsilateral to the trigger yielded sharp action potentials with a median amplitude of 52 μV [interquartile range (IQR): 25–190] that were time shifted relative to the trigger by about 1 ms. Notably, 48% of recordings on the side opposite to the trigger also yielded sharp action potentials. Of those, 17 (29%) had a median amplitude of 63 μV (IQR: 39–96), and most were generated by tonic SMUs. Thus a considerable proportion of GG muscle fibers receive a crossed motor innervation. Crossed innervation may help ensure symmetry and stability of tongue position and movements under normal conditions and following injury or degenerative changes affecting the tongue. PMID:25855691

AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes.

PubMed

Thrash, Barry R; Menges, Craig W; Pierce, Robert H; McCance, Dennis J

2006-04-28

Keratinocyte differentiation and stratification are complex processes involving multiple signaling pathways, which convert a basal proliferative cell into an inviable rigid squame. Loss of attachment to the basement membrane triggers keratinocyte differentiation, while in other epithelial cells, detachment from the extracellular matrix leads to rapid programmed cell death or anoikis. The potential role of AKT in providing a survival signal necessary for stratification and differentiation of primary human keratinocytes was investigated. AKT activity increased during keratinocyte differentiation and was attributed to the specific activation of AKT1 and AKT2. Targeted reduction of AKT1 expression, but not AKT2, by RNA interference resulted in an abnormal epidermis in organotypic skin cultures with a thin parabasal region and a pronounced but disorganized cornified layer. This abnormal stratification was due to significant cell death in the suprabasal layers and was alleviated by caspase inhibition. Normal expression patterns of both early and late markers of keratinocyte differentiation were also disrupted, producing a poorly developed stratum corneum.

Structural basis of semaphorin–plexin signalling

PubMed Central

Janssen, Bert J. C.; Robinson, Ross A.; Pérez-Brangulí, Francesc; Bell, Christian H.; Mitchell, Kevin J.; Siebold, Christian; Jones, E. Yvonne

2013-01-01

Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses1. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively2,3. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB11–2–SEMA4Decto and murine PlxnA21–4–Sema6Aecto), plus unliganded structures of PlxnA21–4 and Sema6Aecto. These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin–plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity. PMID:20877282

The ATLAS Level-1 Calorimeter Trigger: PreProcessor implementation and performance

NASA Astrophysics Data System (ADS)

Åsman, B.; Achenbach, R.; Allbrooke, B. M. M.; Anders, G.; Andrei, V.; Büscher, V.; Bansil, H. S.; Barnett, B. M.; Bauss, B.; Bendtz, K.; Bohm, C.; Bracinik, J.; Brawn, I. P.; Brock, R.; Buttinger, W.; Caputo, R.; Caughron, S.; Cerrito, L.; Charlton, D. G.; Childers, J. T.; Curtis, C. J.; Daniells, A. C.; Davis, A. O.; Davygora, Y.; Dorn, M.; Eckweiler, S.; Edmunds, D.; Edwards, J. P.; Eisenhandler, E.; Ellis, K.; Ermoline, Y.; Föhlisch, F.; Faulkner, P. J. W.; Fedorko, W.; Fleckner, J.; French, S. T.; Gee, C. N. P.; Gillman, A. R.; Goeringer, C.; Hülsing, T.; Hadley, D. R.; Hanke, P.; Hauser, R.; Heim, S.; Hellman, S.; Hickling, R. S.; Hidvégi, A.; Hillier, S. J.; Hofmann, J. I.; Hristova, I.; Ji, W.; Johansen, M.; Keller, M.; Khomich, A.; Kluge, E.-E.; Koll, J.; Laier, H.; Landon, M. P. J.; Lang, V. S.; Laurens, P.; Lepold, F.; Lilley, J. N.; Linnemann, J. T.; Müller, F.; Müller, T.; Mahboubi, K.; Martin, T. A.; Mass, A.; Meier, K.; Meyer, C.; Middleton, R. P.; Moa, T.; Moritz, S.; Morris, J. D.; Mudd, R. D.; Narayan, R.; zur Nedden, M.; Neusiedl, A.; Newman, P. R.; Nikiforov, A.; Ohm, C. C.; Perera, V. J. O.; Pfeiffer, U.; Plucinski, P.; Poddar, S.; Prieur, D. P. F.; Qian, W.; Rieck, P.; Rizvi, E.; Sankey, D. P. C.; Schäfer, U.; Scharf, V.; Schmitt, K.; Schröder, C.; Schultz-Coulon, H.-C.; Schumacher, C.; Schwienhorst, R.; Silverstein, S. B.; Simioni, E.; Snidero, G.; Staley, R. J.; Stamen, R.; Stock, P.; Stockton, M. C.; Tan, C. L. A.; Tapprogge, S.; Thomas, J. P.; Thompson, P. D.; Thomson, M.; True, P.; Watkins, P. M.; Watson, A. T.; Watson, M. F.; Weber, P.; Wessels, M.; Wiglesworth, C.; Williams, S. L.

2012-12-01

The PreProcessor system of the ATLAS Level-1 Calorimeter Trigger (L1Calo) receives about 7200 analogue signals from the electromagnetic and hadronic components of the calorimetric detector system. Lateral division results in cells which are pre-summed to so-called Trigger Towers of size 0.1 × 0.1 along azimuth (phi) and pseudorapidity (η). The received calorimeter signals represent deposits of transverse energy. The system consists of 124 individual PreProcessor modules that digitise the input signals for each LHC collision, and provide energy and timing information to the digital processors of the L1Calo system, which identify physics objects forming much of the basis for the full ATLAS first level trigger decision. This paper describes the architecture of the PreProcessor, its hardware realisation, functionality, and performance.

Do receptors get pregnant too? Adrenergic receptor alterations in human pregnancy.

PubMed

Smiley, R M; Finster, M

1996-01-01

In this review we discuss adrenergic receptor number and function during pregnancy, with emphasis on evidence that pregnancy results in specific receptor alterations from the nonpregnant state. Changes in adrenergic receptor function or distribution in vascular smooth muscle may be in part responsible for the decreased vascular responsiveness seen in human pregnancy, and the lack of the normal alterations may be a part of the syndromes of gestational hypertension, including preeclampsia-eclampsia. The onset of labor may be influenced by adrenergic modulation, and receptor or postreceptor level molecular alterations may trigger or facilitate normal or preterm labor. Human studies are emphasized when possible to assess the role of adrenergic signal transduction regulation in the physiology and pathophysiology of normal and complicated human pregnancy.

Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes*

PubMed Central

Mobasher, Maysa Ahmed; de Toro-Martín, Juan; González-Rodríguez, Águeda; Ramos, Sonia; Letzig, Lynda G.; James, Laura P.; Muntané, Jordi; Álvarez, Carmen; Valverde, Ángela M.

2014-01-01

Many drugs are associated with the development of glucose intolerance or deterioration in glycemic control in patients with pre-existing diabetes. We have evaluated the cross-talk between signaling pathways activated by acetaminophen (APAP) and insulin signaling in hepatocytes with or without expression of the protein-tyrosine phosphatase 1B (PTP1B) and in wild-type and PTP1B-deficient mice chronically treated with APAP. Human primary hepatocytes, Huh7 hepatoma cells with silenced PTP1B, mouse hepatocytes from wild-type and PTP1B-deficient mice, and a mouse model of chronic APAP treatment were used to examine the mechanisms involving PTP1B in the effects of APAP on glucose homeostasis and hepatic insulin signaling. In APAP-treated human hepatocytes at concentrations that did not induce death, phosphorylation of JNK and PTP1B expression and enzymatic activity were increased. APAP pretreatment inhibited activation of the early steps of insulin signaling and decreased Akt phosphorylation. The effects of APAP in insulin signaling were prevented by suramin, a PTP1B inhibitor, or rosiglitazone that decreased PTP1B levels. Likewise, PTP1B deficiency in human or mouse hepatocytes protected against APAP-mediated impairment in insulin signaling. These signaling pathways were modulated in mice with chronic APAP treatment, resulting in protection against APAP-mediated hepatic insulin resistance and alterations in islet alpha/beta cell ratio in PTP1B−/− mice. Our results demonstrate negative cross-talk between signaling pathways triggered by APAP and insulin signaling in hepatocytes, which is in part mediated by PTP1B. Moreover, our in vivo data suggest that chronic use of APAP may be associated with insulin resistance in the liver. PMID:25204659

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.

PubMed

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.

Decorin GAG synthesis and TGF-β signaling mediate Ox-LDL-induced mineralization of human vascular smooth muscle cells.

PubMed

Yan, Jianyun; Stringer, Sally E; Hamilton, Andrew; Charlton-Menys, Valentine; Götting, Christian; Müller, Benjamin; Aeschlimann, Daniel; Alexander, M Yvonne

2011-03-01

Decorin and oxidized low-density lipoprotein (Ox-LDL) independently induce osteogenic differentiation of vascular smooth muscle cells (VSMCs). We aimed to determine whether decorin glycosaminoglycan (GAG) chain synthesis contributes to Ox-LDL-induced differentiation and calcification of human VSMCs in vitro. Human VSMCs treated with Ox-LDL to induce oxidative stress showed increased alkaline phosphatase (ALP) activity, accelerated mineralization, and a difference in both decorin GAG chain biosynthesis and CS/DS structure compared with untreated controls. Ox-LDL increased mRNA abundance of both xylosyltransferase (XT)-I, the key enzyme responsible for GAG chain biosynthesis and Msx2, a marker of osteogenic differentiation. Furthermore, downregulation of XT-I expression using small interfering RNA blocked Ox-LDL-induced VSMC mineralization. Adenoviral-mediated overexpression of decorin, but not a mutated unglycanated form, accelerated mineralization of VSMCs, suggesting GAG chain addition on decorin is crucial for the process of differentiation. The decorin-induced VSMC osteogenic differentiation involved activation of the transforming growth factor (TGF)-β pathway, because it was attenuated by blocking of TGF-β receptor signaling and because decorin overexpression potentiated phosphorylation of the downstream signaling molecule smad2. These studies provide direct evidence that oxidative stress-mediated decorin GAG chain synthesis triggers TGF-β signaling and mineralization of VSMCs in vitro.

Detection and enforcement of failure-to-yield in an emergency vehicle preemption system

NASA Technical Reports Server (NTRS)

Bachelder, Aaron (Inventor); Wickline, Richard (Inventor)

2007-01-01

An intersection controlled by an intersection controller receives trigger signals from on-coming emergency vehicles responding to an emergency call. The intersection controller initiates surveillance of the intersection via cameras installed at the intersection in response to a received trigger signal. The surveillance may begin immediately upon receipt of the trigger signal from an emergency vehicle, or may wait until the intersection controller determines that the signaling emergency vehicle is in the field of view of the cameras at the intersection. Portions of the captured images are tagged by the intersection controller based on tag signals transmitted by the vehicle or based on detected traffic patterns that indicate a potential traffic violation. The captured images are downloaded to a processing facility that analyzes the images and automatically issues citations for captured traffic violations.

Antibodies against CD20 or B-Cell Receptor Induce Similar Transcription Patterns in Human Lymphoma Cell Lines

PubMed Central

Franke, Andreas; Niederfellner, Gerhard J.; Klein, Christian; Burtscher, Helmut

2011-01-01

Background CD20 is a cell surface protein exclusively expressed on B cells. It is a clinically validated target for Non-Hodgkin's lymphomas (NHL) and autoimmune diseases. The B cell receptor (BCR) plays an important role for development and proliferation of pre-B and B cells. Physical interaction of CD20 with BCR and components of the BCR signaling cascade has been reported but the consequences are not fully understood. Methodology In this study we employed antibodies against CD20 and against the BCR to trigger the respective signaling. These antibodies induced very similar expression patterns of up- and down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. Two of the genes that were rapidly and transiently induced by both stimuli are CCL3 and CCL4. 4 hours after stimulation the concentration of these chemokines in culture medium reaches a maximum. Spleen tyrosine kinase Syk is a cytoplasmic tyrosine kinase and a key component of BCR signaling. Both siRNA mediated silencing of Syk and inhibition by selective small molecule inhibitors impaired CCL3/CCL4 protein induction after treatment with either anti-CD20 or anti-BCR antibodies. Conclusion Our results suggest that treatment with anti-CD20 antibodies triggers at least partially a BCR activation-like response in NHL cell lines. PMID:21364752

GPER mediates activation of HIF1α/VEGF signaling by estrogens.

PubMed

De Francesco, Ernestina Marianna; Pellegrino, Michele; Santolla, Maria Francesca; Lappano, Rosamaria; Ricchio, Emilia; Abonante, Sergio; Maggiolini, Marcello

2014-08-01

Biological responses to estrogens in normal and malignant tissues are mainly mediated by the estrogen receptors ERα and ERβ, which function as ligand-activated transcription factors. In addition, the G protein-coupled receptor GPR30 (GPER) mediates estrogenic signaling in breast cancer cells and cancer-associated fibroblasts (CAF) that contribute to cancer progression. In this study, we evaluated the role elicited by GPER in the estrogen-regulated expression and function of vascular endothelial growth factor (VEGF) in ER-negative breast cancer cells and CAF. We demonstrated that 17β-estradiol (E2) and the GPER-selective ligand G-1 triggered a GPER/EGFR/ERK/c-fos signaling pathway that leads to increased VEGF via upregulation of HIF1α. In further extending the mechanisms involved in E2-supported angiogenesis, we also showed that conditioned medium from CAF treated with E2 and G-1 promoted human endothelial tube formation in a GPER-dependent manner. In vivo, ligand-activated GPER was sufficient to enhance tumor growth and the expression of HIF1α, VEGF, and the endothelial marker CD34 in a mouse xenograft model of breast cancer. Our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HIF1α-dependent VEGF expression that supports angiogenesis and progression in breast cancer. ©2014 American Association for Cancer Research.

Networked event-triggered control: an introduction and research trends

NASA Astrophysics Data System (ADS)

Mahmoud, Magdi S.; Sabih, Muhammad

2014-11-01

A physical system can be studied as either continuous time or discrete-time system depending upon the control objectives. Discrete-time control systems can be further classified into two categories based on the sampling: (1) time-triggered control systems and (2) event-triggered control systems. Time-triggered systems sample states and calculate controls at every sampling instant in a periodic fashion, even in cases when states and calculated control do not change much. This indicates unnecessary and useless data transmission and computation efforts of a time-triggered system, thus inefficiency. For networked systems, the transmission of measurement and control signals, thus, cause unnecessary network traffic. Event-triggered systems, on the other hand, have potential to reduce the communication burden in addition to reducing the computation of control signals. This paper provides an up-to-date survey on the event-triggered methods for control systems and highlights the potential research directions.

Data processing device test apparatus and method therefor

DOEpatents

Wilcox, Richard Jacob; Mulig, Jason D.; Eppes, David; Bruce, Michael R.; Bruce, Victoria J.; Ring, Rosalinda M.; Cole, Jr., Edward I.; Tangyunyong, Paiboon; Hawkins, Charles F.; Louie, Arnold Y.

2003-04-08

A method and apparatus mechanism for testing data processing devices are implemented. The test mechanism isolates critical paths by correlating a scanning microscope image with a selected speed path failure. A trigger signal having a preselected value is generated at the start of each pattern vector. The sweep of the scanning microscope is controlled by a computer, which also receives and processes the image signals returned from the microscope. The value of the trigger signal is correlated with a set of pattern lines being driven on the DUT. The trigger is either asserted or negated depending the detection of a pattern line failure and the particular line that failed. In response to the detection of the particular speed path failure being characterized, and the trigger signal, the control computer overlays a mask on the image of the device under test (DUT). The overlaid image provides a visual correlation of the failure with the structural elements of the DUT at the level of resolution of the microscope itself.

Convergent and Divergent Signaling in PAMP-Triggered Immunity and Effector-Triggered Immunity.

PubMed

Peng, Yujun; van Wersch, Rowan; Zhang, Yuelin

2018-04-01

Plants use diverse immune receptors to sense pathogen attacks. Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors localized on the plasma membrane leads to PAMP-triggered immunity (PTI). Detection of pathogen effectors by intracellular or plasma membrane-localized immune receptors results in effector-triggered immunity (ETI). Despite the large variations in the magnitude and duration of immune responses triggered by different PAMPs or pathogen effectors during PTI and ETI, plasma membrane-localized immune receptors activate similar downstream molecular events such as mitogen-activated protein kinase activation, oxidative burst, ion influx, and increased biosynthesis of plant defense hormones, indicating that defense signals initiated at the plasma membrane converge at later points. On the other hand, activation of ETI by immune receptors localized to the nucleus appears to be more directly associated with transcriptional regulation of defense gene expression. Here, we review recent progress in signal transductions downstream of different groups of plant immune receptors, highlighting the converging and diverging molecular events.

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

PubMed Central

Hallahan, D E; Virudachalam, S; Kuchibhotla, J; Kufe, D W; Weichselbaum, R R

1994-01-01

Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a signaling pathway involving the activation of phospholipase A2 and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor alpha gene. Treatment of human cells with ionizing radiation or H2O2 was associated with the production of arachidonic acid. Inhibition of phospholipase A2 abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor alpha gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2 inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor alpha production. Images PMID:8197153

GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation.

PubMed

Chevalier, Nicolas; Vega, Aurélie; Bouskine, Adil; Siddeek, Bénazir; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick

2012-01-01

Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation. These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.

Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex.

PubMed

Fleming, Matthew R; Brown, Maile R; Kronengold, Jack; Zhang, Yalan; Jenkins, David P; Barcia, Gulia; Nabbout, Rima; Bausch, Anne E; Ruth, Peter; Lukowski, Robert; Navaratnam, Dhasakumar S; Kaczmarek, Leonard K

2016-08-30

Human mutations in the cytoplasmic C-terminal domain of Slack sodium-activated potassium (KNa) channels result in childhood epilepsy with severe intellectual disability. Slack currents can be increased by pharmacological activators or by phosphorylation of a Slack C-terminal residue by protein kinase C. Using an optical biosensor assay, we find that Slack channel stimulation in neurons or transfected cells produces loss of mass near the plasma membrane. Slack mutants associated with intellectual disability fail to trigger any change in mass. The loss of mass results from the dissociation of the protein phosphatase 1 (PP1) targeting protein, Phactr-1, from the channel. Phactr1 dissociation is specific to wild-type Slack channels and is not observed when related potassium channels are stimulated. Our findings suggest that Slack channels are coupled to cytoplasmic signaling pathways and that dysregulation of this coupling may trigger the aberrant intellectual development associated with specific childhood epilepsies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Stimulation of Slack K+ channels alters mass at the plasma membrane by triggering dissociation of a phosphatase-regulatory complex

PubMed Central

Fleming, Matthew R.; Brown, Maile R.; Kronengold, Jack; Zhang, Yalan; Jenkins, David P.; Barcia, Gulia; Nabbout, Rima; Bausch, Anne E.; Ruth, Peter; Lukowski, Robert; Navaratnam, Dhasakumar S.; Kaczmarek, Leonard K.

2016-01-01

Summary Human mutations in the cytoplasmic C-terminal domain of Slack sodium-activated potassium (KNa) channels result in childhood epilepsy with severe intellectual disability. Slack currents can be increased by pharmacological activators or by phosphorylation of a Slack C-terminal residue by protein kinase C. Using an optical biosensor assay, we find that Slack channel stimulation in neurons or transfected cells produces loss of mass near the plasma membrane. Slack mutants associated with intellectual disability fail to trigger any change in mass. The loss of mass results from the dissociation of the protein phosphatase 1 (PP1) targeting protein, Phactr-1, from the channel. Phactr1 dissociation is specific to wild-type Slack channels and is not observed when related potassium channels are stimulated. Our findings suggest that Slack channels are coupled to cytoplasmic signaling pathways, and that dysregulation of this coupling may trigger the aberrant intellectual development associated with specific childhood epilepsies. PMID:27545877

Derivation of a respiration trigger signal in small animal list-mode PET based on respiration-induced variations of the ECG signal.

PubMed

Todica, Andrei; Lehner, Sebastian; Wang, Hao; Zacherl, Mathias J; Nekolla, Katharina; Mille, Erik; Xiong, Guoming; Bartenstein, Peter; la Fougère, Christian; Hacker, Marcus; Böning, Guido

2016-02-01

Raw PET list-mode data contains motion artifacts causing image blurring and decreased spatial resolution. Unless corrected, this leads to underestimation of the tracer uptake and overestimation of the lesion size, as well as inaccuracies with regard to left ventricular volume and ejection fraction (LVEF), especially in small animal imaging. A respiratory trigger signal from respiration-induced variations in the electro-cardiogram (ECG) was detected. Original and revised list-mode PET data were used for calculation of left ventricular function parameters using both respiratory gating techniques. For adequately triggered datasets we saw no difference in mean respiratory cycle period between the reference standard (RRS) and the ECG-based (ERS) methods (1120 ± 159 ms vs 1120 ± 159 ms; P = n.s.). While the ECG-based method showed somewhat higher signal noise (66 ± 22 ms vs 51 ± 29 ms; P < .001), both respiratory triggering techniques yielded similar estimates for EDV, ESV, LVEF (RRS: 387 ± 56 µL, 162 ± 34 µL, 59 ± 5%; ERS: 389 ± 59 µL, 163 ± 35 µL, 59 ± 4%; P = n.s.). This study showed that respiratory gating signals can be accurately derived from cardiac trigger information alone, without the additional requirement for dedicated measurement of the respiratory motion in rats.

Group A Streptococcus tissue invasion by CD44-mediated cell signalling

NASA Astrophysics Data System (ADS)

Cywes, Colette; Wessels, Michael R.

2001-12-01

Streptococcus pyogenes (also known as group A Streptococcus, GAS), the agent of streptococcal sore throat and invasive soft-tissue infections, attaches to human pharyngeal or skin epithelial cells through specific recognition of its hyaluronic acid capsular polysaccharide by the hyaluronic-acid-binding protein CD44 (refs 1, 2). Because ligation of CD44 by hyaluronic acid can induce epithelial cell movement on extracellular matrix, we investigated whether molecular mimicry by the GAS hyaluronic acid capsule might induce similar cellular responses. Here we show that CD44-dependent GAS binding to polarized monolayers of human keratinocytes induced marked cytoskeletal rearrangements manifested by membrane ruffling and disruption of intercellular junctions. Transduction of the signal induced by GAS binding to CD44 on the keratinocyte surface involved Rac1 and the cytoskeleton linker protein ezrin, as well as tyrosine phosphorylation of cellular proteins. Studies of bacterial translocation in two models of human skin indicated that cell signalling triggered by interaction of the GAS capsule with CD44 opened intercellular junctions and promoted tissue penetration by GAS through a paracellular route. These results support a model of host cytoskeleton manipulation and tissue invasion by an extracellular bacterial pathogen.

Signal processor for processing ultrasonic receiver signals

DOEpatents

Fasching, George E.

1980-01-01

A signal processor is provided which uses an analog integrating circuit in conjunction with a set of digital counters controlled by a precision clock for sampling timing to provide an improved presentation of an ultrasonic transmitter/receiver signal. The signal is sampled relative to the transmitter trigger signal timing at precise times, the selected number of samples are integrated and the integrated samples are transferred and held for recording on a strip chart recorder or converted to digital form for storage. By integrating multiple samples taken at precisely the same time with respect to the trigger for the ultrasonic transmitter, random noise, which is contained in the ultrasonic receiver signal, is reduced relative to the desired useful signal.

Trigger design for a gamma ray detector of HIRFL-ETF

NASA Astrophysics Data System (ADS)

Du, Zhong-Wei; Su, Hong; Qian, Yi; Kong, Jie

2013-10-01

The Gamma Ray Array Detector (GRAD) is one subsystem of HIRFL-ETF (the External Target Facility (ETF) of the Heavy Ion Research Facility in Lanzhou (HIRFL)). It is capable of measuring the energy of gamma-rays with 1024 CsI scintillators in in-beam nuclear experiments. The GRAD trigger should select the valid events and reject the data from the scintillators which are not hit by the gamma-ray. The GRAD trigger has been developed based on the Field Programmable Gate Array (FPGAs) and PXI interface. It makes prompt trigger decisions to select valid events by processing the hit signals from the 1024 CsI scintillators. According to the physical requirements, the GRAD trigger module supplies 12-bit trigger information for the global trigger system of ETF and supplies a trigger signal for data acquisition (DAQ) system of GRAD. In addition, the GRAD trigger generates trigger data that are packed and transmitted to the host computer via PXI bus to be saved for off-line analysis. The trigger processing is implemented in the front-end electronics of GRAD and one FPGA of the GRAD trigger module. The logic of PXI transmission and reconfiguration is implemented in another FPGA of the GRAD trigger module. During the gamma-ray experiments, the GRAD trigger performs reliably and efficiently. The function of GRAD trigger is capable of satisfying the physical requirements.

First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases.

PubMed

Borroto, Aldo; Reyes-Garau, Diana; Jiménez, M Angeles; Carrasco, Esther; Moreno, Beatriz; Martínez-Pasamar, Sara; Cortés, José R; Perona, Almudena; Abia, David; Blanco, Soledad; Fuentes, Manuel; Arellano, Irene; Lobo, Juan; Heidarieh, Haleh; Rueda, Javier; Esteve, Pilar; Cibrián, Danay; Martinez-Riaño, Ana; Mendoza, Pilar; Prieto, Cristina; Calleja, Enrique; Oeste, Clara L; Orfao, Alberto; Fresno, Manuel; Sánchez-Madrid, Francisco; Alcamí, Antonio; Bovolenta, Paola; Martín, Pilar; Villoslada, Pablo; Morreale, Antonio; Messeguer, Angel; Alarcon, Balbino

2016-12-21

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC 50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases. Copyright © 2016, American Association for the Advancement of Science.

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

PubMed

Wang, Weijun; Zhang, Yaxing; Yang, Ling; Li, Hongliang

2017-02-28

The innate immune system is responsible for sensing pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by several types of germline-encoded pattern-recognition receptors (PRRs). It has the capacity to help the human body maintain homeostasis under normal conditions. However, in pathological conditions, PAMPs or DAMPs trigger aberrant innate immune and inflammatory responses and thus negatively or positively influence the progression of cancer and cardiometabolic diseases. Interestingly, we found that some elements of innate immune signaling are involved in these diseases partially via immune-independent manners, indicating a deeper understanding of the function of innate immune signaling in these diseases is urgent. In this review, we summarize the primary innate immune signaling pathways and their association with cancer and cardiometabolic diseases, with the aim of providing effective therapies for these diseases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Novel Task for the Investigation of Action Acquisition

PubMed Central

Stafford, Tom; Thirkettle, Martin; Walton, Tom; Vautrelle, Nicolas; Hetherington, Len; Port, Michael; Gurney, Kevin; Redgrave, Pete

2012-01-01

We present a behavioural task designed for the investigation of how novel instrumental actions are discovered and learnt. The task consists of free movement with a manipulandum, during which the full range of possible movements can be explored by the participant and recorded. A subset of these movements, the ‘target’, is set to trigger a reinforcing signal. The task is to discover what movements of the manipulandum evoke the reinforcement signal. Targets can be defined in spatial, temporal, or kinematic terms, can be a combination of these aspects, or can represent the concatenation of actions into a larger gesture. The task allows the study of how the specific elements of behaviour which cause the reinforcing signal are identified, refined and stored by the participant. The task provides a paradigm where the exploratory motive drives learning and as such we view it as in the tradition of Thorndike [1]. Most importantly it allows for repeated measures, since when a novel action is acquired the criterion for triggering reinforcement can be changed requiring a new action to be discovered. Here, we present data using both humans and rats as subjects, showing that our task is easily scalable in difficulty, adaptable across species, and produces a rich set of behavioural measures offering new and valuable insight into the action learning process. PMID:22675490

Is lipid signaling through cannabinoid 2 receptors part of a protective system?

PubMed Central

Pacher, P.; Mechoulam, R.

2011-01-01

The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, auto-immune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. PMID:21295074

Is lipid signaling through cannabinoid 2 receptors part of a protective system?

PubMed

Pacher, P; Mechoulam, R

2011-04-01

The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB₂) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB₂ receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB₂ receptor activity holds tremendous therapeutic potential in these pathologies. While CB₂ receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB₂ receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB₂ receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. Published by Elsevier Ltd.

Light induced cytosolic drug delivery from liposomes with gold nanoparticles.

PubMed

Lajunen, Tatu; Viitala, Lauri; Kontturi, Leena-Stiina; Laaksonen, Timo; Liang, Huamin; Vuorimaa-Laukkanen, Elina; Viitala, Tapani; Le Guével, Xavier; Yliperttula, Marjo; Murtomäki, Lasse; Urtti, Arto

2015-04-10

Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion.

PubMed

Lacal, Pedro Miguel; Petrillo, Maria Grazia; Ruffini, Federica; Muzi, Alessia; Bianchini, Rodolfo; Ronchetti, Simona; Migliorati, Graziella; Riccardi, Carlo; Graziani, Grazia; Nocentini, Giuseppe

2013-10-01

The interaction of glucocorticoid-induced tumor necrosis factor receptor-family related (GITR) protein with its ligand (GITRL) modulates different functions, including immune/inflammatory response. These effects are consequent to intracellular signals activated by both GITR and GITRL. Previous results have suggested that lack of GITR expression in GITR(-/-) mice decreases the number of leukocytes within inflamed tissues. We performed experiments to analyze whether the GITRL/GITR system modulates leukocyte adhesion and extravasation. For that purpose, we first evaluated the capability of murine splenocytes to adhere to endothelial cells (EC). Our results indicated that adhesion of GITR(-/-) splenocytes to EC was reduced as compared with wild-type cells, suggesting that GITR plays a role in adhesion and that this effect may be due to GITRL-GITR interaction. Moreover, adhesion was increased when EC were pretreated with an agonist GITR-Fc fusion protein, thus indicating that triggering of GITRL plays a role in adhesion by EC regulation. In a human in vitro model, the adhesion to human EC of HL-60 cells differentiated toward the monocytic lineage was increased by EC pretreatment with agonist GITR-Fc. Conversely, antagonistic anti-GITR and anti-GITRL Ab decreased adhesion, thus further indicating that GITRL triggering increases the EC capability to support leukocyte adhesion. EC treatment with GITR-Fc favored extravasation, as demonstrated by a transmigration assay. Notably, GITRL triggering increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and anti-ICAM-1 and anti-VCAM-1 Abs reversed GITR-Fc effects. Our study demonstrates that GITRL triggering in EC increases leukocyte adhesion and transmigration, suggesting new anti-inflammatory therapeutic approaches based on inhibition of GITRL-GITR interaction.

Synchronizing A Stroboscope With A Video Camera

NASA Technical Reports Server (NTRS)

Rhodes, David B.; Franke, John M.; Jones, Stephen B.; Dismond, Harriet R.

1993-01-01

Circuit synchronizes flash of light from stroboscope with frame and field periods of video camera. Sync stripper sends vertical-synchronization signal to delay generator, which generates trigger signal. Flashlamp power supply accepts delayed trigger signal and sends pulse of power to flash lamp. Designed for use in making short-exposure images that "freeze" flow in wind tunnel. Also used for making longer-exposure images obtained by use of continuous intense illumination.

Characterization of Apoptosis Induced by Emodin and Related Regulatory Mechanisms in Human Neuroblastoma Cells

PubMed Central

Huang, Fu-Jen; Hsuuw, Yan-Der; Chan, Wen-Hsiung

2013-01-01

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a major constituent of rhubarb, has a wide range of therapeutic applications. Recent studies have shown that emodin can induce or prevent cell apoptosis, although the precise molecular mechanisms underlying these effects are unknown. Experiments from the current study revealed that emodin (10–20 μM) induces apoptotic processes in the human neuroblastoma cell line, IMR-32, but exerts no injury effects at treatment doses below 10 μM. Treatment with emodin at concentrations of 10–20 μM led to a direct increase in the reactive oxygen species (ROS) content in IMR-32 cells, along with significant elevation of cytoplasmic free calcium and nitric oxide (NO) levels, loss of mitochondrial membrane potential (MMP), activation of caspases-9 and -3, and cell death. Pretreatment with nitric oxide (NO) scavengers suppressed the apoptotic biochemical changes induced by 20 μM emodin, and attenuated emodin-induced p53 and p21 expression involved in apoptotic signaling. Our results collectively indicate that emodin at concentrations of 10–20 μM triggers apoptosis of IMR-32 cells via a mechanism involving both ROS and NO. Based on the collective results, we propose a model for an emodin-triggered apoptotic signaling cascade that sequentially involves ROS, Ca2+, NO, p53, caspase-9 and caspase-3. PMID:24113589

Exposure to Carbon Ions Triggers Proinflammatory Signals and Changes in Homeostasis and Epidermal Tissue Organization to a Similar Extent as Photons

PubMed Central

Simoniello, Palma; Wiedemann, Julia; Zink, Joana; Thoennes, Eva; Stange, Maike; Layer, Paul G.; Kovacs, Maximilian; Podda, Maurizio; Durante, Marco; Fournier, Claudia

2016-01-01

The increasing application of charged particles in radiotherapy requires a deeper understanding of early and late side effects occurring in skin, which is exposed in all radiation treatments. We measured cellular and molecular changes related to the early inflammatory response of human skin irradiated with carbon ions, in particular cell death induction and changes in differentiation and proliferation of epidermal cells during the first days after exposure. Model systems for human skin from healthy donors of different complexity, i.e., keratinocytes, coculture of skin cells, 3D skin equivalents, and skin explants, were used to investigate the alterations induced by carbon ions (spread-out Bragg peak, dose-averaged LET 100 keV/μm) in comparison to X-ray and UV-B exposure. After exposure to ionizing radiation, in none of the model systems, apoptosis/necrosis was observed. Carbon ions triggered inflammatory signaling and accelerated differentiation of keratinocytes to a similar extent as X-rays at the same doses. High doses of carbon ions were more effective than X-rays in reducing proliferation and inducing abnormal differentiation. In contrast, changes identified following low-dose exposure (≤0.5 Gy) were induced more effectively after X-ray exposure, i.e., enhanced proliferation and change in the polarity of basal cells. PMID:26779439

A 16 channel discriminator VME board with enhanced triggering capabilities

NASA Astrophysics Data System (ADS)

Borsato, E.; Garfagnini, A.; Menon, G.

2012-08-01

Electronics and data acquisition systems used in small and large scale laboratories often have to handle analog signals with varying polarity, amplitude and duration which have to be digitized to be used as trigger signals to validate the acquired data. In the specific case of experiments dealing with ionizing radiation, ancillary particle detectors (for instance plastic scintillators or Resistive Plate Chambers) are used to trigger and select the impinging particles for the experiment. A novel approach using commercial LVDS line receivers as discriminator devices is presented. Such devices, with a proper calibration, can handle positive and negative analog signals in a wide dynamic range (from 20 mV to 800 mV signal amplitude). The clear advantages, with respect to conventional discriminator devices, are reduced costs, high reliability of a mature technology and the possibility of high integration scale. Moreover, commercial discriminator boards with positive input signal and a wide threshold swing are not available on the market. The present paper describes the design and characterization of a VME board capable to handle 16 differential or single-ended input channels. The output digital signals, available independently for each input, can be combined in the board into three independent trigger logic units which provide additional outputs for the end user.

Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release.

PubMed

Yacoub, Daniel; Théorêt, Jean-François; Villeneuve, Louis; Abou-Saleh, Haissam; Mourad, Walid; Allen, Bruce G; Merhi, Yahye

2006-10-06

The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCdelta, but not PKCalpha or PKCbeta, is required for collagen-induced phospholipase C-dependent signaling, activation of alpha(IIb)beta(3), and platelet aggregation. Analysis of PKCdelta phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by alpha(IIb)beta(3) outside-in signaling. Moreover, PKCdelta triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A(2), which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCdelta signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A(2).

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing.

PubMed

Deng, Wenbo; Cha, Jeeyeon; Yuan, Jia; Haraguchi, Hirofumi; Bartos, Amanda; Leishman, Emma; Viollet, Benoit; Bradshaw, Heather B; Hirota, Yasushi; Dey, Sudhansu K

2016-08-01

Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB.

Epstein-Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle.

PubMed

Hau, Pok Man; Tsao, Sai Wah

2017-11-16

The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation.

The LUX experiment - trigger and data acquisition systems

NASA Astrophysics Data System (ADS)

Druszkiewicz, Eryk

2013-04-01

The Large Underground Xenon (LUX) detector is a two-phase xenon time projection chamber designed to detect interactions of dark matter particles with the xenon nuclei. Signals from the detector PMTs are processed by custom-built analog electronics which provide properly shaped signals for the trigger and data acquisition (DAQ) systems. During calibrations, both systems must be able to handle high rates and have large dynamic ranges; during dark matter searches, maximum sensitivity requires low thresholds. The trigger system uses eight-channel 64-MHz digitizers (DDC-8) connected to a Trigger Builder (TB). The FPGA cores on the digitizers perform real-time pulse identification (discriminating between S1 and S2-like signals) and event localization. The TB uses hit patterns, hit maps, and maximum response detection to make trigger decisions, which are reached within few microseconds after the occurrence of an event of interest. The DAQ system is comprised of commercial digitizers with customized firmware. Its real-time baseline suppression allows for a maximum event acquisition rate in excess of 1.5 kHz, which results in virtually no deadtime. The performance of the trigger and DAQ systems during the commissioning runs of LUX will be discussed.

A PVDF Trigger and Tilt Detector for Projectile Impact Experiments

DTIC Science & Technology

1991-11-01

trigger include a fast rise time signal and a predictable signal magnitude. The circuit of a piezoelectric PVDF trigger is modeled in Figure 2-1; the...TR 91-640 DISTRIBUTION Copies Copies Chief of Naval Research Chairman Attn: ONR 1132P (R. Miller ) 1 Department of Defense Explosives ONT 20T (L. V...C. S. Coffey) 1 Washington, DC 20540 (J. Davis) 1 (D. L. Demske) 1 Socidth Nationale des Poudres (J. W. Forbes) 1 et Explosifs (R. H. Guirguis ) 1 Attn

Lactobacillus amylovorus Inhibits the TLR4 Inflammatory Signaling Triggered by Enterotoxigenic Escherichia coli via Modulation of the Negative Regulators and Involvement of TLR2 in Intestinal Caco-2 Cells and Pig Explants

PubMed Central

Finamore, Alberto; Roselli, Marianna; Imbinto, Ambra; Seeboth, Julie; Oswald, Isabelle P.; Mengheri, Elena

2014-01-01

Inflammation derived from pathogen infection involves the activation of toll-like receptor (TLR) signaling. Despite the established immunomodulatory activities of probiotics, studies relating the ability of such bacteria to inhibit the TLR signaling pathways are limited or controversial. In a previous study we showed that Lactobacillus amylovorus DSM 16698T, a novel lactobacillus isolated from unweaned pigs, protects the intestinal cells from enterotoxigenic Escherichia coli (ETEC) K88 infection through cytokine regulation. In the present study we investigated whether the ability of L. amylovorus to counteract the inflammatory status triggered by ETEC in intestine is elicited through inhibition of the TLR4 signaling pathway. We used the human intestinal Caco-2/TC7 cells and intestinal explants isolated from 5 week-old crossbreed Pietrain/Duroc/Large-White piglets, treated with ETEC, L. amylovorus or L. amylovorus cell free supernatant, either alone or simultaneously with ETEC. Western blot analysis showed that L. amylovorus and its cell free supernatant suppress the activation of the different steps of TLR4 signaling in Caco-2/TC7 cells and pig explants, by inhibiting the ETEC induced increase in the level of TLR4 and MyD88, the phosphorylation of the IKKα, IKKβ, IκBα and NF-κB subunit p65, as well as the over-production of inflammatory cytokines IL-8 and IL-1β. The immunofluorescence analysis confirms the lack of phospho-p65 translocation into the nucleus. These anti-inflammatory effects are achieved through modulation of the negative regulators Tollip and IRAK-M. We also found that L. amylovorus blocks the up-regulation of the extracellular heat shock protein (Hsp)72 and Hsp90, that are critical for TLR4 function. By using anti-TLR2 antibody, we demonstrate that TLR2 is required for the suppression of TLR4 signaling activation. These results may contribute to develop therapeutic interventions using L. amylovorus in intestinal disorders of piglets and humans. PMID:24733511

CDF trigger interface board 'FRED'

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

Campbell, M.; Dell' Orso, M.; Giannetti, P.

1985-08-01

We describe FASTBUS boards which interface sixteen different trigger interrupts to the Collider Detector Facility (CDF) data acquisition system. The boards are known to CDF by the acronym 'FRED'. The data acquisition scheme for CDF allows for up to 16 different parts of the detector, called 'Partitions', to run independently. Four partitions are reserved for physics runs and sophisticated calibration and debugging: they use the common Level 1 and Level 2 trigger logic and have access to information from all the components of the CDF detector. These four partitions are called ''CDF Partitions''. The remaining twelve partitions have no accessmore » to the common trigger logic and provide their own Level 1 and Level 2 signals: they are called ''Autonomous Partitions''. Fred collects and interprets signals from independent parts of the CDF trigger system and delivers Level 1 and Level 2 responses to the Trigger Supervisors (FASTBUS masters which control the data acquisition process in each partition).« less

Signal transduction and amplification through enzyme-triggered ligand release and accelerated catalysis.

PubMed

Goggins, Sean; Marsh, Barrie J; Lubben, Anneke T; Frost, Christopher G

2015-08-01

Signal transduction and signal amplification are both important mechanisms used within biological signalling pathways. Inspired by this process, we have developed a signal amplification methodology that utilises the selectivity and high activity of enzymes in combination with the robustness and generality of an organometallic catalyst, achieving a hybrid biological and synthetic catalyst cascade. A proligand enzyme substrate was designed to selectively self-immolate in the presence of the enzyme to release a ligand that can bind to a metal pre-catalyst and accelerate the rate of a transfer hydrogenation reaction. Enzyme-triggered catalytic signal amplification was then applied to a range of catalyst substrates demonstrating that signal amplification and signal transduction can both be achieved through this methodology.

ELECTRONIC TRIGGER CIRCUIT

DOEpatents

Russell, J.A.G.

1958-01-01

An electronic trigger circuit is described of the type where an output pulse is obtained only after an input voltage has cqualed or exceeded a selected reference voltage. In general, the invention comprises a source of direct current reference voltage in series with an impedance and a diode rectifying element. An input pulse of preselected amplitude causes the diode to conduct and develop a signal across the impedance. The signal is delivered to an amplifier where an output pulse is produced and part of the output is fed back in a positive manner to the diode so that the amplifier produces a steep wave front trigger pulsc at the output. The trigger point of the described circuit is not subject to variation due to the aging, etc., of multi-electrode tabes, since the diode circuit essentially determines the trigger point.

The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair

PubMed Central

Fallahi, Emma; O’Driscoll, Niamh A.; Matallanas, David

2016-01-01

The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. PMID:27322327

Distinct responses of human granulosa lutein cells after hCG or LH stimulation in a spheroidal cell culture system.

PubMed

Becker, Julia; Walz, Andrea; Daube, Stefanie; Keck, Christoph; Pietrowski, Detlef

2007-10-01

The growth and development of the corpus luteum (CL) is regulated by gonadotropic hormones. It is formed by granulosa cells (GCs), theca cells, and endothelial cells, and is the primary source of circulating progesterone. During early pregnancy only human chorionic gonadotropin (hCG) but not luteinizing hormone (LH) extends the life span of the CL, although hCG and LH interact with the same receptor and have similar actions on the CL. In this study a recently by our group established spheroidal GC culture assay served as a model of CL development on which we compared the actions of the gonadotropic hormones LH and hCG. To find out which signal pathways take part in the hormonal regulation of GC we stimulated GC-spheroids with modulators of protein kinases A and C dependent signaling cascades and determined their impact on sprout forming activity in GC. Our results indicate that PKA-dependent signaling pathways play a major role in mediating the hormonal-induced signaling cascades leading to sprouting in GC. Furthermore, this study strongly indicates that the different effects of hCG and LH in the maintenance of the CL may be reasoned in different signal transduction pathways triggered by hCG or LH. (c) 2007 Wiley-Liss, Inc.

VLF wave-wave interaction experiments in the magnetosphere

NASA Technical Reports Server (NTRS)

Chang, D. C. D.

1978-01-01

VLF wave-wave interaction experiments were carried out by injecting various forms of VLF pulses into the magnetosphere from a 21.2 km dipole antenna at Siple, Antarctica. The injected signals propagate along a geomagnetic field line and often interact strongly with energetic electrons trapped in the radiation belts near the equator. Signals may be amplified and trigger emissions. These signals may then interact with one another through these energetic electrons. This report is divided into three parts. In the first part, simulations of VLF pulses propagating in the magnetosphere are carried out. In the second part, it is found for the first time that a 10 ms gap in a triggering wave can induce emission, which may then interact with the post-gap signals. In the third part, sideband triggering is reported for the first time.

Triggering of leukocytes by phase contrast in imaging cytometry with scanning fluorescence microscope (SFM)

NASA Astrophysics Data System (ADS)

Bocsi, József; Pierzchalski, Arkadiusz; Marecka, Monika; Malkusch, Wolf; Tárnok, Attila

2009-02-01

Slide-based cytometry (SBC) leads to breakthrough in cytometry of cells in tissues, culture and suspension. Carl Zeiss Imaging Solutions' new automated SFM combines imaging with cytometry. A critical step in image analysis is selection of appropriate triggering signal to detect all objects. Without correct target cell definition analysis is hampered. DNA-staining is among the most common triggering signals. However, the majority of DNA-dyes yield massive spillover into other fluorescence channels limiting their application. By microscopy objects of >5μm diameter can be easily detected by phase-contrast signal (PCS) without any staining. Aim was to establish PCS - triggering for cell identification. Axio Imager.Z1 motorized SFM was used (high-resolution digital camera, AxioCam MRm; AxioVision software: automatic multi-channel scanning, analysis). Leukocytes were stained with FITC (CD4, CD8) and APC (CD3) labelled antibodies in combinations using whole blood method. Samples were scanned in three channels (PCS/FITC/APC). Exposition-times for PCS were set as low as possible; the detection efficiency was verified by fluorescence. CD45-stained leukocytes were counted and compared to the number of PCS detected events. Leukocyte subtyping was compared with other cytometers. In focus the PCS of cells showed ring-form that was not optimal for cell definition. Out of focus PCS allows more effective qualitative and quantitative cell analyses. PCS was an accurate triggering signal for leukocytes enabling cell counting and discrimination of leukocytes from platelets. Leukocyte subpopulation frequencies were comparable to those obtained by other cytometers. In conclusion PCS is a suitable trigger-signal not interfering with fluorescence detection.

Superparamagnetic nanoparticle-based viscosity test

NASA Astrophysics Data System (ADS)

Wu, Kai; Liu, Jinming; Wang, Yi; Ye, Clark; Feng, Yinglong; Wang, Jian-Ping

2015-08-01

Hyperviscosity syndrome is triggered by high blood viscosity in the human body. This syndrome can result in retinopathy, vertigo, coma, and other unanticipated complications. Serum viscosity is one of the important factors affecting whole blood viscosity, which is regarded as an indicator of general health. In this letter, we propose and demonstrate a Brownian relaxation-based mixing frequency method to test human serum viscosity. This method uses excitatory and detection coils and Brownian relaxation-dominated superparamagnetic nanoparticles, which are sensitive to variables of the liquid environment such as viscosity and temperature. We collect the harmonic signals produced by magnetic nanoparticles and estimate the viscosity of unknown solutions by comparison to the calibration curves. An in vitro human serum viscosity test is performed in less than 1.5 min.

Accuracy and effectiveness of self-gating signals in free-breathing three-dimensional cardiac cine magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Li, Shuo; Wang, Lei; Zhu, Yan-Chun; Yang, Jie; Xie, Yao-Qin; Fu, Nan; Wang, Yi; Gao, Song

2016-12-01

Conventional multiple breath-hold two-dimensional (2D) balanced steady-state free precession (SSFP) presents many difficulties in cardiac cine magnetic resonance imaging (MRI). Recently, a self-gated free-breathing three-dimensional (3D) SSFP technique has been proposed as an alternative in many studies. However, the accuracy and effectiveness of self-gating signals have been barely studied before. Since self-gating signals are crucially important in image reconstruction, a systematic study of self-gating signals and comparison with external monitored signals are needed. Previously developed self-gated free-breathing 3D SSFP techniques are used on twenty-eight healthy volunteers. Both electrocardiographic (ECG) and respiratory bellow signals are also acquired during the scan as external signals. Self-gating signal and external signal are compared by trigger and gating window. Gating window is proposed to evaluate the accuracy and effectiveness of respiratory self-gating signal. Relative deviation of the trigger and root-mean-square-deviation of the cycle duration are calculated. A two-tailed paired t-test is used to identify the difference between self-gating and external signals. A Wilcoxon signed rank test is used to identify the difference between peak and valley self-gating triggers. The results demonstrate an excellent correlation (P = 0, R > 0.99) between self-gating and external triggers. Wilcoxon signed rank test shows that there is no significant difference between peak and valley self-gating triggers for both cardiac (H = 0, P > 0.10) and respiratory (H = 0, P > 0.44) motions. The difference between self-gating and externally monitored signals is not significant (two-tailed paired-sample t-test: H = 0, P > 0.90). The self-gating signals could demonstrate cardiac and respiratory motion accurately and effectively as ECG and respiratory bellow. The difference between the two methods is not significant and can be explained. Furthermore, few ECG trigger errors appear in some subjects while these errors are not found in self-gating signals. Project supported by the National Natural Science Foundation of China (Grant Nos. 81501463, 61471349, 81671853, 81571669, and 61671026), the National High Technology Research and Development Program of China (Grant No. 2015AA043203), the Natural Science Foundation of Beijing, China (Grant No. 7162112), Guangdong Innovative Research Team Program of China (Grant No. 2011S013), the Natural Science Foundation of Guangdong Province, China (Grant Nos. 2014A030310360 and 2014A0202015028), the Beijing Center for Mathematics and Information Interdisciplinary Sciences, Shenzhen Fundamental Research Program, China (Grant Nos. JCYJ201500731154850923 and JCYJ20140417113430665), Shenzhen High-level Oversea Talent Program, China (Grant No. KQJSCX20160301144248), and the Nanshan Technology Research Fund, China (Grant No. KC2014JSQN0001A).

Implement trigger for a NI data acquisition card PCI 5105 in the measurement studio development environment for a high speed demodulator based on fiber Fabry-Pérot tunable filter (FFP-TF)

NASA Astrophysics Data System (ADS)

Zhang, Hongtao; Yang, Shangming; Fan, Lingling; Wang, Pengfei; Zhao, Xilin; Wang, Zhenhua; Cui, Hong-Liang

2010-04-01

In this paper we report a scheme of low-cost, small-size differential electrical converter to change analog trigger signals into digital trigger signals. This converter successfully resolves the incompatibility between the digital trigger mode of NI (National Instruments) data acquisition card PCI 5105 in Measurement Studio development environment for a demodulator and the requirement from instability of spectra of fiber Bragg grating (FBG) sensors. The instability is caused by intrinsic drifts of FFP-TF inside this high speed demodulator. The obtained results of frequency response about the converter have clearly demonstrated that this method is effective when the frequency of trigger signal is less than 3,000 Hz. This converter can satisfy the current requirements of demodulator based on FFP-TF, since mostly actual working scanning frequency of FFP-TF is less than 1,000 Hz. This method may be recommended to resolve similar problems for other NI customers who have developed their data acquisition system based on Measurement Studio.

Non-T cell activation linker (NTAL) proteolytic cleavage as a terminator of activatory intracellular signals.

PubMed

Arbulo-Echevarria, Mikel M; Muñoz-Miranda, Juan Pedro; Caballero-García, Andrés; Poveda-Díaz, José L; Fernández-Ponce, Cecilia; Durán-Ruiz, M Carmen; Miazek, Arkadiusz; García-Cózar, Francisco; Aguado, Enrique

2016-08-01

Non-T cell activation linker is an adaptor protein that is tyrosine phosphorylated upon cross-linking of immune receptors expressed on B lymphocytes, NK cells, macrophages, basophils, or mast cells, allowing the recruitment of cytosolic mediators for downstream signaling pathways. Fas receptor acts mainly as a death receptor, and when cross-linked with Fas ligand, many proteins are proteolytically cleaved, including several signaling molecules in T and B cells. Fas receptor triggering also interferes with TCR intracellular signals, probably by means of proteolytic cleavage of several adaptor proteins. We have previously found that the adaptor linker for activation of T cells, evolutionarily related to non-T cell activation linker, is cleaved upon proapoptotic stimuli in T lymphocytes and thymocytes, in a tyrosine phosphorylation-dependent fashion. Here, we describe non-T cell activation linker proteolytic cleavage triggered in human B cells and monocytes by Fas cross-linking and staurosporine treatment. Non-T cell activation linker is cleaved, producing an N-terminal fragment of ∼22 kDa, and such cleavage is abrogated in the presence of caspase 8/granzyme B and caspase 3 inhibitors. Moreover, we have identified an aspartic acid residue at which non-T cell activation linker is cleaved, which similar to linker for activation of T cells, this aspartic acid residue is located close to tyrosine and serine residues, suggesting an interdependence of phosphorylation and proteolytic cleavage. Consistently, induction of non-T cell activation linker phosphorylation by pervanadate inhibits its cleavage. Interestingly, the truncated isoform of non-T cell activation linker, generated after cleavage, has a decreased signaling ability when compared with the full-length molecule. Altogether, our results suggest that cleavage of transmembrane adaptors constitutes a general mechanism for signal termination of immune receptors. © Society for Leukocyte Biology.

Nickel impact on human health: An intrinsic disorder perspective.

PubMed

Zambelli, Barbara; Uversky, Vladimir N; Ciurli, Stefano

2016-12-01

The interplay of the presence of nickel and protein disorder in processes affecting human health is the focus of the present review. Many systems involving nickel as either a cofactor or as a toxic contaminant are characterized by large disorder. The role of nickel in the biochemistry of bacterial enzymes is discussed here, covering both the beneficial effects of nickel in the human microbiota as well as the role of nickel-depending bacteria in human pathogenesis. In addition, the hazardous health effects caused by nickel exposure to humans, namely nickel-induced carcinogenesis and allergy, are triggered by non-specific interactions of nickel with macromolecules and formation of reactive compounds that mediate cellular damage. Cellular response to nickel is also related to signal transduction cascades. This review thus highlights the most promising systems for future studies aimed at decreasing the adverse effects of nickel on human health. Copyright © 2016 Elsevier B.V. All rights reserved.

Induction of group A Streptococcus virulence by a human antimicrobial peptide.

PubMed

Gryllos, Ioannis; Tran-Winkler, Hien J; Cheng, Ming-Fang; Chung, Hachung; Bolcome, Robert; Lu, Wuyuan; Lehrer, Robert I; Wessels, Michael R

2008-10-28

Group A streptococci (Streptococcus pyogenes or GAS) freshly isolated from individuals with streptococcal sore throat or invasive ("flesh-eating") infection often grow as mucoid colonies on primary culture but lose this colony appearance after laboratory passage. The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence determinant associated with severe GAS infections. These observations suggest that signal(s) from the human host trigger increased production of capsule and perhaps other virulence factors during infection. Here we show that subinhibitory concentrations of the human antimicrobial cathelicidin peptide LL-37 stimulate expression of the GAS capsule synthesis operon (hasABC). Up-regulation is mediated by the CsrRS 2-component regulatory system: it requires a functional CsrS sensor protein and can be antagonized by increased extracellular Mg(2+), the other identified environmental signal for CsrS. Up-regulation was also evident for other CsrRS-regulated virulence genes, including the IL-8 protease PrtS/ScpC and the integrin-like/IgG protease Mac/IdeS, findings that suggest a coordinated GAS virulence response elicited by this antimicrobial immune effector peptide. LL-37 signaling through CsrRS led to a marked increase in GAS resistance to opsonophagocytic killing by human leukocytes, an in vitro measure of enhanced GAS virulence, consistent with increased expression of the antiphagocytic capsular polysaccharide and Mac/IdeS. We propose that the human cathelicidin LL-37 has the paradoxical effect of stimulating CsrRS-regulated virulence gene expression, thereby enhancing GAS pathogenicity during infection. The ability of GAS to sense and respond to LL-37 may explain, at least in part, the unique susceptibility of the human species to streptococcal infection.

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

PubMed Central

Besch, Robert; Poeck, Hendrik; Hohenauer, Tobias; Senft, Daniela; Häcker, Georg; Berking, Carola; Hornung, Veit; Endres, Stefan; Ruzicka, Thomas; Rothenfusser, Simon; Hartmann, Gunther

2009-01-01

The retinoic acid–inducible gene I (RIG-I) and melanoma differentiation–associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs. Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I– and MDA-5–initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-xL rescued nonmalignant, but not melanoma, cells from RIG-I– and MDA-5–mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-xL, results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis. PMID:19620789

Peanut lipids display potential adjuvanticity by triggering a pro-inflammatory response in human keratinocytes.

PubMed

Palladino, C; Narzt, M S; Bublin, M; Schreiner, M; Humeniuk, P; Gschwandtner, M; Hafner, C; Hemmer, W; Hoffmann-Sommergruber, K; Mildner, M; Palomares, O; Gruber, F; Breiteneder, H

2018-05-10

Currently, the earliest cellular and molecular signals driving allergic sensitization to peanuts are not fully understood, even though peanut allergens have been studied extensively. Meanwhile, lipids contained within allergen sources are emerging as players in the pathogenesis of allergies. Exposure of infants to peanut oil-containing lotions was described as a risk factor for the development of peanut allergy (1). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake.

PubMed

Truttmann, Matthias C; Misselwitz, Benjamin; Huser, Sonja; Hardt, Wolf-Dietrich; Critchley, David R; Dehio, Christoph

2011-11-01

The VirB/D4 type IV secretion system (T4SS) of the bacterial pathogen Bartonella henselae (Bhe) translocates seven effector proteins (BepA-BepG) into human cells that subvert host cellular functions. Two redundant pathways dependent on BepG or the combination of BepC and BepF trigger the formation of a bacterial uptake structure termed the invasome. Invasome formation is a multi-step process consisting of bacterial adherence, effector translocation, aggregation of bacteria on the cell surface and engulfment, and eventually, complete internalization of the bacterial aggregate occurs in an F-actin-dependent manner. In the present study, we show that Bhe-triggered invasome formation depends on integrin-β1-mediated signaling cascades that enable assembly of the F-actin invasome structure. We demonstrate that Bhe interacts with integrin β1 in a fibronectin- and VirB/D4 T4SS-independent manner and that activated integrin β1 is essential for both effector translocation and the actin rearrangements leading to invasome formation. Furthermore, we show that talin1, but not talin2, is required for inside-out activation of integrin β1 during invasome formation. Finally, integrin-β1-mediated outside-in signaling by FAK, Src, paxillin and vinculin is necessary for invasome formation. This is the first example of a bacterial entry process that fully exploits the bi-directional signaling capacity of integrin receptors in a talin1-specific manner.

Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

PubMed Central

Liu, Ting; Men, Qiuxu; Wu, Guixian; Yu, Chunrong; Huang, Zan; Liu, Xin; Li, Wenhua

2015-01-01

All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells. PMID:25797266

A Simple Power Law Governs Many Sensory Amplifications and Multisensory Enhancements.

PubMed

Billock, Vincent A; Havig, Paul R

2018-05-16

When one sensory response occurs in the presence of a different sensory stimulation, the sensory response is often amplified. The variety of sensory enhancement data tends to obscure the underlying rules, but it has long been clear that weak signals are usually amplified more than strong ones (the Principle of Inverse Effectiveness). Here we show that for many kinds of sensory amplification, the underlying law is simple and elegant: the amplified response is a power law of the unamplified response, with a compressive exponent that amplifies weak signals more than strong. For both psychophysics and cortical electrophysiology, for both humans and animals, and for both sensory integration and enhancement within a sense, gated power law amplification (amplification of one sense triggered by the presence of a different sensory signal) is often sufficient to explain sensory enhancement.

An FPGA-based trigger for the phase II of the MEG experiment

NASA Astrophysics Data System (ADS)

Baldini, A.; Bemporad, C.; Cei, F.; Galli, L.; Grassi, M.; Morsani, F.; Nicolò, D.; Ritt, S.; Venturini, M.

2016-07-01

For the phase II of MEG, we are going to develop a combined trigger and DAQ system. Here we focus on the former side, which operates an on-line reconstruction of detector signals and event selection within 450 μs from event occurrence. Trigger concentrator boards (TCB) are under development to gather data from different crates, each connected to a set of detector channels, to accomplish higher-level algorithms to issue a trigger in the case of a candidate signal event. We describe the major features of the new system, in comparison with phase I, as well as its performances in terms of selection efficiency and background rejection.

Sensitive detection of point mutation using exponential strand displacement amplification-based surface enhanced Raman spectroscopy.

PubMed

Huang, Si-Qiang; Hu, Juan; Zhu, Guichi; Zhang, Chun-Yang

2015-03-15

Accurate identification of point mutation is particularly imperative in the field of biomedical research and clinical diagnosis. Here, we develop a sensitive and specific method for point mutation assay using exponential strand displacement amplification (SDA)-based surface enhanced Raman spectroscopy (SERS). In this method, a discriminating probe and a hairpin probe are designed to specifically recognize the sequence of human K-ras gene. In the presence of K-ras mutant target (C→T), the 3'-terminal of discriminating probe and the 5'-terminal of hairpin probe can be ligated to form a SDA template. Subsequently, the 3'-terminal of hairpin probe can function as a primer to initiate the SDA reaction, producing a large amount of triggers. The resultant triggers can further hybridize with the discriminating probes to initiate new rounds of SDA reaction, leading to an exponential amplification reaction. With the addition of capture probe-modified gold nanoparticles (AuNPs) and the Rox-labeled reporter probes, the amplified triggers can be assembled on the surface of AuNPs through the formation of sandwich hybrids of capture probe-trigger-reporter probe, generating a strong Raman signal. While in the presence of K-ras wild-type target (C), neither ligation nor SDA reaction can be initiated and no Raman signal is observed. The proposed method exhibits high sensitivity with a detection limit of 1.4pM and can accurately discriminate as low as 1% variant frequency from the mixture of mutant target and wild-type target. Importantly, this method can be further applied to analyze the mutant target in the spiked HEK293T cell lysate, holding great potential for genetic analysis and disease prognosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Glucose-Based Peritoneal Dialysis Fluids Downregulate Toll-Like Receptors and Trigger Hyporesponsiveness to Pathogen-Associated Molecular Patterns in Human Peritoneal Mesothelial Cells▿

PubMed Central

Wu, Jun; Yang, Xiao; Zhang, Yun-Fang; Wang, Ya-Ning; Liu, Mei; Dong, Xiu-Qing; Fan, Jin-Jin; Yu, Xue-Qing

2010-01-01

The objective of this study was to investigate the effects of glucose-based peritoneal dialysis (PD) fluids and icodextrin-based PD fluids on the expression of Toll-like receptor 2 (TLR2)/TLR4 and subsequent ligand-induced mitogen-activated protein kinase (MAPK) and NF-κB signaling and tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) mRNA expression in human peritoneal mesothelial cells (HPMCs). A human peritoneal mesothelial cell line (HMrSV5) was stimulated with glucose-based and icodextrin-based peritoneal dialysis fluids. Cell viability was assessed using MTT [3-(4,5-dimethylthiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. TLR2/TLR4 expression was determined by real-time PCR, Western blotting, and an immunofluorescence assay. In addition, cells were pretreated with different PD solutions and then incubated with Pam3CSK4 or lipopolysaccharide (LPS), and the degrees of MAPK and NF-κB activation were reflected by detecting the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and p65, using a Western blot method. TNF-α and IL-1β mRNA expression was measured by real-time PCR. Glucose-based peritoneal dialysis fluids suppressed the expression of TLR2 and TLR4 proteins in HPMCs. Challenge of cells with either Pam3CSK4 or LPS resulted in impaired TNF-α and IL-1β production. Moreover, reduced TLR2 and TLR4 levels in glucose-based peritoneal dialysis solution-treated mesothelial cells were accompanied by reduced p42/44 (ERK1/2), JNK, p38 MAPK, and NF-κB p65 phosphorylation upon TLR ligand engagement. No significant changes in MAPK and NF-κB signaling and TNF-α and IL-1β mRNA expression were observed in icodextrin-based PD solution-treated mesothelial cells. Glucose-based PD solution, but not icodextrin-based PD solution, downregulates expression of TLR2/TLR4 by human peritoneal mesothelial cells and triggers hyporesponsiveness to pathogen-associated molecular patterns. PMID:20200188

Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.

PubMed

Chaabane, Wiem; Cieślar-Pobuda, Artur; El-Gazzah, Mohamed; Jain, Mayur V; Rzeszowska-Wolny, Joanna; Rafat, Mehrdad; Stetefeld, Joerg; Ghavami, Saeid; Los, Marek J

2014-09-01

The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Evaluation of Signaling Pathways Involved in γ-Globin Gene Induction Using Fetal Hemoglobin Inducer Drugs.

PubMed

Rahim, Fakher; Allahmoradi, Hossein; Salari, Fatemeh; Shahjahani, Mohammad; Fard, Ali Dehghani; Hosseini, Seyed Ahmad; Mousakhani, Hadi

2013-01-01

Potent induction of fetal hemoglobin (HbF) production results in alleviating the complications of β-thalassemia and sickle cell disease (SCD). HbF inducer agents can trigger several molecular signaling pathways critical for erythropoiesis. Janus kinase/Signal transducer and activator of transcription (JAK/STAT), mitogen activated protein kinas (MAPK) and Phosphoinositide 3-kinase (PI3K) are considered as main signaling pathways, which may play a significant role in HbF induction. All these signaling pathways are triggered by erythropoietin (EPO) as the main growth factor inducing erythroid differentiation, when it binds to its cell surface receptor, erythropoietin receptor (EPO-R) HbF inducer agents have been shown to upregulate HbF production level by triggering certain signaling pathways. As a result, understanding the pivotal signaling pathways influencing HbF induction leads to effective upregulation of HbF. In this mini review article, we try to consider the correlation between HbF inducer agents and their molecular mechanisms of γ-globin upregulation. Several studies suggest that activating P38 MAPK, RAS and STAT5 signaling pathways result in efficient HbF induction. Nevertheless, the role of other erythroid signaling pathways in HbF induction seems to be indispensible and should be emphasized.

Neurotrophic factors switch between two signaling pathways that trigger axonal growth.

PubMed

Paveliev, Mikhail; Lume, Maria; Velthut, Agne; Phillips, Matthew; Arumäe, Urmas; Saarma, Mart

2007-08-01

Integration of multiple inputs from the extracellular environment, such as extracellular matrix molecules and growth factors, is a crucial process for cell function and information processing in multicellular organisms. Here we demonstrate that co-stimulation of dorsal root ganglion neurons with neurotrophic factors (NTFs) - glial-cell-line-derived neurotrophic factor, neurturin or nerve growth factor - and laminin leads to axonal growth that requires activation of Src family kinases (SFKs). A different, SFK-independent signaling pathway evokes axonal growth on laminin in the absence of the NTFs. By contrast, axonal branching is regulated by SFKs both in the presence and in the absence of NGF. We propose and experimentally verify a Boolean model of the signaling network triggered by NTFs and laminin. Our results demonstrate that NTFs provide an environmental cue that triggers a switch between separate pathways in the cell signaling network.

Transcriptomic profiles of human foreskin fibroblast cells in response to orf virus.

PubMed

Chen, Daxiang; Long, Mingjian; Xiao, Bin; Xiong, Yufeng; Chen, Huiqin; Chen, Yu; Kuang, Zhenzhan; Li, Ming; Wu, Yingsong; Rock, Daniel L; Gong, Daoyuan; Wang, Yong; He, Haijian; Liu, Fang; Luo, Shuhong; Hao, Wenbo

2017-08-29

Orf virus has been utilized as a safe and efficient viral vector against not only diverse infectious diseases, but also against tumors. However, the nature of the genes triggered by the vector in human cells is poorly characterized. Using RNA sequencing technology, we compared specific changes in the transcriptomic profiles in human foreskin fibroblast cells following infection by the orf virus. The results indicated that orf virus upregulates or downregulates expression of a variety of genes, including genes involved in antiviral immune response, apoptosis, cell cycle and a series of signaling pathways, such as the IFN and p53-signaling pathways. The orf virus stimulates or inhibits immune gene expression such as chemokines, chemokine receptors, cytokines, cytokine receptors, and molecules involved in antigen uptake and processing after infection. Expression of pro-apoptotic genes increased at 8 hours post-infection. The p53 signaling pathway was activated to induce apoptosis at the same time. However, the cell cycle program was promoted after infection, which may be due to the immunomodulatory genes of the orf virus. This presents the first description of transcription profile changes in human foreskin fibroblast cells after orf virus infection and provides an in-depth analysis of the interaction between the host and orf virus. These data offer new insights into the understanding of the mechanisms of infection by orf virus and identify potential targets for future studies.

Human papilloma virus infection and psoriasis: Did human papilloma virus infection trigger psoriasis?

PubMed

Jain, Sonia P; Gulhane, Sachin; Pandey, Neha; Bisne, Esha

2015-01-01

Psoriasis is an autoimmune chronic inflammatory skin disease known to be triggered by streptococcal and HIV infections. However, human papilloma virus infection (HPV) as a triggering factor for the development of psoriasis has not been reported yet. We, hereby report a case of plaque type with inverse psoriasis which probably could have been triggered by genital warts (HPV infection) and discuss the possible pathomechanisms for their coexistence and its management.

Direct Comparison of Respiration-Correlated Four-Dimensional Magnetic Resonance Imaging Reconstructed Using Concurrent Internal Navigator and External Bellows.

PubMed

Li, Guang; Wei, Jie; Olek, Devin; Kadbi, Mo; Tyagi, Neelam; Zakian, Kristen; Mechalakos, James; Deasy, Joseph O; Hunt, Margie

2017-03-01

To compare the image quality of amplitude-binned 4-dimensional magnetic resonance imaging (4DMRI) reconstructed using 2 concurrent respiratory (navigator and bellows) waveforms. A prospective, respiratory-correlated 4DMRI scanning program was used to acquire T2-weighted single-breath 4DMRI images with internal navigator and external bellows. After a 10-second training waveform of a surrogate signal, 2-dimensional MRI acquisition was triggered at a level (bin) and anatomic location (slice) until the bin-slice table was completed for 4DMRI reconstruction. The bellows signal was always collected, even when the navigator trigger was used, to retrospectively reconstruct a bellows-rebinned 4DMRI. Ten volunteers participated in this institutional review board-approved 4DMRI study. Four scans were acquired for each subject, including coronal and sagittal scans triggered by either navigator or bellows, and 6 4DMRI images (navigator-triggered, bellows-rebinned, and bellows-triggered) were reconstructed. The simultaneously acquired waveforms and resulting 4DMRI quality were compared using signal correlation, bin/phase shift, and binning motion artifacts. The consecutive bellows-triggered 4DMRI scan was used for indirect comparison. Correlation coefficients between the navigator and bellows signals were found to be patient-specific and inhalation-/exhalation-dependent, ranging from 0.1 to 0.9 because of breathing irregularities (>50% scans) and commonly observed bin/phase shifts (-1.1 ± 0.6 bin) in both 1-dimensional waveforms and diaphragm motion extracted from 4D images. Navigator-triggered 4DMRI contained many fewer binning motion artifacts at the diaphragm than did the bellows-rebinned and bellows-triggered 4DMRI scans. Coronal scans were faster than sagittal scans because of the fewer slices and higher achievable acceleration factors. Navigator-triggered 4DMRI contains substantially fewer binning motion artifacts than bellows-rebinned and bellows-triggered 4DMRI, primarily owing to the deviation of the external from the internal surrogate. The present study compared 2 concurrent surrogates during the same 4DMRI scan and their resulting 4DMRI quality. The navigator-triggered 4DMRI scanning protocol should be preferred to the bellows-based, especially for coronal scans, for clinical respiratory motion simulation. Copyright © 2016 Elsevier Inc. All rights reserved.

The life span-prolonging effect of sirtuin-1 is mediated by autophagy.

PubMed

Morselli, Eugenia; Maiuri, Maria Chiara; Markaki, Maria; Megalou, Evgenia; Pasparaki, Angela; Palikaras, Konstantinos; Criollo, Alfredo; Galluzzi, Lorenzo; Malik, Shoaib Ahmad; Vitale, Ilio; Michaud, Mickael; Madeo, Frank; Tavernarakis, Nektarios; Kroemer, Guido

2010-01-01

The life span of various model organisms can be extended by caloric restriction as well as by autophagy-inducing pharmacological agents. Life span-prolonging effects have also been observed in yeast cells, nematodes and flies upon the overexpression of the deacetylase Sirtuin-1. Intrigued by these observations and by the established link between caloric restriction and Sirtuin-1 activation, we decided to investigate the putative implication of Sirtuin-1 in the response of human cancer cells and Caenorhabditis elegans to multiple triggers of autophagy. Our data indicate that the activation of Sirtuin-1 (by the pharmacological agent resveratrol and/or genetic means) per se ignites autophagy, and that Sirtuin-1 is required for the autophagic response to nutrient deprivation, in both human and nematode cells, but not for autophagy triggered by downstream signals such as the inhibition of mTOR or p53. Since the life spanextending effects of Sirtuin-1 activators are lost in autophagy-deficient C. elegans, our results suggest that caloric restriction and resveratrol extend longevity, at least in experimental settings, by activating autophagy.

Optimising diffusion-weighted MR imaging for demonstrating pancreatic cancer: a comparison of respiratory-triggered, free-breathing and breath-hold techniques.

PubMed

Kartalis, Nikolaos; Loizou, Louiza; Edsborg, Nick; Segersvärd, Ralf; Albiin, Nils

2012-10-01

To compare respiratory-triggered, free-breathing, and breath-hold DWI techniques regarding (1) image quality, and (2) signal intensity (SI) and ADC measurements in pancreatic ductal adenocarcinoma (PDAC). Fifteen patients with histopathologically proven PDAC underwent DWI prospectively at 1.5 T (b = 0, 50, 300, 600 and 1,000 s/mm(2)) with the three techniques. Two radiologists, independently and blindly, assigned total image quality scores [sum of rating diffusion images (lesion detection, anatomy, presence of artefacts) and ADC maps (lesion characterisation, overall image quality)] per technique and ranked them. The lesion SI, signal-to-noise ratio, mean ADC and coefficient of variation (CV) were compared. Total image quality scores for respiratory-triggered, free-breathing and breath-hold techniques were 17.9, 16.5 and 17.1 respectively (respiratory-triggered was significantly higher than free-breathing but not breath-hold). The respiratory-triggered technique had a significantly higher ranking. Lesion SI on all b-values and signal-to-noise ratio on b300 and b600 were significantly higher for the respiratory-triggered technique. For respiratory-triggered, free-breathing and breath-hold techniques the mean ADCs were 1.201, 1.132 and 1.253 × 10(-3) mm(2)/s, and mean CVs were 8.9, 10.8 and 14.1 % respectively (respiratory-triggered and free-breathing techniques had a significantly lower mean CV than the breath-hold technique). In both analyses, respiratory-triggered DWI showed superiority and seems the optimal DWI technique for demonstrating PDAC. • Diffusion-weighted magnetic resonance imaging is increasingly used to detect pancreatic cancer • Images are acquired using various breathing techniques and multiple b-values • Breathing techniques used: respiratory-triggering, free-breathing and breath-hold • Respiratory-triggering seems the optimal breathing technique for demonstrating pancreatic cancer.

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.

PubMed

Knies, Nathalie; Alankus, Begüm; Weilemann, Andre; Tzankov, Alexandar; Brunner, Kristina; Ruff, Tanja; Kremer, Marcus; Keller, Ulrich B; Lenz, Georg; Ruland, Jürgen

2015-12-29

The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

LIGO Triggered Search for Coincidence with High Energy Photon Survey Missions

NASA Technical Reports Server (NTRS)

Camp, Jordan

2009-01-01

LIGO is about to begin a new, higher sensitivity science run, where gravitational detection is plausible. A possible candidate for detection is a compact binary merger, which would also be likely to emit a high energy electromagnetic signal. Coincident observation of the gw signal from a compact merger with an x-ray or gamma-ray signal would add considerable weight to the claim for gw detection. In this talk I will consider the possibility of using LIGO triggers with time and sky position to perform a coincident analysis of EM signals from the RXTE, SWIFT, and FERMI missions.

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

PubMed Central

Cha, Jeeyeon; Yuan, Jia; Haraguchi, Hirofumi; Bartos, Amanda; Bradshaw, Heather B.; Hirota, Yasushi; Dey, Sudhansu K.

2016-01-01

Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB. PMID:27454290

Detrimental effects of adenosine signaling in sickle cell disease

PubMed Central

Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Lijian; Lu, Guangxiu; Alexander, Danny C; Milburn, Michael V; Carter-Dawson, Louvenia; Lewis, Dorothy E; Zhang, Wenzheng; Eltzschig, Holger K; Kellems, Rodney E; Blackburn, Michael R; Juneja, Harinder S; Xia, Yang

2016-01-01

Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A2B receptor (A2BR)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A2BR has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease. PMID:21170046

Detrimental effects of adenosine signaling in sickle cell disease.

PubMed

Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Lijian; Lu, Guangxiu; Alexander, Danny C; Milburn, Michael V; Carter-Dawson, Louvenia; Lewis, Dorothy E; Zhang, Wenzheng; Eltzschig, Holger K; Kellems, Rodney E; Blackburn, Michael R; Juneja, Harinder S; Xia, Yang

2011-01-01

Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.

Activation of human herpesvirus replication by apoptosis.

PubMed

Prasad, Alka; Remick, Jill; Zeichner, Steven L

2013-10-01

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance.

Activation of Human Herpesvirus Replication by Apoptosis

PubMed Central

Prasad, Alka; Remick, Jill

2013-01-01

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance. PMID:23885073

Implementation of a custom time-domain firmware trigger for RADAR-based cosmic ray detection

NASA Astrophysics Data System (ADS)

Prohira, S.; Besson, D.; Kunwar, S.; Ratzlaff, K.; Young, R.

2018-05-01

Interest in Radio-based detection schemes for ultra-high energy cosmic rays (UHECR) has surged in recent years, owing to the potentially very low cost/detection ratio. The method of radio-frequency (RF) scatter has been proposed as potentially the most economical detection technology. Though the first dedicated experiment to employ this method, the Telescope Array RADAR experiment (TARA) reported no signal, efforts to develop more robust and sensitive trigger techniques continue. This paper details the development of a time-domain firmware trigger that exploits characteristics of the expected scattered signal from an UHECR extensive-air shower (EAS). The improved sensitivity of this trigger is discussed, as well as implementation in two separate field deployments from 2016 to 2017.

Type I interferon (IFN-alpha/beta) rescues B-lymphocytes from apoptosis via PI3Kdelta/Akt, Rho-A, NFkappaB and Bcl-2/Bcl(XL).

PubMed

Badr, Gamal; Saad, Heba; Waly, Hanan; Hassan, Khadega; Abdel-Tawab, Hanem; Alhazza, Ibrahim M; Ahmed, Emad A

2010-01-01

Although IFN-alpha was reported to promote the survival of peripheral B-lymphocytes via the PI3-kinase-Akt pathway, the triggered signalling pathways involved in the protection of B cell from apoptosis need to be clarified. Using flow cytometry and western blot analysis, we have found that type 1 IFNs (IFN-alpha/beta) protect human B cells in culture from spontaneous apoptosis and from apoptosis mediated by anti-CD95 agonist, in a dose- and time-dependant manner. IFN-alpha/beta-mediated anti-apoptotic effect on human B cells was totally abrogated by blockade of IFNR1 chain. Our data indicate that PI3Kdelta, Rho-A, NFkappaB and Bcl-2/Bcl(XL) are active downstream of IFN receptors and are the major effectors of IFN-alpha/beta-rescued B cells from apoptosis. Furthermore, immunohistochemical results show marked reduction in numbers of CD20 positive B cell in both spleen and Peyer's patches from mice treated with anti-IFNR1 blocking antibody compared with control group. Moreover, ultrastructural observations of these organs show an obvious increase in apoptotic cells from mice treated with anti-IFNR1 blocking antibody. Our results provide more details about the triggered signalling pathways and the phosphorylation cascade which are involved in the protection of B cell from apoptosis after treatment with IFN-alpha/beta. Copyright 2010 Elsevier Inc. All rights reserved.

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

PubMed Central

Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla; Bátkai, Sándor; Park, Ogyi; Tanashian, Galin; Gao, Rachel Y; Patel, Vivek; Wink, David A.; Liaudet, Lucas; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2011-01-01

Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors. PMID:21362471

The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival

PubMed Central

Hardonnière, Kévin; Saunier, Elise; Lemarié, Anthony; Fernier, Morgane; Gallais, Isabelle; Héliès-Toussaint, Cécile; Mograbi, Baharia; Antonio, Samantha; Bénit, Paule; Rustin, Pierre; Janin, Maxime; Habarou, Florence; Ottolenghi, Chris; Lavault, Marie-Thérèse; Benelli, Chantal; Sergent, Odile; Huc, Laurence; Bortoli, Sylvie; Lagadic-Gossmann, Dominique

2016-01-01

Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration). PMID:27488617

Plasma membrane order and fluidity are diversely triggered by elicitors of plant defence

PubMed Central

Sandor, Roman; Der, Christophe; Grosjean, Kevin; Anca, Iulia; Noirot, Elodie; Leborgne-Castel, Nathalie; Lochman, Jan; Simon-Plas, Françoise; Gerbeau-Pissot, Patricia

2016-01-01

Although plants are exposed to a great number of pathogens, they usually defend themselves by triggering mechanisms able to limit disease development. Alongside signalling events common to most such incompatible interactions, modifications of plasma membrane (PM) physical properties could be new players in the cell transduction cascade. Different pairs of elicitors (cryptogein, oligogalacturonides, and flagellin) and plant cells (tobacco and Arabidopsis) were used to address the issue of possible modifications of plant PM biophysical properties induced by elicitors and their links to other events of the defence signalling cascade. We observed an increase of PM order whatever the elicitor/plant cell pair used, provided that a signalling cascade was induced. Such membrane modification is dependent on the NADPH oxidase-mediated reactive oxygen species production. Moreover, cryptogein, which is the sole elicitor able to trap sterols, is also the only one able to trigger an increase in PM fluidity. The use of cryptogein variants with altered sterol-binding properties confirms the strong correlation between sterol removal from the PM and PM fluidity enhancement. These results propose PM dynamics as a player in early signalling processes triggered by elicitors of plant defence. PMID:27604805

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome.

PubMed

Chung, Lawton K; Park, Yong Hwan; Zheng, Yueting; Brodsky, Igor E; Hearing, Patrick; Kastner, Daniel L; Chae, Jae Jin; Bliska, James B

2016-09-14

Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Clonidine Induces Apoptosis of Human Corneal Epithelial Cells through Death Receptors-Mediated, Mitochondria-Dependent Signaling Pathway.

PubMed

Fan, Dan; Fan, Ting-Jun

2017-03-01

Clonidine, an α2-adrenoreceptor agonist, is an anti-glaucoma drug clinically used in many developing countries, and its abuse might damage the cornea and impair human vision. However, its cytotoxicity and precise mechanisms need to be elucidated. Herein, we investigated the cytotoxicity of clonidine and its underlying mechanisms, using an in vitro model of human corneal epithelial (HCEP) cells and an in vivo model of cat corneas, respectively. HCEP cells were treated with various doses of clonidine for 1-28 h, resulting in abnormal morphology, decline of cell viability and G1 phase arrest in a time- and/or dose-dependent manner. Moreover, clonidine treatment induced elevation of plasma membrane permeability, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation in HCEP cells. Furthermore, we found that clonidine treatment resulted in activated caspase-2, -3, -8, and -9, disruption of the mitochondrial transmembrane potential, downregulation of Bcl-2, and upregulation of Bad, cytoplasmic cytochrome c and apoptosis inducing factor, suggesting that clonidine-induced apoptosis is triggered through Fas/TNFR1 death receptors and Bcl-2 family proteins-mediated mitochondria-dependent pathways. Finally, our in vivo results displayed that 0.25% clonidine could induce DNA fragmentation of cat corneal epithelial cells. In summary, our findings suggest that clonidine above 1/32 of its clinical therapeutic dosage is cytotoxic to corneal epithelial cells by inducing cell apoptosis both in vitro and in vivo, and its pro-apoptotic effect on HCEP cells is triggered by a Fas/TNFR1 death receptors-mediated, mitochondria-dependent signaling pathway. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Studies on fast triggering and high precision tracking with Resistive Plate Chambers

NASA Astrophysics Data System (ADS)

Aielli, G.; Ball, R.; Bilki, B.; Chapman, J. W.; Cardarelli, R.; Dai, T.; Diehl, E.; Dubbert, J.; Ferretti, C.; Feng, H.; Francis, K.; Guan, L.; Han, L.; Hou, S.; Levin, D.; Li, B.; Liu, L.; Paolozzi, L.; Repond, J.; Roloff, J.; Santonico, R.; Song, H. Y.; Wang, X. L.; Wu, Y.; Xia, L.; Xu, L.; Zhao, T.; Zhao, Z.; Zhou, B.; Zhu, J.

2013-06-01

We report on studies of fast triggering and high precision tracking using Resistive Plate Chambers (RPCs). Two beam tests were carried out with the 180 GeV/c muon beam at CERN using glass RPCs with gas gaps of 1.15 mm and equipped with readout strips with 1.27 mm pitch. This is the first beam test of RPCs with fine-pitch readout strips that explores precision tracking and triggering capabilities. RPC signals were acquired with precision timing and charge integrating readout electronics at both ends of the strips. The time resolution was measured to be better than 600 ps and the average spatial resolution was found to be 220 μm using charge information and 287 μm only using signal arrival time information. The dual-ended readout allows the determination of the average and the difference of the signal arrival times. The average time was found to be independent of the incident particle position along the strip and is useful for triggering purposes. The time difference yielded a determination of the hit position with a precision of 7.5 mm along the strip. These results demonstrate the feasibility using RPCs for fast and high-resolution triggering and tracking.

The Level 0 Pixel Trigger system for the ALICE experiment

NASA Astrophysics Data System (ADS)

Aglieri Rinella, G.; Kluge, A.; Krivda, M.; ALICE Silicon Pixel Detector project

2007-01-01

The ALICE Silicon Pixel Detector contains 1200 readout chips. Fast-OR signals indicate the presence of at least one hit in the 8192 pixel matrix of each chip. The 1200 bits are transmitted every 100 ns on 120 data readout optical links using the G-Link protocol. The Pixel Trigger System extracts and processes them to deliver an input signal to the Level 0 trigger processor targeting a latency of 800 ns. The system is compact, modular and based on FPGA devices. The architecture allows the user to define and implement various trigger algorithms. The system uses advanced 12-channel parallel optical fiber modules operating at 1310 nm as optical receivers and 12 deserializer chips closely packed in small area receiver boards. Alternative solutions with multi-channel G-Link deserializers implemented directly in programmable hardware devices were investigated. The design of the system and the progress of the ALICE Pixel Trigger project are described in this paper.

EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion

PubMed Central

Sugiyama, Nami; Gucciardo, Erika; Tatti, Olga; Varjosalo, Markku; Hyytiäinen, Marko; Gstaiger, Matthias

2013-01-01

Changes in EphA2 signaling can affect cancer cell–cell communication and motility through effects on actomyosin contractility. However, the underlying cell–surface interactions and molecular mechanisms of how EphA2 mediates these effects have remained unclear. We demonstrate here that EphA2 and membrane-anchored membrane type-1 matrix metalloproteinase (MT1-MMP) were selectively up-regulated and coexpressed in invasive breast carcinoma cells, where, upon physical interaction in same cell–surface complexes, MT1-MMP cleaved EphA2 at its Fibronectin type-III domain 1. This cleavage, coupled with EphA2-dependent Src activation, triggered intracellular EphA2 translocation, as well as an increase in RhoA activity and cell junction disassembly, which suggests an overall repulsive effect between cells. Consistent with this, cleavage-prone EphA2-D359I mutant shifted breast carcinoma cell invasion from collective to rounded single-cell invasion within collagen and in vivo. Up-regulated MT1-MMP also codistributed with intracellular EphA2 in invasive cells within human breast carcinomas. These results reveal a new proteolytic regulatory mechanism of cell–cell signaling in cancer invasion. PMID:23629968

Controlling gain one photon at a time

PubMed Central

Schwartz, Gregory W; Rieke, Fred

2013-01-01

Adaptation is a salient property of sensory processing. All adaptational or gain control mechanisms face the challenge of obtaining a reliable estimate of the property of the input to be adapted to and obtaining this estimate sufficiently rapidly to be useful. Here, we explore how the primate retina balances the need to change gain rapidly and reliably when photons arrive rarely at individual rod photoreceptors. We find that the weakest backgrounds that decrease the gain of the retinal output signals are similar to those that increase human behavioral threshold, and identify a novel site of gain control in the retinal circuitry. Thus, surprisingly, the gain of retinal signals begins to decrease essentially as soon as background lights are detectable; under these conditions, gain control does not rely on a highly averaged estimate of the photon count, but instead signals from individual photon absorptions trigger changes in gain. DOI: http://dx.doi.org/10.7554/eLife.00467.001 PMID:23682314

Involvement of nuclear factor κB in platelet CD40 signaling.

PubMed

Hachem, Ahmed; Yacoub, Daniel; Zaid, Younes; Mourad, Walid; Merhi, Yahye

2012-08-17

CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to potentiate platelet activation and aggregation, in a CD40-dependent manner, via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In many cells, the CD40L/CD40 dyad also induces activation of nuclear factor kappa B (NF-κB). Given that platelets contain NF-κB, we hypothesized that it may be involved in platelet CD40 signaling and function. In human platelets, sCD40L induces association of CD40 with its adaptor protein the tumor necrosis factor receptor associated factor 2 and triggers phosphorylation of IκBα, which are abolished by CD40L blockade. Inhibition of IκBα phosphorylation reverses sCD40L-induced IκBα phosphorylation without affecting p38 MAPK phosphorylation. On the other hand, inhibition of p38 MAPK phosphorylation has no effect on IκBα phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. In functional studies, inhibition of IκBα phosphorylation reverses sCD40L-induced platelet activation and potentiation of platelet aggregation in response to a sub-threshold concentration of collagen. This study demonstrates that the sCD40L/CD40 axis triggers NF-κB activation in platelets. This signaling pathway plays a critical role in platelet activation and aggregation upon sCD40L stimulation and may represent an important target against thrombo-inflammatory disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

The Essential Role of Double-Stranded RNA-Dependent Antiviral Signaling in the Degradation of Nonself Single-Stranded RNA in Nonimmune Cells.

PubMed

Kimura, Sayaka; Matsumiya, Tomoh; Shiba, Yuko; Nakanishi, Michi; Hayakari, Ryo; Kawaguchi, Shogo; Yoshida, Hidemi; Imaizumi, Tadaatsu

2018-06-20

The recognition of nonself dsRNA by retinoic acid-inducible gene-I (RIG-I) leads to the engagement of RIG-I-like receptor signaling. In addition, nonself dsRNA triggers a robust latent RNase (RNase L) activation and leads to the degradation of ribosomal structures and cell death. In contrast, nonself ssRNA is known to be recognized by TLR 7/8 in immune cells such as plasmacytoid dendritic cells and B cells, but little is known regarding the involvement of nonself ssRNA in antiviral signaling in nonimmune cells, including epithelial cells. Moreover, the fate of intracellular nonself ssRNA remains unknown. To address this issue, we developed a quantitative RT-PCR-based approach that monitors the kinetics of nonself ssRNA cleavage following the transfection of HeLa human cervical carcinoma cells, using model nonself ssRNA. We discovered that the degradation of ssRNA is independent of RIG-I and type I IFN signaling because ssRNA did not trigger RIG-I-mediated antiviral signaling. We also found that the kinetics of self (5'-capped) and nonself ssRNA decay were unaltered, suggesting that nonself ssRNA is not recognized by nonimmune cells. We further demonstrated that the cleavage of nonself ssRNA is accelerated when nonself dsRNA is also introduced into cells. In addition, the cleavage of nonself ssRNA is completely abolished by knockdown of RNase L. Overall, our data demonstrate the important role of dsRNA-RNase L in nonself ssRNA degradation and may partly explain the positive regulation of the antiviral responses in nonimmune cells. Copyright © 2018 by The American Association of Immunologists, Inc.

Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways

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

Yang, Tsung-Yuan; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan; Yen, Cheng-Chieh

2016-03-01

Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic β-cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic β-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascadesmore » and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKα, and GSK3-α/β. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKα effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-α/β (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKα each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic β-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways. - Highlights: • Molybdenum (Mo) induces pancreatic β-cell dysfunction and apoptosis. • Mo causes β-cell death via mitochondria-dependent caspase cascades signals. • ER stress-triggered apoptotic pathway also regulates Mo-induced β-cell death. • Interdependent of JNK and AMPK activation involves in Mo-induced β-cell apoptosis.« less

Notch Promotes Dynamin-Dependent Endocytosis of Nephrin

PubMed Central

Waters, Aoife M.; Wu, Megan Yi Jun; Huang, Yi-Wei; Liu, Guang Ying; Holmyard, Doug; Onay, Tuncer; Jones, Nina; Egan, Sean E.; Robinson, Lisa A.

2012-01-01

Notch signaling in podocytes causes proteinuria and glomerulosclerosis in humans and rodents, but the underlying mechanism remains unknown. Here, we analyzed morphologic, molecular, and cellular events before the onset of proteinuria in newborn transgenic mice that express activated Notch in podocytes. Immunohistochemistry revealed a loss of the slit diaphragm protein nephrin exclusively in podocytes expressing activated Notch. Podocyte-specific deletion of Rbpj, which is essential for canonical Notch signaling, prevented this loss of nephrin. Overexpression of activated Notch decreased cell surface nephrin and increased cytoplasmic nephrin in transfected HEK293T cells; pharmacologic inhibition of dynamin, but not depletion of cholesterol, blocked these effects on nephrin, suggesting that Notch promotes dynamin-dependent, raft-independent endocytosis of nephrin. Supporting an association between Notch signaling and nephrin trafficking, electron microscopy revealed shortened podocyte foot processes and fewer slit diaphragms among the transgenic mice compared with controls. These data suggest that Notch signaling induces endocytosis of nephrin, thereby triggering the onset of proteinuria. PMID:22052054

Host-pathogen interaction in Fusarium oxysporum infections: where do we stand?

PubMed

Husaini, Amjad M; Sakina, Aafreen; Cambay, Souliha R

2018-03-16

Fusarium oxysporum, a ubiquitous soil-borne pathogen causes devastating vascular wilt in more than 100 plant species and ranks fifth among top ten fungal plant pathogens. It has emerged as a human pathogen too, causing infections in immune-compromised patients. It is, therefore, important to gain insight into the molecular processes involved in the pathogenesis of this trans-kingdom pathogen. A complex network comprising of interconnected and over lapping signal pathways; mitogen-activated protein kinase (MAPK) signaling pathways, Ras proteins, G-protein signaling components and their downstream pathways, components of the velvet (LaeA/VeA/VelB) complex and cAMP pathways, is involved in perceiving the host. This network regulates the expression of various pathogenicity genes. Plants have however evolved an elaborate protection system to combat this attack. They too possess intricate mechanisms at molecular level, which once triggered by pathogen attack transduce signals to activate defense response. This review focuses on understanding and presenting a wholistic picture of the molecular mechanisms of F. oxysporum-host interactions in plant immunity.

Hippo vs. Crab: tissue-specific functions of the mammalian Hippo pathway.

PubMed

Nishio, Miki; Maehama, Tomohiko; Goto, Hiroki; Nakatani, Keisuke; Kato, Wakako; Omori, Hirofumi; Miyachi, Yosuke; Togashi, Hideru; Shimono, Yohei; Suzuki, Akira

2017-01-01

The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic. © 2017 The Authors Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Leptin induces ADAMTS-4, ADAMTS-5, and ADAMTS-9 genes expression by mitogen-activated protein kinases and NF-ĸB signaling pathways in human chondrocytes.

PubMed

Yaykasli, Kursat Oguz; Hatipoglu, Omer Faruk; Yaykasli, Emine; Yildirim, Kubra; Kaya, Ertugrul; Ozsahin, Mustafa; Uslu, Mustafa; Gunduz, Esra

2015-01-01

Elucidation of the causes of inflammation has vital importance in the development of new approaches for the treatment of arthritic diseases. The degradation of aggrecan by upregulated disintegrin and metalloproteinase with trombospondin motifs (ADAMTSs) is the key event in the development of both rheumatoid arthritis (RA) and osteoarthritis (OA). Increased levels of leptin in both RA and OA have been demonstrated, thus linking leptin to arthritic diseases, but the mechanism has not been clarified. This study investigated the putative role of signaling pathways (p38, JNK, MEK1, NF-ĸB, and PI3) involved in leptin-induced cartilage destruction. Normal human articular chondrocytes were cultured with recombinant human leptin at 100, 250, 500, and 1000 ng/mL doses for 6, 12, 24, and 48 h, after which ADAMTS-4, -5, and -9 genes expression were determined by real time-polymerase chain reaction (RT-PCR) and Western Blot methods. The signaling pathways involved in leptin-induced ADAMTSs upregulation were also investigated by using inhibitors of signaling pathways. It was demonstrated that ADAMTSs expression level was peaked at 1000 ng/mL doses for 48 hours, and MAPKs (p38, JNK, and MEK) and NF-ĸB signaling pathways involving in leptin triggered ADAMTSs upregulation. Obesity as a risk for RA and OA may contribute to the inflammation of both RA and OA diseases by secreting adipokines like leptin. We hypothesize that leptin is involved in the development of RA and OA accompanied with obesity by increasing ADAMTS-4, -5, and -9 genes expression via MAPKs and NF-ĸB signaling pathways. © 2014 International Federation for Cell Biology.

Trigger readout electronics upgrade for the ATLAS Liquid Argon Calorimeters

NASA Astrophysics Data System (ADS)

Dinkespiler, B.

2017-09-01

The upgrade of the Large Hadron Collider (LHC) scheduled for the 2019-2020 shut-down period, referred to as Phase-I upgrade, will increase the instantaneous luminosity to about three times the design value. Since the current ATLAS trigger system does not allow sufficient increase of the trigger rate, an improvement of the trigger system is required. The Liquid Argon (LAr) Calorimeter read-out will therefore be modified to deliver digital trigger signals with a higher spatial granularity in order to improve the identification efficiencies of electrons, photons, tau, jets and missing energy, at high background rejection rates at the Level-1 trigger. The new trigger signals will be arranged in 34000 so-called Super Cells which achieves 5-10 times better granularity than the trigger towers currently used and allows an improved background rejection. The readout of the trigger signals will process the signal of the Super Cells at every LHC bunch-crossing at 12-bit precision and a frequency of 40 MHz. The data will be transmitted to the Back End using a custom serializer and optical converter and 5.12 Gb/s optical links. In order to verify the full functionality of the future Liquid Argon trigger system, a demonstrator set-up has been installed on the ATLAS detector and is operated in parallel to the regular ATLAS data taking during the LHC Run-2 in 2015 and 2016. Noise level and linearity on the energy measurement have been verified to be within our requirements. In addition, we have collected data from 13 TeV proton collisions during the LHC 2015 and 2016 runs, and have observed real pulses from the detector through the demonstrator system. The talk will give an overview of the Phase-I Upgrade of the ATLAS Liquid Argon Calorimeter readout and present the custom developed hardware including their role in real-time data processing and fast data transfer. This contribution will also report on the performance of the newly developed ASICs including their radiation tolerance and on the performance of the prototype boards in the demonstrator system based on various measurements with the 13 TeV collision data. Results of the high-speed link test with the prototypes of the final electronic boards will be also reported.

Functional conservation and innovation of amphioxus RIP1-mediated signaling in cell fate determination.

PubMed

Li, Jun; Yuan, Shaochun; Qi, Lin; Huang, Shengfeng; Huang, Guangrui; Yang, Manyi; Xu, Liqun; Li, Yuxin; Zhang, Renwei; Yu, Yingcai; Chen, Shangwu; Xu, Anlong

2011-10-15

Recently, receptor interacting protein (RIP)-1 has been recognized as an intracellular sensor at the crossroads of apoptosis, necroptosis, and cell survival. To reveal when this crucial molecule originated and how its function in integrating stress signals evolved, in this study we report on two RIP1 homologs in Chinese amphioxus (Branchiostoma belcheri tsingtauense), designated B. belcheri tsingtauense RIP1a and B. belcheri tsingtauense RIP1b. Phylogenetic analysis indicates that they are generated by domain recombination and lineage-specific duplication. Similar to human RIP1, both B. belcheri tsingtauense RIP1a and B. belcheri tsingtauense RIP1b activate NF-κB in a kinase activity-independent manner and induce apoptosis through the Fas-associated death domain protein-caspase cascade. Moreover, we found that the natural point mutation of Q to I in the RIP homotypic interaction motif of B. belcheri tsingtauense RIP1a provides negative feedback for amphioxus RIP1-mediated signaling. Thus, our study not only suggests that RIP1 has emerged as a molecular switch in triggering cell death or survival in a basal chordate, but also adds new insights into the regulation mechanisms of RIP1-related signaling, providing a novel perspective on human diseases mediated by RIP1.

Identification of a Novel Gnao-Mediated Alternate Olfactory Signaling Pathway in Murine OSNs.

PubMed

Scholz, Paul; Mohrhardt, Julia; Jansen, Fabian; Kalbe, Benjamin; Haering, Claudia; Klasen, Katharina; Hatt, Hanns; Osterloh, Sabrina

2016-01-01

It is generally agreed that in olfactory sensory neurons (OSNs), the binding of odorant molecules to their specific olfactory receptor (OR) triggers a cAMP-dependent signaling cascade, activating cyclic-nucleotide gated (CNG) channels. However, considerable controversy dating back more than 20 years has surrounded the question of whether alternate signaling plays a role in mammalian olfactory transduction. In this study, we demonstrate a specific alternate signaling pathway in Olfr73-expressing OSNs. Methylisoeugenol (MIEG) and at least one other known weak Olfr73 agonist (Raspberry Ketone) trigger a signaling cascade independent from the canonical pathway, leading to the depolarization of the cell. Interestingly, this pathway is mediated by Gnao activation, leading to Cl(-) efflux; however, the activation of adenylyl cyclase III (ACIII), the recruitment of Ca(2+) from extra-or intracellular stores, and phosphatidylinositol 3-kinase-dependent signaling (PI signaling) are not involved. Furthermore, we demonstrated that our newly identified pathway coexists with the canonical olfactory cAMP pathway in the same OSN and can be triggered by the same OR in a ligand-selective manner. We suggest that this pathway might reflect a mechanism for odor recognition predominantly used in early developmental stages before olfactory cAMP signaling is fully developed. Taken together, our findings support the existence of at least one odor-induced alternate signal transduction pathway in native OSNs mediated by Olfr73 in a ligand-selective manner.

GPR30, the Non-Classical Membrane G Protein Related Estrogen Receptor, Is Overexpressed in Human Seminoma and Promotes Seminoma Cell Proliferation

PubMed Central

Chevalier, Nicolas; Vega, Aurélie; Bouskine, Adil; Siddeek, Bénazir; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick

2012-01-01

Background Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. Results We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation. Conclusion These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas. PMID:22496838

Neurocomputational account of how the human brain decides when to have a break

PubMed Central

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-01-01

No pain, no gain: cost–benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion. PMID:23341598

Noninvasive monitoring local variations of fever and edema on human: potential for point-of-care inflammation assessment

NASA Astrophysics Data System (ADS)

Li, Zebin; Li, Xianglin; Li, Ting

2018-02-01

Tissue inflammation is often accompanied by fever and edema, which are common and troublesome problems that probably trigger disability, lymphangitis, cosmetic deformity and cellulitis. Here we developed a device, which can measure concentration and temperature variations of water in local human body by extended near infrared spectroscopy in 900 1000 nm wavelength range. An experiment of four steps incremental cycling exercise was designed to change tissue water concentration and temperature of subjects. Body temperature was also estimated by tympanic thermometer and surface thermometer as comparisons during the experiment. In the stage of recovery after exercise, the signal detected by custom device is similar to tympanic thermometer at the beginning, but it is closer to the temperature of surface later. In particular, this signal shows a better linearity, and a significant change when the exercise was suspended. This study demonstrated the potential of optical touch-sensing for inflammation severity monitoring by measuring water concentration and temperature variations in local lesions.

The Cryptococcus neoformans Capsule: a Sword and a Shield

PubMed Central

O'Meara, Teresa R.

2012-01-01

Summary: The human fungal pathogen Cryptococcus neoformans is characterized by its ability to induce a distinct polysaccharide capsule in response to a number of host-specific environmental stimuli. The induction of capsule is a complex biological process encompassing regulation at multiple steps, including the biosynthesis, transport, and maintenance of the polysaccharide at the cell surface. By precisely regulating the composition of its cell surface and secreted polysaccharides, C. neoformans has developed intricate ways to establish chronic infection and dormancy in the human host. The plasticity of the capsule structure in response to various host conditions also underscores the complex relationship between host and parasite. Much of this precise regulation of capsule is achieved through the transcriptional responses of multiple conserved signaling pathways that have been coopted to regulate this C. neoformans-specific virulence-associated phenotype. This review focuses on specific host stimuli that trigger the activation of the signal transduction cascades and on the downstream transcriptional responses that are required for robust encapsulation around the cell. PMID:22763631

Neurocomputational account of how the human brain decides when to have a break.

PubMed

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-02-12

No pain, no gain: cost-benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion.

Recombinant Brugia malayi pepsin inhibitor (rBm33) exploits host signaling events to regulate inflammatory responses associated with lymphatic filarial infections.

PubMed

Sreenivas, Kirthika; Kalyanaraman, Haripriya; Babu, Subash; Narayanan, Rangarajan Badri

2017-11-01

Prolonged existence of filarial parasites and their molecules within the host modulate the host immune system to instigate their survival and induce inflammatory responses that contribute to disease progression. Recombinant Brugia malayi pepsin inhibitor (rBm33) modulates the host immune responses by skewing towards Th1 responses characterized by secretion of inflammatory molecules such as TNF-α, IL-6, nitric oxide (NO). Here we also specified the molecular signaling events triggered by rBm33 in peripheral blood mononuclear cells (PBMCs) of filarial endemic normals (EN). rBm33 predominantly enhanced the levels of nitric oxide in cultured PBMCs but did not result in oxidative stress to the host cells. Further, rBm33 treatment of human PBMCs resulted in higher GSH/GSSG levels. MYD88 dependent activation was found to be associated with rBm33 specific inflammatory cytokine production. rBm33 triggered intracellular signaling events also involved JNK activation in host PBMCs. In addition, c-Fos and not NF-κB was identified as the transcription factor regulating the expression of inflammatory cytokines in rBm33 stimulated PBMCs. rBm33 marked its role in filarial pathology by altered levels of growth factors but did not have a significant impact on matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs) activity of host PBMCs. Thus, the study outlines the signaling network of rBm33 induced inflammatory responses within the host immune cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trigger probe for determining the orientation of the power distribution of an electron beam

DOEpatents

Elmer, John W [Danville, CA; Palmer, Todd A [Livermore, CA; Teruya, Alan T [Livermore, CA

2007-07-17

The present invention relates to a probe for determining the orientation of electron beams being profiled. To accurately time the location of an electron beam, the probe is designed to accept electrons from only a narrowly defined area. The signal produced from the probe is then used as a timing or triggering fiducial for an operably coupled data acquisition system. Such an arrangement eliminates changes in slit geometry, an additional signal feedthrough in the wall of a welding chamber and a second timing or triggering channel on a data acquisition system. As a result, the present invention improves the accuracy of the resulting data by minimizing the adverse effects of current slit triggering methods so as to accurately reconstruct electron or ion beams.

Failures of cognitive control or attention? The case of stop-signal deficits in schizophrenia.

PubMed

Matzke, Dora; Hughes, Matthew; Badcock, Johanna C; Michie, Patricia; Heathcote, Andrew

2017-05-01

We used Bayesian cognitive modelling to identify the underlying causes of apparent inhibitory deficits in the stop-signal paradigm. The analysis was applied to stop-signal data reported by Badcock et al. (Psychological Medicine 32: 87-297, 2002) and Hughes et al. (Biological Psychology 89: 220-231, 2012), where schizophrenia patients and control participants made rapid choice responses, but on some trials were signalled to stop their ongoing response. Previous research has assumed an inhibitory deficit in schizophrenia, because estimates of the mean time taken to react to the stop signal are longer in patients than controls. We showed that these longer estimates are partly due to failing to react to the stop signal ("trigger failures") and partly due to a slower initiation of inhibition, implicating a failure of attention rather than a deficit in the inhibitory process itself. Correlations between the probability of trigger failures and event-related potentials reported by Hughes et al. are interpreted as supporting the attentional account of inhibitory deficits. Our results, and those of Matzke et al. (2016), who report that controls also display a substantial although lower trigger-failure rate, indicate that attentional factors need to be taken into account when interpreting results from the stop-signal paradigm.

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

PubMed Central

Merlini, Laura

2016-01-01

Cell fusion is universal in eukaryotes for fertilization and development, but what signals this process is unknown. Here, we show in Schizosaccharomyces pombe that fusion does not require a dedicated signal but is triggered by spatial focalization of the same pheromone–GPCR (G-protein-coupled receptor)–MAPK signaling cascade that drives earlier mating events. Autocrine cells expressing the receptor for their own pheromone trigger fusion attempts independently of cell–cell contact by concentrating pheromone release at the fusion focus, a dynamic actin aster underlying the secretion of cell wall hydrolases. Pheromone receptor and MAPK cascade are similarly enriched at the fusion focus, concomitant with fusion commitment in wild-type mating pairs. This focalization promotes cell fusion by immobilizing the fusion focus, thus driving local cell wall dissolution. We propose that fusion commitment is imposed by a local increase in MAPK concentration at the fusion focus, driven by a positive feedback between fusion focus formation and focalization of pheromone release and perception. PMID:27798845

Sensitive SERS detection of DNA methyltransferase by target triggering primer generation-based multiple signal amplification strategy.

PubMed

Li, Ying; Yu, Chuanfeng; Han, Huixia; Zhao, Caisheng; Zhang, Xiaoru

2016-07-15

A novel and sensitive surface-enhanced Raman scattering (SERS) method is proposed for the assay of DNA methyltransferase (MTase) activity and evaluation of inhibitors by developing a target triggering primer generation-based multiple signal amplification strategy. By using of a duplex substrate for Dam MTase, two hairpin templates and a Raman probe, multiple signal amplification mode is achieved. Once recognized by Dam MTase, the duplex substrate can be cleaved by Dpn I endonuclease and two primers are released for triggering the multiple signal amplification reaction. Consequently, a wide dynamic range and remarkably high sensitivity are obtained under isothermal conditions. The detection limit is 2.57×10(-4)UmL(-1). This assay exhibits an excellent selectivity and is successfully applied in the screening of inhibitors for Dam MTase. In addition, this novel sensing system is potentially universal as the recognition element can be conveniently designed for other target analytes by changing the substrate of DNA MTase. Copyright © 2016 Elsevier B.V. All rights reserved.

Threatening joy: approach and avoidance reactions to emotions are influenced by the group membership of the expresser.

PubMed

Paulus, Andrea; Wentura, Dirk

2014-01-01

It has been repeatedly stated that approach and avoidance reactions to emotional faces are triggered by the intention signalled by the emotion. This line of thought suggests that each emotion signals a specific intention triggering a specific behavioural reaction. However, empirical results examining this assumption are inconsistent, suggesting that it might be too short-sighted. We hypothesise that the same emotional expression can signal different social messages and, therefore, trigger different reactions; which social message is signalled by an emotional expression should be influenced by moderating variables, such as the group membership of the expresser. In two experiments, we show that group membership influences approach and avoidance reactions to emotional expressions: Emotions (fear and happiness) expressed by in-group members elicited concordant behaviour, whereas emotions expressed by out-group members activated the reverse pattern. A third experiment, in which participants directly evaluated smiling and fearful individuals resembling in-group and out-group members supported this result.

Wild-type rabies virus induces autophagy in human and mouse neuroblastoma cell lines.

PubMed

Peng, Jiaojiao; Zhu, Shenghe; Hu, Lili; Ye, Pingping; Wang, Yifei; Tian, Qin; Mei, Mingzhu; Chen, Hao; Guo, Xiaofeng

2016-10-02

Different rabies virus (RABV) strains have their own biological characteristics, but little is known about their respective impact on autophagy. Therefore, we evaluated whether attenuated RABV HEP-Flury and wild-type RABV GD-SH-01 strains triggered autophagy. We found that GD-SH-01 infection significantly increased the number of autophagy-like vesicles, the accumulation of enhanced green fluorescent protein (EGFP)-LC3 fluorescence puncta and the conversion of LC3-I to LC3-II, while HEP-Flury was not able to induce this phenomenon. When evaluating autophagic flux, we found that GD-SH-01 infection triggers a complete autophagic response in the human neuroblastoma cell line (SK), while autophagosome fusion with lysosomes was inhibited in a mouse neuroblastoma cell line (NA). In these cells, GD-SH-01 led to apoptosis and mitochondrial dysfunction while triggering autophagy, and apoptosis could be decreased by enhancing autophagy. To further identify the virus constituent causing autophagy, 5 chimeric recombinant viruses carrying single genes of HEP-Flury instead of those of GD-SH-01 were rescued. While the HEP-Flury virus carrying the wild-type matrix protein (M) gene of RABV triggered LC3-I to LC3-II conversion in SK and NA cells, replacement of genes of nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) produced only minor autophagy. But no one single structural protein of GD-SH-01 induced autophagy. Moreover, the AMPK signaling pathway was activated by GD-SH-01 in SK. Therefore, our data provide strong evidence that autophagy is induced by GD-SH-01 and can decrease apoptosis in vitro. Furthermore, the M gene of GD-SH-01 may cooperatively induce autophagy.

Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage.

PubMed

Schneider-Merck, Tanja; Lammerts van Bueren, Jeroen J; Berger, Sven; Rossen, Kai; van Berkel, Patrick H C; Derer, Stefanie; Beyer, Thomas; Lohse, Stefan; Bleeker, Wim K; Peipp, Matthias; Parren, Paul W H I; van de Winkel, Jan G J; Valerius, Thomas; Dechant, Michael

2010-01-01

Ab-dependent cellular cytotoxicity (ADCC) is usually considered an important mechanism of action for immunotherapy with human IgG1 but not IgG2 Abs. The epidermal growth factor receptor (EGF-R) Ab panitumumab represents the only human IgG2 Ab approved for immunotherapy and inhibition of EGF-R signaling has been described as its principal mechanism of action. In this study, we investigated effector mechanisms of panitumumab compared with zalutumumab, an EGF-R Ab of the human IgG1 isotype. Notably, panitumumab was as effective as zalutumumab in recruiting ADCC by myeloid effector cells (i.e., neutrophils and monocytes) in contrast to NK cell-mediated ADCC, which was only induced by the IgG1 Ab. Neutrophil-mediated tumor cell killing could be stimulated by myeloid growth factors and was triggered via FcgammaRIIa. Panitumumab-mediated ADCC was significantly affected by the functional FcgammaRIIa-R131H polymorphism and was induced more effectively by neutrophils from FcgammaRIIa-131H homozygous donors than from -131R individuals. This polymorphism did not affect neutrophil ADCC induced by the IgG1 Ab zalutumumab. The in vivo activity of both Abs was assessed in two animal models: a high-dose model, in which signaling inhibition is a dominant mechanism of action, and a low-dose model, in which effector cell recruitment plays a prominent role. Zalutumumab was more effective than panitumumab in the high-dose model, reflecting its stronger ability to induce EGF-R downmodulation and growth inhibition. In the low-dose model, zalutumumab and panitumumab similarly prevented tumor growth. Thus, our results identify myeloid cell-mediated ADCC as a potent and additional mechanism of action for EGF-R-directed immunotherapy.

UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)*

PubMed Central

Kemp, Michael G.; Lindsey-Boltz, Laura A.; Sancar, Aziz

2015-01-01

The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies.

PubMed

Rath, Eva; Haller, Dirk

2011-06-01

Multiple cellular stress responses have been implicated in chronic diseases such as obesity, diabetes, cardiovascular, and inflammatory bowel diseases. Even though phenotypically different, chronic diseases share cellular stress signaling pathways, in particular endoplasmic reticulum (ER) unfolded protein response (UPR). The purpose of the ER UPR is to restore ER homeostasis after challenges of the ER function. Among the triggers of ER UPR are changes in the redox status, elevated protein synthesis, accumulation of unfolded or misfolded proteins, energy deficiency and glucose deprivation, cholesterol depletion, and microbial signals. Numerous mouse models have been used to characterize the contribution of ER UPR to several pathologies, and ER UPR-associated signaling has also been demonstrated to be relevant in humans. Additionally, recent evidence suggests that the ER UPR is interrelated with metabolic and inflammatory pathways, autophagy, apoptosis, and mitochondrial stress signaling. Furthermore, microbial as well as nutrient sensing is integrated into the ER-associated signaling network. The data discussed in the present review highlight the interaction of ER UPR with inflammatory pathways, metabolic processes and mitochondrial function, and their interrelation in the context of chronic diseases.

Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells

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

Pan, Hong; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, 107, Wenhua Xi Road, Jinan 250012; Wu, Xinyi, E-mail: xywu8868@163.com

2012-04-13

Highlights: Black-Right-Pointing-Pointer Hypoxia attenuates Acanthamoeba-induced the production of IL-8 and IFN-{beta}. Black-Right-Pointing-Pointer Hypoxia inhibits TLR4 expression in a time-dependent manner in HCECs. Black-Right-Pointing-Pointer Hypoxia inhibits Acanthamoeba-induced the activation of NF-{kappa}B and ERK1/2 in HCECs. Black-Right-Pointing-Pointer Hypoxia decreases Acanthamoeba-induced inflammatory response via TLR4 signaling. Black-Right-Pointing-Pointer LPS-induced the secretion of IL-6 and IL-8 is abated by hypoxia via TLR4 signaling. -- Abstract: Acanthamoeba keratitis (AK) is a vision-threatening corneal infection that is intimately associated with contact lens use which leads to hypoxic conditions on the corneal surface. However, the effect of hypoxia on the Acanthamoeba-induced host inflammatory response of corneal epithelial cellsmore » has not been studied. In the present study, we investigated the effect of hypoxia on the Acanthamoeba-induced production of inflammatory mediators interleukin-8 (IL-8) and interferon-{beta} (IFN-{beta}) in human corneal epithelial cells and then evaluated its effects on the Toll-like receptor 4 (TLR4) signaling, including TLR4 and myeloid differentiation primary response gene (88) (MyD88) expression as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and extracellular signal-regulated kinases 1/2 (ERK1/2). We then studied the effect of hypoxia on a TLR4-specific inflammatory response triggered by the TLR4 ligand lipopolysaccharide (LPS). Our data showed that hypoxia significantly decreased the production of IL-8 and IFN-{beta}. Furthermore, hypoxia attenuated Acanthamoeba-triggered TLR4 expression as well as the activation of NF-{kappa}B and ERK1/2, indicating that hypoxia abated Acanthamoeba-induced inflammatory responses by affecting TLR4 signaling. Hypoxia also inhibited LPS-induced IL-6 and IL-8 secretion, myeloid differentiation primary response gene (88) MyD88 expression and NF-{kappa}B activation, confirming that hypoxia suppressed the LPS-induced inflammatory response by affecting TLR4 signaling. In conclusion, our results demonstrated that hypoxia attenuated the host immune and inflammatory response against Acanthamoeba infection by suppressing TLR4 signaling, indicating that hypoxia might impair the host cell's ability to eliminate the Acanthamoeba invasion and that hypoxia could enhance cell susceptibility to Acanthamoeba infection. These results may explain why contact lens use is one of the most prominent risk factors for AK.« less

Plant immunity triggered by microbial molecular signatures.

PubMed

Zhang, Jie; Zhou, Jian-Min

2010-09-01

Pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) are recognized by host cell surface-localized pattern-recognition receptors (PRRs) to activate plant immunity. PAMP-triggered immunity (PTI) constitutes the first layer of plant immunity that restricts pathogen proliferation. PTI signaling components often are targeted by various Pseudomonas syringae virulence effector proteins, resulting in diminished plant defenses and increased bacterial virulence. Some of the proteins targeted by pathogen effectors have evolved to sense the effector activity by associating with cytoplasmic immune receptors classically known as resistance proteins. This allows plants to activate a second layer of immunity termed effector-triggered immunity (ETI). Recent studies on PTI regulation and P. syringae effector targets have uncovered new components in PTI signaling. Although MAP kinase (MAPK) cascades have been considered crucial for PTI, emerging evidence indicates that a MAPK-independent pathway also plays an important role in PTI signaling.

PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells.

PubMed

Deng, Xiaobei; Rui, Wei; Zhang, Fang; Ding, Wenjun

2013-06-01

It has been well documented in in vitro studies that ambient airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM(2.5)) is capable of inducing oxidative stress, which plays a key role in PM(2.5)-mediated cytotoxicity. Although nuclear factor erythroid-2-related factor 2 (Nrf2) has been shown to regulate the intracellular defense mechanisms against oxidative stress, a potential of the Nrf2-mediated cellular defense against oxidative stress induced by PM(2.5) remains to be determined. This study was aimed to explore the potential signaling pathway of Nrf2-mediated defense mechanisms against PM(2.5)-induced oxidative stress in human type II alveolar epithelial A549 cells. We exposed A549 cells to PM(2.5) particles collected from Beijing at a concentration of 16 μg/cm(2). We observed that PM(2.5) triggered an increase of intracellular reactive oxygen species (ROS) in a time-dependent manner during a period of 2 h exposure. We also found that Nrf2 overexpression suppressed and Nrf2 knockdown increased PM(2.5)-induced ROS generation. Using Western blot and confocal microscopy, we found that PM(2.5) exposure triggered significant translocation of Nrf2 into nucleus, resulting in AKT phosphorylation and significant transcription of ARE-driven phases II enzyme genes, such as NAD(P)H:quinone oxidoreductase (NQO-1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) in A549 cells. Evaluation of signaling pathways showed that a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not an ERK 1/2 inhibitor (PD98059) or a p38 MAPK (SB203580), significantly down-regulated PM(2.5)-induced Nrf2 nuclear translocation and HO-1 mRNA expression, indicating PI3K/AKT is involved in the signaling pathway leads to the PM(2.5)-induced nuclear translocation of Nrf2 and subsequent Nrf2-mediated HO-1 transcription. Taken together, our results suggest that PM(2.5)-induced ROS may function as signaling molecules to activate Nrf2-mediated defenses, such as HO-1 expression, against oxidative stress induced by PM(2.5) through the PI3K/AKT signaling pathway.

A search in strainmeter data for slow slip associated with triggered and ambient tremor near Parkfield, California

USGS Publications Warehouse

Smith, E.F.; Gomberg, J.

2009-01-01

We test the hypothesis that, as in subduction zones, slow slip facilitates triggered and ambient tremor in the transform boundary setting of California. Our study builds on the study of Peng et al. (2009) of triggered and ambient tremor near Parkfield, California during time intervals surrounding 31, potentially triggering, M ≥ 7.5 teleseismic earthquakes; waves from 10 of these triggered tremor and 29 occurred in periods of ambient tremor activity. We look for transient slow slip during 3-month windows that include 11 of these triggering and nontriggering teleseisms, using continuous strain data recorded on two borehole Gladwin tensor strainmeters (GTSM) located within the distribution of tremor epicenters. We model the GTSM data assuming only tidal and “drift” signals are present and find no detectable slow slip, either ongoing when the teleseismic waves passed or triggered by them. We infer a conservative detection threshold of about 5 nanostrain for abrupt changes and about twice this for slowly evolving signals. This could be lowered slightly by adding analyses of other data types, modeled slow slip signals, and GTSM data calibration. Detection of slow slip also depends on the slipping fault's location and size, which we describe in terms of equivalent earthquake moment magnitude, M. In the best case of the GTSM above a very shallow slipping fault, detectable slip events must exceed M~2, and if the slow slip is beneath the seismogenic zone (below ~15 km depth), even M~5 events are likely to remain hidden.

Manipulation of ubiquitin/SUMO pathways in human herpesviruses infection.

PubMed

Gan, Jin; Qiao, Niu; Strahan, Roxanne; Zhu, Caixia; Liu, Lei; Verma, Subhash C; Wei, Fang; Cai, Qiliang

2016-11-01

Post-translational modification of proteins with ubiquitin/small ubiquitin-like modifier (SUMO) molecules triggers multiple signaling pathways that are critical for many aspects of cellular physiology. Given that viruses hijack the biosynthetic and degradative systems of their host, it is not surprising that viruses encode proteins to manipulate the host's cellular machinery for ubiquitin/SUMO modification at multiple levels. Infection with a herpesvirus, among the most ubiquitous human DNA viruses, has been linked to many human diseases, including cancers. The interplay between human herpesviruses and the ubiquitylation/SUMOylation modification system has been extensively investigated in the past decade. In this review, we present an overview of recent advances to address how the ubiquitin/SUMO-modified system alters the latency and lytic replication of herpesvirus and how herpesviruses usurp the ubiquitin/SUMO pathways against the host's intrinsic and innate immune response to favor their pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd.

Air-Flow-Driven Triboelectric Nanogenerators for Self-Powered Real-Time Respiratory Monitoring.

PubMed

Wang, Meng; Zhang, Jiahao; Tang, Yingjie; Li, Jun; Zhang, Baosen; Liang, Erjun; Mao, Yanchao; Wang, Xudong

2018-06-04

Respiration is one of the most important vital signs of humans, and respiratory monitoring plays an important role in physical health management. A low-cost and convenient real-time respiratory monitoring system is extremely desirable. In this work, we demonstrated an air-flow-driven triboelectric nanogenerator (TENG) for self-powered real-time respiratory monitoring by converting mechanical energy of human respiration into electric output signals. The operation of the TENG was based on the air-flow-driven vibration of a flexible nanostructured polytetrafluoroethylene (n-PTFE) thin film in an acrylic tube. This TENG can generate distinct real-time electric signals when exposed to the air flow from different breath behaviors. It was also found that the accumulative charge transferred in breath sensing corresponds well to the total volume of air exchanged during the respiration process. Based on this TENG device, an intelligent wireless respiratory monitoring and alert system was further developed, which used the TENG signal to directly trigger a wireless alarm or dial a cell phone to provide timely alerts in response to breath behavior changes. This research offers a promising solution for developing self-powered real-time respiratory monitoring devices.

Plasma membrane order and fluidity are diversely triggered by elicitors of plant defence.

PubMed

Sandor, Roman; Der, Christophe; Grosjean, Kevin; Anca, Iulia; Noirot, Elodie; Leborgne-Castel, Nathalie; Lochman, Jan; Simon-Plas, Françoise; Gerbeau-Pissot, Patricia

2016-09-01

Although plants are exposed to a great number of pathogens, they usually defend themselves by triggering mechanisms able to limit disease development. Alongside signalling events common to most such incompatible interactions, modifications of plasma membrane (PM) physical properties could be new players in the cell transduction cascade. Different pairs of elicitors (cryptogein, oligogalacturonides, and flagellin) and plant cells (tobacco and Arabidopsis) were used to address the issue of possible modifications of plant PM biophysical properties induced by elicitors and their links to other events of the defence signalling cascade. We observed an increase of PM order whatever the elicitor/plant cell pair used, provided that a signalling cascade was induced. Such membrane modification is dependent on the NADPH oxidase-mediated reactive oxygen species production. Moreover, cryptogein, which is the sole elicitor able to trap sterols, is also the only one able to trigger an increase in PM fluidity. The use of cryptogein variants with altered sterol-binding properties confirms the strong correlation between sterol removal from the PM and PM fluidity enhancement. These results propose PM dynamics as a player in early signalling processes triggered by elicitors of plant defence. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Acoustic emission intrusion detector

DOEpatents

Carver, Donald W.; Whittaker, Jerry W.

1980-01-01

An intrusion detector is provided for detecting a forcible entry into a secured structure while minimizing false alarms. The detector uses a piezoelectric crystal transducer to sense acoustic emissions. The transducer output is amplified by a selectable gain amplifier to control the sensitivity. The rectified output of the amplifier is applied to a Schmitt trigger circuit having a preselected threshold level to provide amplitude discrimination. Timing circuitry is provided which is activated by successive pulses from the Schmitt trigger which lie within a selected time frame for frequency discrimination. Detected signals having proper amplitude and frequency trigger an alarm within the first complete cycle time of a detected acoustical disturbance signal.

Eight-Channel Digital Signal Processor and Universal Trigger Module

NASA Astrophysics Data System (ADS)

Skulski, Wojtek; Wolfs, Frank

2003-04-01

A 10-bit, 8-channel, 40 megasamples per second digital signal processor and waveform digitizer DDC-8 (nicknamed Universal Trigger Module) is presented. The digitizer features 8 analog inputs, 1 analog output for a reconstructed analog waveform, 16 NIM logic inputs, 8 NIM logic outputs, and a pool of 16 TTL logic lines which can be individually configured as either inputs or outputs. The first application of this device is to enhance the present trigger electronics for PHOBOS at RHIC. The status of the development and the first results are presented. Possible applications of the new device are discussed. Supported by the NSF grant PHY-0072204.

A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ.

PubMed

Lee, Mark S; Glassman, Caleb R; Deshpande, Neha R; Badgandi, Hemant B; Parrish, Heather L; Uttamapinant, Chayasith; Stawski, Philipp S; Ting, Alice Y; Kuhns, Michael S

2015-08-18

The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3ζζ subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity, we determined that the cytosolic juxtamembrane regions of the CD3ζζ subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3ζζ intracellular motifs that initiate chemical signaling, as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines. Copyright © 2015 Elsevier Inc. All rights reserved.

Can vocal conditioning trigger a semiotic ratchet in marmosets?

PubMed

Turesson, Hjalmar K; Ribeiro, Sidarta

2015-01-01

The complexity of human communication has often been taken as evidence that our language reflects a true evolutionary leap, bearing little resemblance to any other animal communication system. The putative uniqueness of the human language poses serious evolutionary and ethological challenges to a rational explanation of human communication. Here we review ethological, anatomical, molecular, and computational results across several species to set boundaries for these challenges. Results from animal behavior, cognitive psychology, neurobiology, and semiotics indicate that human language shares multiple features with other primate communication systems, such as specialized brain circuits for sensorimotor processing, the capability for indexical (pointing) and symbolic (referential) signaling, the importance of shared intentionality for associative learning, affective conditioning and parental scaffolding of vocal production. The most substantial differences lie in the higher human capacity for symbolic compositionality, fast vertical transmission of new symbols across generations, and irreversible accumulation of novel adaptive behaviors (cultural ratchet). We hypothesize that increasingly-complex vocal conditioning of an appropriate animal model may be sufficient to trigger a semiotic ratchet, evidenced by progressive sign complexification, as spontaneous contact calls become indexes, then symbols and finally arguments (strings of symbols). To test this hypothesis, we outline a series of conditioning experiments in the common marmoset (Callithrix jacchus). The experiments are designed to probe the limits of vocal communication in a prosocial, highly vocal primate 35 million years far from the human lineage, so as to shed light on the mechanisms of semiotic complexification and cultural transmission, and serve as a naturalistic behavioral setting for the investigation of language disorders.

Can vocal conditioning trigger a semiotic ratchet in marmosets?

PubMed Central

Turesson, Hjalmar K.; Ribeiro, Sidarta

2015-01-01

The complexity of human communication has often been taken as evidence that our language reflects a true evolutionary leap, bearing little resemblance to any other animal communication system. The putative uniqueness of the human language poses serious evolutionary and ethological challenges to a rational explanation of human communication. Here we review ethological, anatomical, molecular, and computational results across several species to set boundaries for these challenges. Results from animal behavior, cognitive psychology, neurobiology, and semiotics indicate that human language shares multiple features with other primate communication systems, such as specialized brain circuits for sensorimotor processing, the capability for indexical (pointing) and symbolic (referential) signaling, the importance of shared intentionality for associative learning, affective conditioning and parental scaffolding of vocal production. The most substantial differences lie in the higher human capacity for symbolic compositionality, fast vertical transmission of new symbols across generations, and irreversible accumulation of novel adaptive behaviors (cultural ratchet). We hypothesize that increasingly-complex vocal conditioning of an appropriate animal model may be sufficient to trigger a semiotic ratchet, evidenced by progressive sign complexification, as spontaneous contact calls become indexes, then symbols and finally arguments (strings of symbols). To test this hypothesis, we outline a series of conditioning experiments in the common marmoset (Callithrix jacchus). The experiments are designed to probe the limits of vocal communication in a prosocial, highly vocal primate 35 million years far from the human lineage, so as to shed light on the mechanisms of semiotic complexification and cultural transmission, and serve as a naturalistic behavioral setting for the investigation of language disorders. PMID:26500583

Epidermal growth factor- and hepatocyte growth factor-receptor activity in serum-free cultures of human hepatocytes.

PubMed

Runge, D M; Runge, D; Dorko, K; Pisarov, L A; Leckel, K; Kostrubsky, V E; Thomas, D; Strom, S C; Michalopoulos, G K

1999-02-01

Serum-free primary cultures of hepatocytes are a useful tool to study factors triggering hepatocyte proliferation and regeneration. We have developed a chemically defined serum-free system that allows human hepatocyte proliferation in the presence of epidermal growth factor and hepatocyte growth factor. DNA synthesis and accumulation were determined by [3H]thymidine incorporation and fluorometry, respectively. Western blot analyses and co-immunoprecipitations were used to investigate the association of proteins involved in epidermal growth factor and hepatocyte growth factor activation and signaling: epidermal growth factor receptor, hepatocyte growth factor receptor (MET), urokinase-type plasminogen activator and its receptor, and a member of the signal transducer and activator of transcription family, STAT-3. Primary human hepatocytes proliferated under serum-free conditions in a chemically defined medium for up to 12 days. Epidermal growth factor-receptor and MET were present and functional, decreasing over time. MET, urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor co-precipitated to varying degrees during the culture period. STAT-3 co-precipitated with epidermal growth factor-receptor and MET to varying degrees. Proliferation of human hepatocytes can improve by modification of a chemically defined medium originally used for rat hepatocyte cultures. In these long-term cultures of human hepatocytes, hepatocyte growth factor and epidermal growth factor can stimulate growth and differentiation by interacting with their receptors and initiating downstream signaling. This involves complex formation of the receptors with other plasma membrane components for MET (urokinase-type plasminogen activator in context of its receptor) and activation of STAT-3 for both receptors.

Involvement of a Gardos-type potassium channel in head activator-induced mitosis of BON cells.

PubMed

Kayser, S T; Ulrich, H; Schaller, H C

1998-06-01

The human neuroendocrine cell line BON was used to study second messengers involved in signal transduction for entry into mitosis. BON cells produce the neuropeptide head activator (HA) and use it as autocrine growth factor. HA stimulates BON cell proliferation by triggering entry into mitosis. HA-induced mitosis is mediated by an inhibitory G protein, the action of which is blocked by pertussis toxin. HA signaling requires inhibition of the cAMP pathway, calcium influx, and hyperpolarization of cells. The latter is a very important and sensitive step involving a calcium-activated potassium channel. Cell cycle progression and proliferation of BON cells are most efficiently inhibited with specific inhibitors of this potassium channel. Pharmacology and RNA analysis suggest identity with the recently cloned Gardos-type potassium channel.

Migraine with Aura

MedlinePlus

... processes visual signals (visual cortex) and causes these visual hallucinations. Many of the same factors that trigger migraine can also trigger migraine with aura, including stress, bright lights, some foods and medications, too much or too little sleep, ...

Regeneration of fat cells from myofibroblasts during wound healing.

PubMed

Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi; Li, Yun Rose; Dedhia, Priya H; Zheng, Ying; Shao, Mengle; Gay, Denise L; Ramos, Raul; Hsi, Tsai-Ching; Oh, Ji Won; Wang, Xiaojie; Ramirez, Amanda; Konopelski, Sara E; Elzein, Arijh; Wang, Anne; Supapannachart, Rarinthip June; Lee, Hye-Lim; Lim, Chae Ho; Nace, Arben; Guo, Amy; Treffeisen, Elsa; Andl, Thomas; Ramirez, Ricardo N; Murad, Rabi; Offermanns, Stefan; Metzger, Daniel; Chambon, Pierre; Widgerow, Alan D; Tuan, Tai-Lan; Mortazavi, Ali; Gupta, Rana K; Hamilton, Bruce A; Millar, Sarah E; Seale, Patrick; Pear, Warren S; Lazar, Mitchell A; Cotsarelis, George

2017-02-17

Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro . Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans. Copyright © 2017, American Association for the Advancement of Science.

Streptomyces exploration is triggered by fungal interactions and volatile signals.

PubMed

Jones, Stephanie E; Ho, Louis; Rees, Christiaan A; Hill, Jane E; Nodwell, Justin R; Elliot, Marie A

2017-01-03

It has long been thought that the life cycle of Streptomyces bacteria encompasses three developmental stages: vegetative hyphae, aerial hyphae and spores. Here, we show interactions between Streptomyces and fungi trigger a previously unobserved mode of Streptomyces development. We term these Streptomyces cells 'explorers', for their ability to adopt a non-branching vegetative hyphal conformation and rapidly transverse solid surfaces. Fungi trigger Streptomyces exploratory growth in part by altering the composition of the growth medium, and Streptomyces explorer cells can communicate this exploratory behaviour to other physically separated streptomycetes using an airborne volatile organic compound (VOC). These results reveal that interkingdom interactions can trigger novel developmental behaviours in bacteria, here, causing Streptomyces to deviate from its classically-defined life cycle. Furthermore, this work provides evidence that VOCs can act as long-range communication signals capable of propagating microbial morphological switches.

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways.

PubMed

Stellzig, J; Chariot, A; Shostak, K; Ismail Göktuna, S; Renner, F; Acker, T; Pagenstecher, A; Schmitz, M L

2013-11-11

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.

Near-infrared signals associated with electrical stimulation of peripheral nerves

NASA Astrophysics Data System (ADS)

Fantini, Sergio; Chen, Debbie K.; Martin, Jeffrey M.; Sassaroli, Angelo; Bergethon, Peter R.

2009-02-01

We report our studies on the optical signals measured non-invasively on electrically stimulated peripheral nerves. The stimulation consists of the delivery of 0.1 ms current pulses, below the threshold for triggering any visible motion, to a peripheral nerve in human subjects (we have studied the sural nerve and the median nerve). In response to electrical stimulation, we observe an optical signal that peaks at about 100 ms post-stimulus, on a much longer time scale than the few milliseconds duration of the electrical response, or sensory nerve action potential (SNAP). While the 100 ms optical signal we measured is not a direct optical signature of neural activation, it is nevertheless indicative of a mediated response to neural activation. We argue that this may provide information useful for understanding the origin of the fast optical signal (also on a 100 ms time scale) that has been measured non-invasively in the brain in response to cerebral activation. Furthermore, the optical response to peripheral nerve activation may be developed into a diagnostic tool for peripheral neuropathies, as suggested by the delayed optical signals (average peak time: 230 ms) measured in patients with diabetic neuropathy with respect to normal subjects (average peak time: 160 ms).

OVOL2 antagonizes TGF-β signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis

PubMed Central

Wu, Di; Liu, Na; Liu, Qing-Feng; Wu, Qiu-Wan; Xie, Yuan-Yuan; Liu, Yun-Jia; Zheng, Zhong-Zheng; Chan, Err-Cheng; Zhang, Zhi-Ming; Li, Bo-An

2017-01-01

Great progress has been achieved in the study of the role of TGF-β signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-β signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-β signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-β signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-β signaling output level in vitro and in vivo. The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression. PMID:28455959

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

PubMed Central

Stellzig, J; Chariot, A; Shostak, K; Ismail Göktuna, S; Renner, F; Acker, T; Pagenstecher, A; Schmitz, M L

2013-01-01

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity. PMID:24217713

Consistent chronostasis effects across saccade categories imply a subcortical efferent trigger

PubMed Central

Yarrow, Kielan; Johnson, Helen; Haggard, Patrick; Rothwell, John C

2005-01-01

Saccadic chronostasis refers to the subjective temporal lengthening of the first visual stimulus perceived after an eye movement, and is most commonly experienced as the “stopped clock” illusion. Other temporal illusions arising in the context of movement (e.g. “intentional binding”) appear to depend upon the volitional nature of the preceding motor act. Here we assess chronostasis across different saccade types, ranging from highly volitional (self-timed saccades, anti saccades) to highly reflexive (peripherally-cued saccades, express saccades). Chronostasis was similar in magnitude across all these conditions, despite wide variations in their neural bases. The illusion must therefore be triggered by a “lowest common denominator” signal common to all the conditions tested and their respective neural circuits. Specifically, it is suggested that chronostasis is triggered by a low-level signal arising in response to efferent signals generated in the superior colliculus. PMID:15200711

Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats.

PubMed

Liu, Qi; Si, Tianlei; Xu, Xiaoyun; Liang, Fuqiang; Wang, Lufeng; Pan, Siyi

2015-08-04

The decreased reproductive capacity of men is an important factor contributing to infertility. Accumulating evidence has shown that Electromagnetic radiation potentially has negative effects on human health. However, whether radio frequency electromagnetic radiation (RF-EMR) affects the human reproductive system still requires further investigation. Therefore, The present study investigates whether RF-EMR at a frequency of 900 MHz can trigger sperm cell apoptosis and affect semen morphology, concentration, and microstructure. Twenty four rats were exposed to 900 MHz electromagnetic radiation with a special absorption rate of 0.66 ± 0.01 W/kg for 2 h/d. After 50d, the sperm count, morphology, apoptosis, reactive oxygen species (ROS), and total antioxidant capacity (TAC), representing the sum of enzymatic and nonenzymatic antioxidants, were investigated. Western blotting and reverse transcriptase PCR were used to determine the expression levels of apoptosis-related proteins and genes, including bcl-2, bax, cytochrome c, and capase-3. In the present study, the percentage of apoptotic sperm cells in the exposure group was significantly increased by 91.42% compared with the control group. Moreover, the ROS concentration in exposure group was increased by 46.21%, while the TAC was decreased by 28.01%. Radiation also dramatically decreased the protein and mRNA expression of bcl-2 and increased that of bax, cytochrome c, and capase-3. RF-EMR increases the ROS level and decreases TAC in rat sperm. Excessive oxidative stress alters the expression levels of apoptosis-related genes and triggers sperm apoptosis through bcl-2, bax, cytochrome c and caspase-3 signaling pathways.

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells

PubMed Central

Peters, Gregory A.; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Patel, Bansari; Amini, Peyvand; Tan, Huiqing

2017-01-01

The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1β (IL-1β) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1β and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A–dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1β and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A–mediated functional progesterone withdrawal. PMID:27886516

Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer.

PubMed

Marshall, Stephen

2006-08-01

Traditionally, nutrients such as glucose and amino acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, it is now apparent that nutrients also function as signaling molecules in functionally diverse signal transduction pathways. Glucose and amino acids trigger signaling cascades that regulate various aspects of fuel and energy metabolism and control the growth, proliferation, and survival of cells. Here, we provide a functional and regulatory overview of three well-established nutrient signaling pathways-the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Nutrient signaling pathways are interconnected, coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Thus, nutrient signaling pathways do not function in isolation. Rather, they appear to serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. Understanding the diverse roles of nutrients and delineating nutrient signaling pathways should facilitate drug discovery research and the search for novel therapeutic compounds to prevent and treat various human diseases such as diabetes, obesity, and cancer.

UWB dual burst transmit driver

DOEpatents

Dallum, Gregory E [Livermore, CA; Pratt, Garth C [Discovery Bay, CA; Haugen, Peter C [Livermore, CA; Zumstein, James M [Livermore, CA; Vigars, Mark L [Livermore, CA; Romero, Carlos E [Livermore, CA

2012-04-17

A dual burst transmitter for ultra-wideband (UWB) communication systems generates a pair of precisely spaced RF bursts from a single trigger event. An input trigger pulse produces two oscillator trigger pulses, an initial pulse and a delayed pulse, in a dual trigger generator. The two oscillator trigger pulses drive a gated RF burst (power output) oscillator. A bias driver circuit gates the RF output oscillator on and off and sets the RF burst packet width. The bias driver also level shifts the drive signal to the level that is required for the RF output device.

Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia

PubMed Central

Schäfer, Michaela; Oeing, Christian U.; Rohm, Maria; Baysal-Temel, Ezgi; Lehmann, Lorenz H.; Bauer, Ralf; Volz, H. Christian; Boutros, Michael; Sohn, Daniela; Sticht, Carsten; Gretz, Norbert; Eichelbaum, Katrin; Werner, Tessa; Hirt, Marc N.; Eschenhagen, Thomas; Müller-Decker, Karin; Strobel, Oliver; Hackert, Thilo; Krijgsveld, Jeroen; Katus, Hugo A.; Berriel Diaz, Mauricio; Backs, Johannes; Herzig, Stephan

2015-01-01

Objectives Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. Methods and results By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven “cachexokines”, including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. Conclusions As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia. PMID:26909315

A new scalable modular data acquisition system for SPECT (PET)

NASA Astrophysics Data System (ADS)

Stenstrom, P.; Rillbert, A.; Bergquist, M.; Habte, F.; Bohm, C.; Larsson, S. A.

1998-06-01

Describes a modular decentralized data acquisition system that continuously samples shaped PMT pulses from a SPECT detector. The pulse waveform data are used by signal processors to accurately reconstruct amplitude and time for each scintillation event. Data acquisition for a PMT channel is triggered in two alternative ways, either when its own signal exceeds a selected digital threshold, or when it receives a trigger pulse from one of its neighboring PMTs. The triggered region is restricted to seven, thirteen or nineteen neighboring PMT channels. Each acquisition module supports three PMT channels and connects to all other modules and a reconstruction computer via Firewire to cover the 72 channels in the Stockholm University/Karolinska Hospital cylindrical SPECT camera.

An amplified graphene oxide-based fluorescence aptasensor based on target-triggered aptamer hairpin switch and strand-displacement polymerization recycling for bioassays.

PubMed

Hu, Kun; Liu, Jinwen; Chen, Jia; Huang, Yong; Zhao, Shulin; Tian, Jianniao; Zhang, Guohai

2013-04-15

An amplified graphene oxide (GO) based fluorescence aptasensor based on target-triggered aptamer hairpin switch and strand-displacement polymerization recycling is developed for bioassays. The dye-labeled single-strand DNA (aptamer hairpin) was adsorbed on the surface of GO, which result in the fluorescence quenching of dye, and exhibiting minimal background fluorescence. Upon the target, primer and polymerase, the stem of the aptamer hairpin was opened, and binds with the primer to triggers the circular target strand-displacement polymerization reaction, which produces huge amounts of duplex helixes DNA and lead to strong fluorescence emission due to shielding of nucelobases within its double-helix structure. During the polymerization reaction, the primer was extended, and target was displaced. And the displaced target recognizes and hybridizes with another hairpin probe, triggering the next round of polymerization reaction, and the circle process induces fluorescence signal amplification for the detection of analyte. To test the feasibility of the aptasensor systems, interferon-gamma (IFN-γ) was employed as a model analyte. A detection limit as low as 1.5 fM is obtained based on the GO aptasensor with a linear range of three orders of magnitude. The present method was successfully applied for the detection of IFN-γ in human plasma. Copyright © 2012 Elsevier B.V. All rights reserved.

Optically triggered high voltage switch network and method for switching a high voltage

DOEpatents

El-Sharkawi, Mohamed A.; Andexler, George; Silberkleit, Lee I.

1993-01-19

An optically triggered solid state switch and method for switching a high voltage electrical current. A plurality of solid state switches (350) are connected in series for controlling electrical current flow between a compensation capacitor (112) and ground in a reactive power compensator (50, 50') that monitors the voltage and current flowing through each of three distribution lines (52a, 52b and 52c), which are supplying three-phase power to one or more inductive loads. An optical transmitter (100) controlled by the reactive power compensation system produces light pulses that are conveyed over optical fibers (102) to a switch driver (110') that includes a plurality of series connected optical triger circuits (288). Each of the optical trigger circuits controls a pair of the solid state switches and includes a plurality of series connected resistors (294, 326, 330, and 334) that equalize or balance the potential across the plurality of trigger circuits. The trigger circuits are connected to one of the distribution lines through a trigger capacitor (340). In each switch driver, the light signals activate a phototransistor (300) so that an electrical current flows from one of the energy reservoir capacitors through a pulse transformer (306) in the trigger circuit, producing gate signals that turn on the pair of serially connected solid state switches (350).

Systematic Detection of Remotely Triggered Seismicity in Africa Following Recent Large Earthquakes

NASA Astrophysics Data System (ADS)

Ayorinde, A. O.; Peng, Z.; Yao, D.; Bansal, A. R.

2016-12-01

It is well known that large distant earthquakes can trigger micro-earthquakes/tectonic tremors during or immediately following their surface waves. Globally, triggered earthquakes have been mostly found in active plate boundary regions. It is not clear whether they could occur within stable intraplate regions in Africa as well as the active East African Rift Zone. In this study we conduct a systematic study of remote triggering in Africa following recent large earthquakes, including the 2004 Mw9.1 Sumatra and 2012 Mw8.6 Indian Ocean earthquakes. In particular, the 2012 Indian Ocean earthquake is the largest known strike slip earthquake and has triggered a global increase of magnitude larger than 5.5 earthquakes as well as numerous micro-earthquakes/tectonic tremors around the world. The entire Africa region was examined for possible remotely triggered seismicity using seismic data downloaded from the Incorporated Research Institutes for Seismology (IRIS) Data Management Center (DMC) and GFZ German Research Center for Geosciences. We apply a 5-Hz high-pass-filter to the continuous waveforms and visually identify high-frequency signals during and immediately after the large amplitude surface waves. Spectrograms are computed as additional tools to identify triggered seismicities and we further confirm them by statistical analysis comparing the high-frequency signals before and after the distant mainshocks. So far we have identified possible triggered seismicity in Botswana and northern Madagascar. This study could help to understand dynamic triggering in diverse tectonic settings of the African continent.

Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling.

PubMed

Roggero, R; Robert-Hebmann, V; Harrington, S; Roland, J; Vergne, L; Jaleco, S; Devaux, C; Biard-Piechaczyk, M

2001-08-01

Apoptosis of CD4(+) T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4(+) T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4(+) T-cell depletion in AIDS.

Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochrome c-Mediated Apoptosis Independently of Fas Signaling

PubMed Central

Roggero, Rodolphe; Robert-Hebmann, Véronique; Harrington, Steve; Roland, Joachim; Vergne, Laurence; Jaleco, Sara; Devaux, Christian; Biard-Piechaczyk, Martine

2001-01-01

Apoptosis of CD4+ T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4+ T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4+ T-cell depletion in AIDS. PMID:11462036

MOSFET analog memory circuit achieves long duration signal storage

NASA Technical Reports Server (NTRS)

1966-01-01

Memory circuit maintains the signal voltage at the output of an analog signal amplifier when the input signal is interrupted or removed. The circuit uses MOSFET /Metal Oxide Semiconductor Field Effect Transistor/ devices as voltage-controlled switches, triggered by an external voltage-sensing device.

Triggering signaling pathways using F-actin self-organization.

PubMed

Colin, A; Bonnemay, L; Gayrard, C; Gautier, J; Gueroui, Z

2016-10-04

The spatiotemporal organization of proteins within cells is essential for cell fate behavior. Although it is known that the cytoskeleton is vital for numerous cellular functions, it remains unclear how cytoskeletal activity can shape and control signaling pathways in space and time throughout the cell cytoplasm. Here we show that F-actin self-organization can trigger signaling pathways by engineering two novel properties of the microfilament self-organization: (1) the confinement of signaling proteins and (2) their scaffolding along actin polymers. Using in vitro reconstitutions of cellular functions, we found that both the confinement of nanoparticle-based signaling platforms powered by F-actin contractility and the scaffolding of engineered signaling proteins along actin microfilaments can drive a signaling switch. Using Ran-dependent microtubule nucleation, we found that F-actin dynamics promotes the robust assembly of microtubules. Our in vitro assay is a first step towards the development of novel bottom-up strategies to decipher the interplay between cytoskeleton spatial organization and signaling pathway activity.

Triggering signaling pathways using F-actin self-organization

PubMed Central

Colin, A.; Bonnemay, L.; Gayrard, C.; Gautier, J.; Gueroui, Z.

2016-01-01

The spatiotemporal organization of proteins within cells is essential for cell fate behavior. Although it is known that the cytoskeleton is vital for numerous cellular functions, it remains unclear how cytoskeletal activity can shape and control signaling pathways in space and time throughout the cell cytoplasm. Here we show that F-actin self-organization can trigger signaling pathways by engineering two novel properties of the microfilament self-organization: (1) the confinement of signaling proteins and (2) their scaffolding along actin polymers. Using in vitro reconstitutions of cellular functions, we found that both the confinement of nanoparticle-based signaling platforms powered by F-actin contractility and the scaffolding of engineered signaling proteins along actin microfilaments can drive a signaling switch. Using Ran-dependent microtubule nucleation, we found that F-actin dynamics promotes the robust assembly of microtubules. Our in vitro assay is a first step towards the development of novel bottom-up strategies to decipher the interplay between cytoskeleton spatial organization and signaling pathway activity. PMID:27698406

Control of Human Endometrial Stromal Cell Motility by PDGF-BB, HB-EGF and Trophoblast-Secreted Factors

PubMed Central

Schwenke, Maren; Knöfler, Martin; Velicky, Philipp; Weimar, Charlotte H. E.; Kruse, Michelle; Samalecos, Annemarie; Wolf, Anja; Macklon, Nick S.; Bamberger, Ana-Maria; Gellersen, Birgit

2013-01-01

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site. PMID:23349855

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5).

PubMed

Xu, Xiuduan; Wang, Hongli; Liu, Shasha; Xing, Chen; Liu, Yang; Aodengqimuge; Zhou, Wei; Yuan, Xiaoyan; Ma, Yongfu; Hu, Meiru; Hu, Yongliang; Zou, Shuxian; Gu, Ye; Peng, Shuangqing; Yuan, Shengtao; Li, Weiping; Ma, Yuanfang; Song, Lun

2016-10-02

ABSTARCT Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.

Role of protein kinase C in TBT-induced inhibition of lytic function and MAPK activation in human natural killer cells.

PubMed

Abraha, Abraham B; Rana, Krupa; Whalen, Margaret M

2010-11-01

Human natural killer (NK) cells are lymphocytes that destroy tumor and virally infected cells. Previous studies have shown that exposure of NK cells to tributyltin (TBT) greatly diminishes their ability to destroy tumor cells (lytic function) while activating mitogen-activated protein kinases (MAPK) (p44/42, p38, and JNK) in NK cells. The signaling pathway that regulates NK lytic function appears to include activation of protein kinase C(PKC) as well as MAPK activity. TBT-induced activation of MAPKs would trigger a portion of the NK lytic signaling pathway, which would then leave the NK cell unable to trigger this pathway in response to a subsequent encounter with a target cell. In the present study we evaluated the involvement of PKC in inhibition of NK lysis of tumor cells and activation of MAPKs caused by TBT exposure. TBT caused a 2–3-fold activation of PKC at concentrations ranging from 50 to 300 nM (16–98 ng/ml),indicating that activation of PKC occurs in response to TBT exposure. This would then leave the NK cell unable to respond to targets. Treatment with the PKC inhibitor, bisindolylmaleimide I, caused an 85% decrease in the ability of NK cells to lyse tumor cells, validating the involvement of PKC in the lytic signaling pathway. The role of PKC in the activation of MAPKs by TBT was also investigated using bisindolylmaleimide I. The results indicated that, in NK cells where PKC activation was blocked, there was no activation of the MAPK, p44/42 in response to TBT.However, TBT-induced activation of the MAPKs, p38 and JNK did not require PKC activation. These results indicate the pivotal role of PKC in the TBT-induced loss of NK lytic function including activation of p44/42 by TBT in NK cells.

Role of protein kinase C in the TBT-induced inhibition of lytic function and MAPK activation in human natural killer cells

PubMed Central

Abraha, Abraham B.; Rana, Krupa; Whalen, Margaret M.

2010-01-01

Human natural killer (NK) cells are lymphocytes that destroy tumor and virally infected cells. Previous studies have shown that exposures of NK cells to tributyltin (TBT) greatly diminish their ability to destroy tumor cells (lytic function) while activating mitogen-activated protein kinases (MAPK) (p44/42, p38, and JNK) in the NK cells. The signaling pathway that regulates NK lytic function appears to include activation of protein kinase C (PKC) as well as MAPK activity. The TBT-induced activation of MAPKs would trigger a portion of the NK lytic signaling pathway, which would then leave the NK cell unable to trigger this pathway in response to a subsequent encounter with a target cell. In the present study we evaluated the involvement of PKC in the inhibition of NK lysis of tumor cells and activation of MAPKs caused by TBT exposures. TBT caused a 2–3 fold activation of PKC at concentrations ranging from 50–300 nM (16–98 ng/mL), indicating that activation of PKC occurs in response to TBT exposures. This would then leave the NK cell unable to respond to targets. Treatment with the PKC inhibitor, bisindolylmaleimide I, caused an 85% decrease in the ability of NK cells to lyse tumor cells validating the involvement of PKC in the lytic signaling pathway. The role of PKC in the activation of MAPKs by TBT was also investigated using bisindolylmaleimide I. The results indicated that in NK cells where PKC activation was blocked there was no activation of the MAPK, p44/42 in response to TBT. However, TBT-induced activation of the MAPKs, p38 and JNK did not require PKC activation. These results indicate the pivotal role of PKC in the TBT-induced loss of NK lytic function including the activation of p44/42 by TBT in NK cells. PMID:20390410

PKCalpha-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells.

PubMed

Mauro, Annunziata; Ciccarelli, Carmela; De Cesaris, Paola; Scoglio, Arianna; Bouché, Marina; Molinaro, Mario; Aquino, Angelo; Zani, Bianca Maria

2002-09-15

We have previously suggested that PKCalpha has a role in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-mediated growth arrest and myogenic differentiation in human embryonal rhabdomyosarcoma cells (RD). Here, by monitoring the signalling pathways triggered by TPA, we demonstrate that PKCalpha mediates these effects by inducing transient activation of c-Jun N-terminal protein kinases (JNKs) and sustained activation of both p38 kinase and extracellular signal-regulated kinases (ERKs) (all referred to as MAPKs). Activation of MAPKs following ectopic expression of constitutively active PKCalpha, but not its dominant-negative form, is also demonstrated. We investigated the selective contribution of MAPKs to growth arrest and myogenic differentiation by monitoring the activation of MAPK pathways, as well as by dissecting MAPK pathways using MEK1/2 inhibitor (UO126), p38 inhibitor (SB203580) and JNK and p38 agonist (anisomycin) treatments. Growth-arresting signals are triggered either by transient and sustained JNK activation (by TPA and anisomycin, respectively) or by preventing both ERK and JNK activation (UO126) and are maintained, rather than induced, by p38. We therefore suggest a key role for JNK in controlling ERK-mediated mitogenic activity. Notably, sarcomeric myosin expression is induced by both TPA and UO126 but is abrogated by the p38 inhibitor. This finding indicates a pivotal role for p38 in controlling the myogenic program. Anisomycin persistently activates p38 and JNKs but prevents myosin expression induced by TPA. In accordance with this negative role, reactivation of JNKs by anisomycin, in UO126-pre-treated cells, also prevents myosin expression. This indicates that, unlike the transient JNK activation that occurs in the TPA-mediated myogenic process, long-lasting JNK activation supports the growth-arrest state but antagonises p38-mediated myosin expression. Lastly, our results with the MEK inhibitor suggest a key role of the ERK pathway in regulating myogenic-related morphology in differentiated RD cells.

Cycling hypoxia: A key feature of the tumor microenvironment.

PubMed

Michiels, Carine; Tellier, Céline; Feron, Olivier

2016-08-01

A compelling body of evidence indicates that most human solid tumors contain hypoxic areas. Hypoxia is the consequence not only of the chaotic proliferation of cancer cells that places them at distance from the nearest capillary but also of the abnormal structure of the new vasculature network resulting in transient blood flow. Hence two types of hypoxia are observed in tumors: chronic and cycling (intermittent) hypoxia. Most of the current work aims at understanding the role of chronic hypoxia in tumor growth, response to treatment and metastasis. Only recently, cycling hypoxia, with spatial and temporal fluctuations in oxygen levels, has emerged as another key feature of the tumor environment that triggers different responses in comparison to chronic hypoxia. Either type of hypoxia is associated with distinct effects not only in cancer cells but also in stromal cells. In particular, cycling hypoxia has been demonstrated to favor, to a higher extent than chronic hypoxia, angiogenesis, resistance to anti-cancer treatments, intratumoral inflammation and tumor metastasis. These review details these effects as well as the signaling pathway it triggers to switch on specific transcriptomic programs. Understanding the signaling pathways through which cycling hypoxia induces these processes that support the development of an aggressive cancer could convey to the emergence of promising new cancer treatments. Copyright © 2016 Elsevier B.V. All rights reserved.

Taste receptors of the gut: emerging roles in health and disease.

PubMed

Depoortere, Inge

2014-01-01

Recent progress in unravelling the nutrient-sensing mechanisms in the taste buds of the tongue has triggered studies on the existence and role of chemosensory cells in the gut. Indeed, the gastrointestinal tract is the key interface between food and the human body and can sense basic tastes in much the same way as the tongue, through the use of similar G-protein-coupled taste receptors. These receptors 'taste' the luminal content and transmit signals that regulate nutrient transporter expression and nutrient uptake, and also the release of gut hormones and neurotransmitters involved in the regulation of energy and glucose homeostasis. Hence, they play a prominent role in the communication between the lumen, epithelium, smooth muscle cells, afferent nerve fibres and the brain to trigger adaptive responses that affect gastrointestinal function, food intake and glucose metabolism. This review summarises how sensing of nutrients by taste receptors along the gut plays a key role in the process of digestion, and how disturbances or adaptations of these chemosensory signalling pathways may contribute to the induction or resolution of a number of pathological conditions related to diabetes, obesity, or diet-induced symptom generation in irritable bowel syndrome. Targeting these receptors may represent a promising novel route for the treatment of a number of these diseases.

Measuring strategic success.

PubMed

Gish, Ryan

2002-08-01

Strategic triggers and metrics help healthcare providers achieve financial success. Metrics help assess progress toward long-term goals. Triggers signal market changes requiring a change in strategy. All metrics may not move in concert. Organizations need to identify indicators, monitor performance.

Streptomyces exploration is triggered by fungal interactions and volatile signals

PubMed Central

Jones, Stephanie E; Ho, Louis; Rees, Christiaan A; Hill, Jane E; Nodwell, Justin R; Elliot, Marie A

2017-01-01

It has long been thought that the life cycle of Streptomyces bacteria encompasses three developmental stages: vegetative hyphae, aerial hyphae and spores. Here, we show interactions between Streptomyces and fungi trigger a previously unobserved mode of Streptomyces development. We term these Streptomyces cells ‘explorers’, for their ability to adopt a non-branching vegetative hyphal conformation and rapidly transverse solid surfaces. Fungi trigger Streptomyces exploratory growth in part by altering the composition of the growth medium, and Streptomyces explorer cells can communicate this exploratory behaviour to other physically separated streptomycetes using an airborne volatile organic compound (VOC). These results reveal that interkingdom interactions can trigger novel developmental behaviours in bacteria, here, causing Streptomyces to deviate from its classically-defined life cycle. Furthermore, this work provides evidence that VOCs can act as long-range communication signals capable of propagating microbial morphological switches. DOI: http://dx.doi.org/10.7554/eLife.21738.001 PMID:28044982

A novel in situ trigger combination method

DOE PAGES

Buzatu, Adrian; Warburton, Andreas; Krumnack, Nils; ...

2013-01-30

Searches for rare physics processes using particle detectors in high-luminosity colliding hadronic beam environments require the use of multi-level trigger systems to reject colossal background rates in real time. In analyses like the search for the Higgs boson, there is a need to maximize the signal acceptance by combining multiple different trigger chains when forming the offline data sample. In such statistically limited searches, datasets are often amassed over periods of several years, during which the trigger characteristics evolve and system performance can vary significantly. Reliable production cross-section measurements and upper limits must take into account a detailed understanding ofmore » the effective trigger inefficiency for every selected candidate event. We present as an example the complex situation of three trigger chains, based on missing energy and jet energy, that were combined in the context of the search for the Higgs (H) boson produced in association with a $W$ boson at the Collider Detector at Fermilab (CDF). We briefly review the existing techniques for combining triggers, namely the inclusion, division, and exclusion methods. We introduce and describe a novel fourth in situ method whereby, for each candidate event, only the trigger chain with the highest a priori probability of selecting the event is considered. We compare the inclusion and novel in situ methods for signal event yields in the CDF $WH$ search. This new combination method, by virtue of its scalability to large numbers of differing trigger chains and insensitivity to correlations between triggers, will benefit future long-running collider experiments, including those currently operating on the Large Hadron Collider.« less

A novel in situ trigger combination method

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

Buzatu, Adrian; Warburton, Andreas; Krumnack, Nils

Searches for rare physics processes using particle detectors in high-luminosity colliding hadronic beam environments require the use of multi-level trigger systems to reject colossal background rates in real time. In analyses like the search for the Higgs boson, there is a need to maximize the signal acceptance by combining multiple different trigger chains when forming the offline data sample. In such statistically limited searches, datasets are often amassed over periods of several years, during which the trigger characteristics evolve and system performance can vary significantly. Reliable production cross-section measurements and upper limits must take into account a detailed understanding ofmore » the effective trigger inefficiency for every selected candidate event. We present as an example the complex situation of three trigger chains, based on missing energy and jet energy, that were combined in the context of the search for the Higgs (H) boson produced in association with a $W$ boson at the Collider Detector at Fermilab (CDF). We briefly review the existing techniques for combining triggers, namely the inclusion, division, and exclusion methods. We introduce and describe a novel fourth in situ method whereby, for each candidate event, only the trigger chain with the highest a priori probability of selecting the event is considered. We compare the inclusion and novel in situ methods for signal event yields in the CDF $WH$ search. This new combination method, by virtue of its scalability to large numbers of differing trigger chains and insensitivity to correlations between triggers, will benefit future long-running collider experiments, including those currently operating on the Large Hadron Collider.« less

Gravity loading induces adenosine triphosphate release and phosphorylation of extracellular signal-regulated kinases in human periodontal ligament cells.

PubMed

Ito, Mai; Arakawa, Toshiya; Okayama, Miki; Shitara, Akiko; Mizoguchi, Itaru; Takuma, Taishin

2014-11-01

The periodontal ligament (PDL) receives mechanical stress (MS) from dental occlusion or orthodontic tooth movement. Mechanical stress is thought to be a trigger for remodeling of the PDL and alveolar bone, although its signaling mechanism is still unclear. So we investigated the effect of MS on adenosine triphosphate (ATP) release and extracellular signal-regulated kinases (ERK) phosphorylation in PDL cells. Mechanical stress was applied to human PDL cells as centrifugation-mediated gravity loading. Apyrase, Ca(2+)-free medium and purinergic receptor agonists and antagonists were utilized to analyze the contribution of purinergic receptors to ERK phosphorylation. Gravity loading and ATP increased ERK phosphorylation by 5 and 2.5 times, respectively. Gravity loading induced ATP release from PDL cells by tenfold. Apyrase and suramin diminished ERK phosphorylation induced by both gravity loading and ATP. Under Ca(2+)-free conditions the phosphorylation by gravity loading was partially decreased, whereas ATP-induced phosphorylation was unaffected. Receptors P2Y4 and P2Y6 were prominently expressed in the PDL cells. Gravity loading induced ATP release and ERK phosphorylation in PDL fibroblasts, and ATP signaling via P2Y receptors was partially involved in this phosphorylation, which in turn would enhance gene expression for the remodeling of PDL tissue during orthodontic tooth movement. © 2013 Wiley Publishing Asia Pty Ltd.

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.

PubMed

Wu, Jian; Tian, Linjie; Yu, Xiao; Pattaradilokrat, Sittiporn; Li, Jian; Wang, Mingjun; Yu, Weishi; Qi, Yanwei; Zeituni, Amir E; Nair, Sethu C; Crampton, Steve P; Orandle, Marlene S; Bolland, Silvia M; Qi, Chen-Feng; Long, Carole A; Myers, Timothy G; Coligan, John E; Wang, Rongfu; Su, Xin-zhuan

2014-01-28

Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

Zebrafish Transgenic Line huORFZ Is an Effective Living Bioindicator for Detecting Environmental Toxicants

PubMed Central

Chu, Chien; Li, Hong-Ping; Tsai, Huai-Jen

2014-01-01

Reliable animal models are invaluable for monitoring the extent of pollution in the aquatic environment. In this study, we demonstrated the potential of huORFZ, a novel transgenic zebrafish line that harbors a human upstream open reading frame of the chop gene fused with GFP reporter, as an animal model for monitoring environmental pollutants and stress-related cellular processes. When huORFZ embryos were kept under normal condition, no leaked GFP signal could be detected. When treated with hazardous chemicals, including heavy metals and endocrine-disrupting chemicals near their sublethal concentrations (LC50), huORFZ embryos exhibited different tissue-specific GFP expression patterns. For further analysis, copper (Cu2+), cadmium (Cd2+) and Chlorpyrifos were applied. Cu2+ triggered GFP responses in skin and muscle, whereas Cd2+ treatment triggered GFP responses in skin, olfactory epithelium and pronephric ducts. Moreover, fluorescence intensity, as exhibited by huORFZ embryos, was dose-dependent. After surviving treated embryos were returned to normal condition, survival rates, as well as TUNEL signals, returned to pretreatment levels with no significant morphological defects observed. Such results indicated the reversibility of treatment conditions used in this study, as long as embryos survived such conditions. Notably, GFP signals decreased along with recovery, suggesting that GFP signaling of huORFZ embryos likely reflected the overall physiological condition of the individual. To examine the performance of the huORFZ line under real-world conditions, we placed huORFZ embryos in different river water samples. We found that the huORFZ embryos correctly detected the presence of various kinds of pollutants. Based on these findings, we concluded that such uORFchop-based system can be integrated into a first-line water alarm system monitoring the discharge of hazardous pollutants. PMID:24594581

Development of a beam test telescope based on the Alibava readout system

NASA Astrophysics Data System (ADS)

Marco-Hernández, R.

2011-01-01

A telescope for a beam test have been developed as a result of a collaboration among the University of Liverpool, Centro Nacional de Microelectrónica (CNM) of Barcelona and Instituto de Física Corpuscular (IFIC) of Valencia. This system is intended to carry out both analogue charge collection and spatial resolution measurements with different types of microstrip or pixel silicon detectors in a beam test environment. The telescope has four XY measurement as well as trigger planes (XYT board) and it can accommodate up to twelve devices under test (DUT board). The DUT board uses two Beetle ASICs for the readout of chilled silicon detectors. The board could operate in a self-triggering mode. The board features a temperature sensor and it can be mounted on a rotary stage. A peltier element is used for cooling the DUT. Each XYT board measures the track space points using two silicon strip detectors connected to two Beetle ASICs. It can also trigger on the particle tracks in the beam test. The board includes a CPLD which allows for the synchronization of the trigger signal to a common clock frequency, delaying and implementing coincidence with other XYT boards. An Alibava mother board is used to read out and to control each XYT/DUT board from a common trigger signal and a common clock signal. The Alibava board has a TDC on board to have a time stamp of each trigger. The data collected by each Alibava board is sent to a master card by means of a local data/address bus following a custom digital protocol. The master board distributes the trigger, clock and reset signals. It also merges the data streams from up to sixteen Alibava boards. The board has also a test channel for testing in a standard mode a XYT or DUT board. This board is implemented with a Xilinx development board and a custom patch board. The master board is connected with the DAQ software via 100M Ethernet. Track based alignment software has also been developed for the data obtained with the DAQ software.

Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects.

PubMed

Gazendam, Roel P; van Hamme, John L; Tool, Anton T J; Hoogenboezem, Mark; van den Berg, J Merlijn; Prins, Jan M; Vitkov, Ljubomir; van de Veerdonk, Frank L; van den Berg, Timo K; Roos, Dirk; Kuijpers, Taco W

2016-02-01

Neutrophils are known to play a pivotal role in the host defense against Aspergillus infections. This is illustrated by the prevalence of Aspergillus infections in patients with neutropenia or phagocyte functional defects, such as chronic granulomatous disease. However, the mechanisms by which human neutrophils recognize and kill Aspergillus are poorly understood. In this work, we have studied in detail which neutrophil functions, including neutrophil extracellular trap (NET) formation, are involved in the killing of Aspergillus fumigatus conidia and hyphae, using neutrophils from patients with well-defined genetic immunodeficiencies. Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1), which triggers a PI3K-dependent nonoxidative intracellular mechanism of killing. When the conidia escape from early killing and germinate, the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase. A. fumigatus induces NET formation; however, NETs did not contribute to A. fumigatus killing. Thus, our findings reveal distinct killing mechanisms of Aspergillus conidia and hyphae by human neutrophils, leading to a comprehensive insight in the innate antifungal response. Copyright © 2016 by The American Association of Immunologists, Inc.

Targeting of CD22-positive B-cell lymphoma cells by synthetic divalent sialic acid analogues.

PubMed

Schweizer, Astrid; Wöhner, Miriam; Prescher, Horst; Brossmer, Reinhard; Nitschke, Lars

2012-10-01

CD22 is an inhibitory co-receptor of the B-cell receptor (BCR) on B cells. Since CD22 is ubiquitously expressed in the B-cell lineage and CD22 endocytosis can be triggered efficiently, antibodies and antibody-based immunotoxins against CD22 are used to target B cells both in B-cell lymphomas and leukemias, as well as in autoimmune diseases. CD22 recognizes α2,6-linked sialic acids as endogenous ligands. We have developed new synthetic sialosides as ligands for human CD22. These sialosides bind CD22 on human B cells with high affinity and can efficiently enhance IgM-triggered Ca(2+) signaling. We coupled these sialosides to Pseudomonas exotoxin A to generate a novel CD22 ligand-based immunotoxin. This sialoside-exotoxin-A construct can specifically kill CD22-positive B-cell lymphoma cells. It binds specifically to CD22-positive B-cell lymphoma cells and is dominant over endogenous cis-ligands on the B-cell surface. The sialoside-exotoxin-A construct is efficiently internalized by endocytosis into B-cell lymphoma cell lines. Thus we show the development of a new therapeutic compound for targeting CD22 on human B cells, both for B-cell lymphoma, as well as for B-cell-mediated autoimmune diseases. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Erroneous cardiac ECG-gated PET list-mode trigger events can be retrospectively identified and replaced by an offline reprocessing approach: first results in rodents

NASA Astrophysics Data System (ADS)

Böning, Guido; Todica, Andrei; Vai, Alessandro; Lehner, Sebastian; Xiong, Guoming; Mille, Erik; Ilhan, Harun; la Fougère, Christian; Bartenstein, Peter; Hacker, Marcus

2013-11-01

The assessment of left ventricular function, wall motion and myocardial viability using electrocardiogram (ECG)-gated [18F]-FDG positron emission tomography (PET) is widely accepted in human and in preclinical small animal studies. The nonterminal and noninvasive approach permits repeated in vivo evaluations of the same animal, facilitating the assessment of temporal changes in disease or therapy response. Although well established, gated small animal PET studies can contain erroneous gating information, which may yield to blurred images and false estimation of functional parameters. In this work, we present quantitative and visual quality control (QC) methods to evaluate the accuracy of trigger events in PET list-mode and physiological data. Left ventricular functional analysis is performed to quantify the effect of gating errors on the end-systolic and end-diastolic volumes, and on the ejection fraction (EF). We aim to recover the cardiac functional parameters by the application of the commonly established heart rate filter approach using fixed ranges based on a standardized population. In addition, we propose a fully reprocessing approach which retrospectively replaces the gating information of the PET list-mode file with appropriate list-mode decoding and encoding software. The signal of a simultaneously acquired ECG is processed using standard MATLAB vector functions, which can be individually adapted to reliably detect the R-peaks. Finally, the new trigger events are inserted into the PET list-mode file. A population of 30 mice with various health statuses was analyzed and standard cardiac parameters such as mean heart rate (119 ms ± 11.8 ms) and mean heart rate variability (1.7 ms ± 3.4 ms) derived. These standard parameter ranges were taken into account in the QC methods to select a group of nine optimal gated and a group of eight sub-optimal gated [18F]-FDG PET scans of mice from our archive. From the list-mode files of the optimal gated group, we randomly deleted various fractions (5% to 60%) of contained trigger events to generate a corrupted group. The filter approach was capable to correct the corrupted group and yield functional parameters with no significant difference to the optimal gated group. We successfully demonstrated the potential of the fully reprocessing approach by applying it to the sub-optimal group, where the functional parameters were significantly improved after reprocessing (mean EF from 41% ± 16% to 60% ± 13%). When applied to the optimal gated group the fully reprocessing approach did not alter the functional parameters significantly (mean EF from 64% ± 8% to 64 ± 7%). This work presents methods to determine and quantify erroneous gating in small animal gated [18F]-FDG PET scans. We demonstrate the importance of a quality check for cardiac triggering contained in PET list-mode data and the benefit of optionally reprocessing the fully recorded physiological information to retrospectively modify or fully replace the cardiac triggering in PET list-mode data. We aim to provide a preliminary guideline of how to proceed in the presence of errors and demonstrate that offline reprocessing by filtering erroneous trigger events and retrospective gating by ECG processing is feasible. Future work will focus on the extension by additional QC methods, which may exploit the amplitude of trigger events and ECG signal by means of pattern recognition. Furthermore, we aim to transfer the proposed QC methods and the fully reprocessing approach to human myocardial PET/CT.

Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the β2-adrenoceptor.

PubMed

Reinartz, Michael T; Kälble, Solveig; Littmann, Timo; Ozawa, Takeaki; Dove, Stefan; Kaever, Volkhard; Wainer, Irving W; Seifert, Roland

2015-01-01

Functional selectivity is well established as an underlying concept of ligand-specific signaling via G protein-coupled receptors (GPCRs). Functionally, selective drugs could show greater therapeutic efficacy and fewer adverse effects. Dual coupling of the β2-adrenoceptor (β2AR) triggers a signal transduction via Gsα and Giα proteins. Here, we examined 12 fenoterol stereoisomers in six molecular and cellular assays. Using β2AR-Gsα and β2AR-Giα fusion proteins, (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol were identified as biased ligands with preference for Gs. G protein-independent signaling via β-arrestin-2 was disfavored by these ligands. Isolated human neutrophils constituted an ex vivo model of β2AR signaling and demonstrated functional selectivity through the dissociation of cAMP accumulation and the inhibition of formyl peptide-stimulated production of reactive oxygen species. Ligand bias was calculated using an operational model of agonism and revealed that the fenoterol scaffold constitutes a promising lead structure for the development of Gs-biased β2AR agonists.

Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway.

PubMed

Tang, Ning; Shi, Lei; Yu, Zhenlong; Dong, Peipei; Wang, Chao; Huo, Xiaokui; Zhang, Baojing; Huang, Shanshan; Deng, Sa; Liu, Kexin; Ma, Tonghui; Wang, Xiaobo; Wu, Lijun; Ma, Xiao-Chi

2016-01-19

Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.

A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks.

PubMed

Mailloux, Shay; Halámek, Jan; Katz, Evgeny

2014-03-07

A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3-input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug-mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine.

GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release.

PubMed

Filardo, Edward J; Thomas, Peter

2005-10-01

Heterotrimeric G proteins and seven-transmembrane-spanning (7TM) receptors are implicated in rapid estrogen signaling. The orphan 7TM receptor GPR30 is linked to estrogen-mediated activation of adenylyl cyclase, release of epidermal growth factor (EGF)-related ligands, and specific estrogen binding. GPR30 acts independently of estrogen receptors, ERalpha and ERbeta, and probably functions as a heptahelical ER. 7TM receptors elicit signals that stimulate second messengers, and convey intracellular signals via EGF receptors. Identification of GPR30 as a Gs-coupled 7TM receptor that triggers release of heparin-binding EGF establishes its role in cell signaling cascades initiated by estrogens, and explains their capacity to activate second messengers and promote EGF-like effects. Thus, estrogen can signal by the same mechanism as various other hormones, through a specific 7TM receptor.

Sugars and plant innate immunity.

PubMed

Bolouri Moghaddam, Mohammad Reza; Van den Ende, Wim

2012-06-01

Sugars are involved in many metabolic and signalling pathways in plants. Sugar signals may also contribute to immune responses against pathogens and probably function as priming molecules leading to pathogen-associated molecular patterns (PAMP)-triggered immunity and effector-triggered immunity in plants. These putative roles also depend greatly on coordinated relationships with hormones and the light status in an intricate network. Although evidence in favour of sugar-mediated plant immunity is accumulating, more in-depth fundamental research is required to unravel the sugar signalling pathways involved. This might pave the way for the use of biodegradable sugar-(like) compounds to counteract plant diseases as cheaper and safer alternatives for toxic agrochemicals.

AMPLITUDE DISCRIMINATOR HAVING SEPARATE TRIGGERING AND RECOVERY CONTROLS UTILIZING AUTOMATIC TRIGGERING

DOEpatents

Chase, R.L.

1962-01-23

A transistorized amplitude discriminator circuit is described in which the initial triggering sensitivity and the recovery threshold are separately adjustable in a convenient manner. The discriminator is provided with two independent bias components, one of which is for circuit hysteresis (recovery) and one of which is for trigger threshold level. A switching circuit is provided to remove the second bias component upon activation of the trigger so that the recovery threshold is always at the point where the trailing edge of the input signal pulse goes through zero or other desired value. (AEC)

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

PubMed Central

2018-01-01

The current interest of the scientific community for research in the field of calcium sensing in general and on the calcium-sensing Receptor (CaR) in particular is demonstrated by the still increasing number of papers published on this topic. The extracellular calcium-sensing receptor is the best-known G-protein-coupled receptor (GPCR) able to sense external Ca2+ changes. Widely recognized as a fundamental player in systemic Ca2+ homeostasis, the CaR is ubiquitously expressed in the human body where it activates multiple signalling pathways. In this review, old and new notions regarding the mechanisms by which extracellular Ca2+ microdomains are created and the tools available to measure them are analyzed. After a survey of the main signalling pathways triggered by the CaR, a special attention is reserved for the emerging concepts regarding CaR function in the heart, CaR trafficking and pharmacology. Finally, an overview on other Ca2+ sensors is provided. PMID:29584660

Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction.

PubMed

Danis, Judit; Janovák, Luca; Gubán, Barbara; Göblös, Anikó; Szabó, Kornélia; Kemény, Lajos; Bata-Csörgő, Zsuzsanna; Széll, Márta

2018-03-08

Keratinocytes are non-professional immune cells contributing actively to innate immune responses partially by reacting to a wide range of molecular patterns by activating pattern recognition receptors. Cytosolic nucleotide fragments as pathogen- or self-derived trigger factors are activating inflammasomes and inducing anti-viral signal transduction pathways as well as inducing expression of inflammatory cytokines. We aimed to compare the induced inflammatory reactions in three keratinocyte cell types-normal human epidermal keratinocytes, the HaCaT cell line and the HPV-KER cell line-upon exposure to the synthetic RNA and DNA analogues poly(I:C) and poly(dA:dT) to reveal the underlying signaling events. Both agents induced the expression of interleukin-6 and tumor necrosis factor α in all cell types; however, notable kinetic and expression level differences were found. Western blot analysis revealed rapid activation of the nuclear factor κB (NF-κB), mitogen activated protein kinase and signal transducers of activator of transcription (STAT) signal transduction pathways in keratinocytes upon poly(I:C) treatment, while poly(dA:dT) induced slower activation. Inhibition of NF-κB, p38, STAT-1 and STAT-3 signaling resulted in decreased cytokine expression, whereas inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling showed a negative feedback role in both poly(I:C)- and poly(dA:dT)-induced cytokine expression. Based on our in vitro results nucleotide fragments are able to induce inflammatory reactions in keratinocytes, but with different rate and kinetics of cytokine expression, explained by faster activation of signaling routes by poly(I:C) than poly(dA:dT).

Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction

PubMed Central

Danis, Judit; Janovák, Luca; Gubán, Barbara; Göblös, Anikó; Szabó, Kornélia; Bata-Csörgő, Zsuzsanna; Széll, Márta

2018-01-01

Keratinocytes are non-professional immune cells contributing actively to innate immune responses partially by reacting to a wide range of molecular patterns by activating pattern recognition receptors. Cytosolic nucleotide fragments as pathogen- or self-derived trigger factors are activating inflammasomes and inducing anti-viral signal transduction pathways as well as inducing expression of inflammatory cytokines. We aimed to compare the induced inflammatory reactions in three keratinocyte cell types—normal human epidermal keratinocytes, the HaCaT cell line and the HPV-KER cell line—upon exposure to the synthetic RNA and DNA analogues poly(I:C) and poly(dA:dT) to reveal the underlying signaling events. Both agents induced the expression of interleukin-6 and tumor necrosis factor α in all cell types; however, notable kinetic and expression level differences were found. Western blot analysis revealed rapid activation of the nuclear factor κB (NF-κB), mitogen activated protein kinase and signal transducers of activator of transcription (STAT) signal transduction pathways in keratinocytes upon poly(I:C) treatment, while poly(dA:dT) induced slower activation. Inhibition of NF-κB, p38, STAT-1 and STAT-3 signaling resulted in decreased cytokine expression, whereas inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling showed a negative feedback role in both poly(I:C)- and poly(dA:dT)-induced cytokine expression. Based on our in vitro results nucleotide fragments are able to induce inflammatory reactions in keratinocytes, but with different rate and kinetics of cytokine expression, explained by faster activation of signaling routes by poly(I:C) than poly(dA:dT). PMID:29518010

Search for the Standard Model Higgs boson produced in association with a W Boson in the isolated-track charged-lepton channel using the Collider Detector at Fermilab

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

Buzatu, Adrian

2011-08-01

The Higgs boson is the only elementary particle predicted by the Standard Model (SM) that has not yet been observed experimentally. If it exists, it explains the spontaneous electroweak symmetry breaking and the origin of mass for gauge bosons and fermions. We test the validity of the SM by performing a search for the associated production of a Higgs boson and a W boson in the channel where the Higgs boson decays to a bottom-antibottom quark pair and the W boson decays to a charged lepton and a neutrino (the WH channel). We study a dataset of proton-antiproton collisions atmore » a centre-of-mass energy √s = 1.96 TeV provided by the Tevatron accelerator, corresponding to an integrated luminosity of 5.7 fb -1, and recorded using the Collider Detector at Fermilab (CDF).We select events consistent with the signature of exactly one charged lepton (electron or muon), missing transverse energy due to the undetected neutrino (MET) and two collimated streams of particles (jets), at least one of which is required to be identified as originating from a bottom quark. We improve the discrimination of Higgs signal from backgrounds through the use of an artificial neural network. Using a Bayesian statistical inference approach, we set for each hypothetical Higgs boson mass in the range 100-150 GeV/c 2 with 5 GeV/c 2 increments a 95% credibility level (CL) upper limit on the ratio between the Higgs production cross section times branching fraction and the SM prediction. Our main original contributions are the addition of a novel charged lepton reconstruction algorithm with looser requirements (ISOTRK) with respect the electron or muon tight criteria (TIGHT), as well as the introduction of a novel trigger-combination method that allows to maximize the event yield while avoiding trigger correlations and that is used for the ISOTRK category. The ISOTRK candidate is a high-transverse-momentum good-quality track isolated from other activity in the tracking system and not required to match a calorimeter cluster, as for a tight electron candidate, or an energy deposit in the muon detector, as for a tight muon candidate. The ISOTRK category recovers real charged leptons that otherwise would be lost in the non-instrumented regions of the detector. This allows the reconstruction of more W boson candidates, which in turn increases the number of reconstructed WH signal candidate events, and therefore improves the sensitivity of the WH search. For the TIGHT charged lepton categories, we employ charged-lepton-dedicated triggers to improve the rate of WH signal acceptance during data taking. Since there is no ISOTRK-dedicated trigger at CDF, for the ISOTRK charged lepton category we employ three MET-plus-jets-based triggers. For each trigger we first identify the jet selection where the trigger efficiency is flat with respect to jet information (transverse energy and direction of motion in the transverse plane for the two jets in the event) and then we parametrize the trigger efficiency as a function of trigger MET. On an event-by-event basis, for each trigger we compute a trigger efficiency as a function of trigger parametrization, trigger MET, jet information, trigger prescale and information about whether the trigger is defined or not. For the ISOTRK category we combine the three triggers using a novel method, which allows the combination of any number of triggers in order to maximize the event yield while avoiding trigger correlations. On an event-by-event basis, only the trigger with the largest efficiency is used. By avoiding a logical 'OR' between triggers, the loss in the yield of events accepted by the trigger combination is compensated by a smaller and easier-to-compute corresponding systematic uncertainty. The addition of the ISOTRK charged lepton category to the TIGHT category produces an increase of 33% in the WH signal yield and a decrease of 15.5% to 19.0% in the median expected 95% CL cross-section upper limits across the entire studied Higgs mass interval. The improvement in analysis sensitivity is smaller than the improvement in signal yield because the ISOTRK category has a smaller signal over background ratio than the TIGHT category, due to the looser ISOTRK reconstruction criteria. The observed (median expected) 95% CL SM Higgs upper limits on cross section times branching ratio vary between 2.39 x SM (2.73 x SM) for a Higgs mass of 100 GeV/c 2 to 31.1 x SM (31.2 x SM) for a Higgs mass of 150 GeV/c 2, while the value for a 115 GeV/c 2 Higgs boson is that of 5.08 x SM (3.79 x SM). The novel trigger combination method is already in use by several CDF analyses. It is applicable to any analysis that uses triggers based on MET and jets, such as supersymmetry searches at the ATLAS and CMS experiments at the Large Hadron Collider. In its most general form, the method can be used by any analysis that combines any number of different triggers.« less

Plasmacytoid predendritic cells initiate psoriasis through interferon-α production

PubMed Central

Nestle, Frank O.; Conrad, Curdin; Tun-Kyi, Adrian; Homey, Bernhard; Gombert, Michael; Boyman, Onur; Burg, Günter; Liu, Yong-Jun; Gilliet, Michel

2005-01-01

Psoriasis is one of the most common T cell–mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-α–producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-α early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-α signaling or inhibiting the ability of PDCs to produce IFN-α prevented the T cell–dependent development of psoriasis. Furthermore, IFN-α reconstitution experiments demonstrated that PDC-derived IFN-α is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-α represent potential early targets for the treatment of psoriasis. PMID:15998792

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization.

PubMed

Qi, Qian-Rong; Zhao, Xu-Yu; Zuo, Ru-Juan; Wang, Tong-Song; Gu, Xiao-Wei; Liu, Ji-Long; Yang, Zeng-Ming

2015-01-01

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

PubMed Central

Qi, Qian-Rong; Zhao, Xu-Yu; Zuo, Ru-Juan; Wang, Tong-Song; Gu, Xiao-Wei; Liu, Ji-Long; Yang, Zeng-Ming

2015-01-01

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans. PMID:25892397

Fiber-based generator for wearable electronics and mobile medication.

PubMed

Zhong, Junwen; Zhang, Yan; Zhong, Qize; Hu, Qiyi; Hu, Bin; Wang, Zhong Lin; Zhou, Jun

2014-06-24

Smart garments for monitoring physiological and biomechanical signals of the human body are key sensors for personalized healthcare. However, they typically require bulky battery packs or have to be plugged into an electric plug in order to operate. Thus, a smart shirt that can extract energy from human body motions to run body-worn healthcare sensors is particularly desirable. Here, we demonstrated a metal-free fiber-based generator (FBG) via a simple, cost-effective method by using commodity cotton threads, a polytetrafluoroethylene aqueous suspension, and carbon nanotubes as source materials. The FBGs can convert biomechanical motions/vibration energy into electricity utilizing the electrostatic effect with an average output power density of ∼0.1 μW/cm(2) and have been identified as an effective building element for a power shirt to trigger a wireless body temperature sensor system. Furthermore, the FBG was demonstrated as a self-powered active sensor to quantitatively detect human motion.

Stimuli-Responsive DNA-Based Hydrogels: From Basic Principles to Applications.

PubMed

Kahn, Jason S; Hu, Yuwei; Willner, Itamar

2017-04-18

The base sequence of nucleic acids encodes structural and functional information into the DNA biopolymer. External stimuli such as metal ions, pH, light, or added nucleic acid fuel strands provide triggers to reversibly switch nucleic acid structures such as metal-ion-bridged duplexes, i-motifs, triplex nucleic acids, G-quadruplexes, or programmed double-stranded hybrids of oligonucleotides (DNA). The signal-triggered oligonucleotide structures have been broadly applied to develop switchable DNA nanostructures and DNA machines, and these stimuli-responsive assemblies provide functional scaffolds for the rapidly developing area of DNA nanotechnology. Stimuli-responsive hydrogels undergoing signal-triggered hydrogel-to-solution transitions or signal-controlled stiffness changes attract substantial interest as functional matrices for controlled drug delivery, materials exhibiting switchable mechanical properties, acting as valves or actuators, and "smart" materials for sensing and information processing. The integration of stimuli-responsive oligonucleotides with hydrogel-forming polymers provides versatile means to exploit the functional information encoded in the nucleic acid sequences to yield stimuli-responsive hydrogels exhibiting switchable physical, structural, and chemical properties. Stimuli-responsive DNA-based nucleic acid structures are integrated in acrylamide polymer chains and reversible, switchable hydrogel-to-solution transitions of the systems are demonstrated by applying external triggers, such as metal ions, pH-responsive strands, G-quadruplex, and appropriate counter triggers that bridge and dissociate the polymer chains. By combining stimuli-responsive nucleic acid bridges with thermosensitive poly(N-isopropylacrylamide) (pNIPAM) chains, systems undergoing reversible solution ↔ hydrogel ↔ solid transitions are demonstrated. Specifically, by bridging acrylamide polymer chains by two nucleic acid functionalities, where one type of bridging unit provides a stimuli-responsive element and the second unit acts as internal "bridging memory", shape-memory hydrogels undergoing reversible and switchable transitions between shaped hydrogels and shapeless quasi-liquid states are demonstrated. By using stimuli-responsive hydrogel cross-linking units that can assemble the bridging units by two different input signals, the orthogonally-triggered functions of the shape-memory were shown. Furthermore, a versatile approach to assemble stimuli-responsive DNA-based acrylamide hydrogel films on surfaces is presented. The method involves the activation of the hybridization chain-reaction (HCR) by a surface-confined promoter strand, in the presence of acrylamide chains modified with two DNA hairpin structures and appropriate stimuli-responsive tethers. The resulting hydrogel-modified surfaces revealed switchable stiffness properties and signal-triggered catalytic functions. By applying the method to assemble the hydrogel microparticles, substrate-loaded, stimuli-responsive microcapsules are prepared. The signal-triggered DNA-based hydrogel microcapsules are applied as drug carriers for controlled release. The different potential applications and future perspectives of stimuli responsive hydrogels are discussed. Specifically, the use of these smart materials and assemblies as carriers for controlled drug release and as shape-memory matrices for information storage and inscription and the use of surface-confined stimuli-responsive hydrogels, exhibiting switchable stiffness properties, for catalysis and controlled growth of cells are discussed.

The proapoptotic effect of formononetin in human osteosarcoma cells: involvement of inactivation of ERK and Akt pathways.

PubMed

Liu, Yun; He, JinJie; Chen, XiaoMing; Li, Jian; Shen, MaoRong; Yu, WenJun; Yang, Yuan; Xiao, ZengMing

2014-01-01

Previous studies have shown that some phytoestrogens inhibits proliferation and induces apoptosis in estrogen-dependent cancers via estrogen receptor (ER)-mediated signaling pathway. In view of the expression of ER in human osteosarcoma cells, the purpose of this study is to investigate whether formononetin and calycosin, two of the major isoflavones in Radix astragali, could also elicit anti-tumor activity against osteosarcoma, along with the underlying mechanism. Human osteosarcoma cells U2OS were respectively treated with various concentrations of formononetin or calycosin. Cell proliferation was determined by MTT assay, while apoptosis by flow cytometry. Next, the expression levels of apoptosis-related genes ERK, Akt, Bcl-2, Bax and caspase-3 were quantified by real-time PCR and Western blotting. Formononetin exhibited higher anti-proliferative activities toward human osteosarcoma cells U2OS, when compared with calycosin. Therefore, U2OS cells were then respectively treated with various concentrations of formononetin, in order to elucidate the isoflavones-related signaling pathway. It was found that formononetin dose-dependently triggered apoptosis of U2OS cells in vitro. Furthermore, treatment of formononetin led to significant inactivation of ERK and Akt, followed by downregulation of Bcl-2, upregulation of Bax and finally increased expression of caspase-3. Formononetin is more effective than calycosin at promoting cell death of U2OS cells by induction of apoptosis, which is mediated by inactivation of ERK and Akt signaling pathways. Thus isoflavones, especially formononetin, may be useful as anti-cancer drugs for osteosarcoma through their apoptosis-inducing effects. © 2014 S. Karger AG, Basel.

Vitamin D and prebiotics may benefit the intestinal microbacteria and improve glucose homeostasis in prediabetes and type 2 diabetes.

PubMed

Barengolts, Elena

2013-01-01

To review the role of human large bowel microbacteria (microbiota) in the glucose homeostasis, to address vitamin D (VD) and prebiotics interactions with microbiota, and to summarize recent randomized clinical trials (RCTs) of VD and prebiotics supplementation in prediabetes (PreDM) and type 2 diabetes mellitus (T2DM). Primary literature was reviewed in the following areas: composition and activity of human microbiota associated with PreDM and T2DM, interactions between microbiota and glucose homeostasis, the interaction of microbiota with VD/prebiotics, and RCTs of VD/prebiotics in subjects with PreDM or T2DM. The human microbiota is comprised of 100 trillion bacteria with an aggregate genome that is 150-fold larger than the human genome. Data from the animal models and human studies reveal that an "obesogenic" diet results into the initial event of microbiota transformation from symbiosis to dysbiosis. The microbial antigens, such as Gram(-) bacteria and lipopolysaccharide (LPS), translocate to the host interior and trigger increased energy harvesting and Toll-like receptor (TLR) activation with subsequent inflammatory pathways signaling. The "double hit" of steatosis (ectopic fat accumulation) and "-itis" (inflammation) and contribution of "corisks" (e.g., vitamin D deficiency [VDD]) are required to activate molecular signaling, including impaired insulin signaling and secretion, that ends with T2DM and associated diseases. Dietary changes (e.g., prebiotics, VD supplementation) may ameliorate this process if initiated prior to the process becoming irreversible. Emerging evidence suggests an important role of microbiota in glucose homeostasis. VD supplementation and prebiotics may be useful in managing PreDM and T2DM.

Burkholderia pseudomallei Capsule Exacerbates Respiratory Melioidosis but Does Not Afford Protection against Antimicrobial Signaling or Bacterial Killing in Human Olfactory Ensheathing Cells

PubMed Central

Dando, Samantha J.; Ipe, Deepak S.; Batzloff, Michael; Sullivan, Matthew J.; Crossman, David K.; Crowley, Michael; Strong, Emily; Kyan, Stephanie; Leclercq, Sophie Y.; Ekberg, Jenny A. K.; St. John, James

2016-01-01

Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an often severe infection that regularly involves respiratory disease following inhalation exposure. Intranasal (i.n.) inoculation of mice represents an experimental approach used to study the contributions of bacterial capsular polysaccharide I (CPS I) to virulence during acute disease. We used aerosol delivery of B. pseudomallei to establish respiratory infection in mice and studied CPS I in the context of innate immune responses. CPS I improved B. pseudomallei survival in vivo and triggered multiple cytokine responses, neutrophil infiltration, and acute inflammatory histopathology in the spleen, liver, nasal-associated lymphoid tissue, and olfactory mucosa (OM). To further explore the role of the OM response to B. pseudomallei infection, we infected human olfactory ensheathing cells (OECs) in vitro and measured bacterial invasion and the cytokine responses induced following infection. Human OECs killed >90% of the B. pseudomallei in a CPS I-independent manner and exhibited an antibacterial cytokine response comprising granulocyte colony-stimulating factor, tumor necrosis factor alpha, and several regulatory cytokines. In-depth genome-wide transcriptomic profiling of the OEC response by RNA-Seq revealed a network of signaling pathways activated in OECs following infection involving a novel group of 378 genes that encode biological pathways controlling cellular movement, inflammation, immunological disease, and molecular transport. This represents the first antimicrobial program to be described in human OECs and establishes the extensive transcriptional defense network accessible in these cells. Collectively, these findings show a role for CPS I in B. pseudomallei survival in vivo following inhalation infection and the antibacterial signaling network that exists in human OM and OECs. PMID:27091931

Event-Triggered Fault Detection of Nonlinear Networked Systems.

PubMed

Li, Hongyi; Chen, Ziran; Wu, Ligang; Lam, Hak-Keung; Du, Haiping

2017-04-01

This paper investigates the problem of fault detection for nonlinear discrete-time networked systems under an event-triggered scheme. A polynomial fuzzy fault detection filter is designed to generate a residual signal and detect faults in the system. A novel polynomial event-triggered scheme is proposed to determine the transmission of the signal. A fault detection filter is designed to guarantee that the residual system is asymptotically stable and satisfies the desired performance. Polynomial approximated membership functions obtained by Taylor series are employed for filtering analysis. Furthermore, sufficient conditions are represented in terms of sum of squares (SOSs) and can be solved by SOS tools in MATLAB environment. A numerical example is provided to demonstrate the effectiveness of the proposed results.

FPGA-based trigger system for the LUX dark matter experiment

NASA Astrophysics Data System (ADS)

Akerib, D. S.; Araújo, H. M.; Bai, X.; Bailey, A. J.; Balajthy, J.; Beltrame, P.; Bernard, E. P.; Bernstein, A.; Biesiadzinski, T. P.; Boulton, E. M.; Bradley, A.; Bramante, R.; Cahn, S. B.; Carmona-Benitez, M. C.; Chan, C.; Chapman, J. J.; Chiller, A. A.; Chiller, C.; Currie, A.; Cutter, J. E.; Davison, T. J. R.; de Viveiros, L.; Dobi, A.; Dobson, J. E. Y.; Druszkiewicz, E.; Edwards, B. N.; Faham, C. H.; Fiorucci, S.; Gaitskell, R. J.; Gehman, V. M.; Ghag, C.; Gibson, K. R.; Gilchriese, M. G. D.; Hall, C. R.; Hanhardt, M.; Haselschwardt, S. J.; Hertel, S. A.; Hogan, D. P.; Horn, M.; Huang, D. Q.; Ignarra, C. M.; Ihm, M.; Jacobsen, R. G.; Ji, W.; Kazkaz, K.; Khaitan, D.; Knoche, R.; Larsen, N. A.; Lee, C.; Lenardo, B. G.; Lesko, K. T.; Lindote, A.; Lopes, M. I.; Malling, D. C.; Manalaysay, A. G.; Mannino, R. L.; Marzioni, M. F.; McKinsey, D. N.; Mei, D.-M.; Mock, J.; Moongweluwan, M.; Morad, J. A.; Murphy, A. St. J.; Nehrkorn, C.; Nelson, H. N.; Neves, F.; O`Sullivan, K.; Oliver-Mallory, K. C.; Ott, R. A.; Palladino, K. J.; Pangilinan, M.; Pease, E. K.; Phelps, P.; Reichhart, L.; Rhyne, C.; Shaw, S.; Shutt, T. A.; Silva, C.; Skulski, W.; Solovov, V. N.; Sorensen, P.; Stephenson, S.; Sumner, T. J.; Szydagis, M.; Taylor, D. J.; Taylor, W.; Tennyson, B. P.; Terman, P. A.; Tiedt, D. R.; To, W. H.; Tripathi, M.; Tvrznikova, L.; Uvarov, S.; Verbus, J. R.; Webb, R. C.; White, J. T.; Whitis, T. J.; Witherell, M. S.; Wolfs, F. L. H.; Yin, J.; Young, S. K.; Zhang, C.

2016-05-01

LUX is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils resulting from interactions with dark matter particles. Signals from the detector are processed with an FPGA-based digital trigger system that analyzes the incoming data in real-time, with just a few microsecond latency. The system enables first pass selection of events of interest based on their pulse shape characteristics and 3D localization of the interactions. It has been shown to be > 99 % efficient in triggering on S2 signals induced by only few extracted liquid electrons. It is continuously and reliably operating since its full underground deployment in early 2013. This document is an overview of the systems capabilities, its inner workings, and its performance.

NF-κB as a target for oncogenic viruses

PubMed Central

Sun, Shao-Cong; Cesarman, Ethel

2013-01-01

NF-κB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-κB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IκBs. Various cellular stimuli induce the activation of an IκB kinase (IKK), which phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-κB. Under normal conditions, the activation of NF-κB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-κB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-κB signaling pathway is a target of several human oncogenic viruses, including the human T-cell leukemia virus type 1 (HTLV1), the Kaposi sarcoma-associated herpesvirus (KSHV), and the Epstein bar virus (EBV). These viruses encode specific oncoproteins that target different signaling components of the NF-κB pathway, leading to persistent activation of NF-κB. This chapter will discuss the molecular mechanisms by which NF-κB is activated by the viral oncoproteins. PMID:20845110

p62 regulates CD40-mediated NFκB activation in macrophages through interaction with TRAF6

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

Seibold, Kristina; Ehrenschwender, Martin, E-mail: martin.ehrenschwender@ukr.de

CD40 is a member of the tumor necrosis factor (TNF) receptor family. Activation-induced recruitment of adapter proteins, so-called TNF-receptor-associated factors (TRAFs) to the cytoplasmic tail of CD40 triggers signaling cascades important in the immune system, but has also been associated with excessive inflammation in diseases such as atherosclerosis and rheumatoid arthritis. Especially, pro-inflammatory nuclear factor κB (NFκB) signaling emanating from CD40-associated TRAF6 appears to be a key pathogenic driving force. Consequently, targeting the CD40-TRAF6 interaction is emerging as a promising therapeutic strategy, but the underlying molecular machinery of this signaling axis is to date poorly understood. Here, we identified themore » multifunctional adaptor protein p62 as a critical regulator in CD40-mediated NFκB signaling via TRAF6. CD40 activation triggered formation of a TRAF6-p62 complex. Disturbing this interaction tremendously reduced CD40-mediated NFκB signaling in macrophages, while TRAF6-independent signaling pathways remained unaffected. This highlights p62 as a potential target in hyper-inflammatory, CD40-associated pathologies. - Highlights: • CD40 activation triggers interaction of the adapter protein TRAF6 with p62. • TRAF6-p62 interaction regulates CD40-mediated NFκB signaling in macrophages. • Defective TRAF6-p62 interaction reduces CD40-mediated NFκB activation in macrophages.« less

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling.

PubMed

Melki, Isabelle; Rose, Yoann; Uggenti, Carolina; Van Eyck, Lien; Frémond, Marie-Louise; Kitabayashi, Naoki; Rice, Gillian I; Jenkinson, Emma M; Boulai, Anaïs; Jeremiah, Nadia; Gattorno, Marco; Volpi, Sefano; Sacco, Olivero; Terheggen-Lagro, Suzanne W J; Tiddens, Harm A W M; Meyts, Isabelle; Morren, Marie-Anne; De Haes, Petra; Wouters, Carine; Legius, Eric; Corveleyn, Anniek; Rieux-Laucat, Frederic; Bodemer, Christine; Callebaut, Isabelle; Rodero, Mathieu P; Crow, Yanick J

2017-08-01

Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

PubMed Central

Serr, Isabelle; Scherm, Martin G.; Zahm, Adam M.; Schug, Jonathan; Flynn, Victoria K.; Hippich, Markus; Kälin, Stefanie; Becker, Maike; Achenbach, Peter; Nikolaev, Alexei; Gerlach, Katharina; Liebsch, Nicole; Loretz, Brigitta; Lehr, Claus-Michael; Kirchner, Benedikt; Spornraft, Melanie; Haase, Bettina; Segars, James; Küper, Christoph; Palmisano, Ralf; Waisman, Ari; Willis, Richard A.; Kim, Wan-Uk; Weigmann, Benno; Kaestner, Klaus H.; Ziegler, Anette-Gabriele; Daniel, Carolin

2018-01-01

Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)–mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)–mediated NFAT5, which interferes with FoxP3+ Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity. PMID:29298866

IFN-γ Induces Mimic Extracellular Trap Cell Death in Lung Epithelial Cells Through Autophagy-Regulated DNA Damage.

PubMed

Lin, Chiou-Feng; Chien, Shun-Yi; Chen, Chia-Ling; Hsieh, Chia-Yuan; Tseng, Po-Chun; Wang, Yu-Chih

2016-02-01

Treatment of interferon-γ (IFN-γ) causes cell growth inhibition and cytotoxicity in lung epithelial malignancies. Regarding the induction of autophagy related to IFN-γ signaling, this study investigated the link between autophagy and IFN-γ cytotoxicity. In A549 human lung cancer cells, IFN-γ treatment induced concurrent apoptotic and nonapoptotic events. Unexpectedly, the nonapoptotic cells present mimic extracellular trap cell death (ETosis), which was regulated by caspase-3 and by autophagy induction through immunity-related GTPase family M protein 1 and activating transcription factor 6. Furthermore, IFN-γ signaling controlled mimic ETosis through a mechanism involving an autophagy- and Fas-associated protein with death domain-controlled caspase-8/-3 activation. Following caspase-mediated lamin degradation, IFN-γ caused DNA damage-associated ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM)-regulated mimic ETosis. Upon ATR/ATM signaling, peptidyl arginine deiminase 4 (PAD4)-mediated histone 3 citrullination promoted mimic ETosis. Such IFN-γ-induced effects were defective in PC14PE6/AS2 human lung cancer cells, which were unsusceptible to IFN-γ-induced autophagy. Due to autophagy-based caspase cascade activation, IFN-γ triggers unconventional caspase-mediated DNA damage, followed by ATR/ATM-regulated PAD4-mediated histone citrullination during mimic ETosis in lung epithelial malignancy.

Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway.

PubMed

Toubiana, Julie; Rossi, Anne-Lise; Belaidouni, Nadia; Grimaldi, David; Pene, Frederic; Chafey, Philippe; Comba, Béatrice; Camoin, Luc; Bismuth, Georges; Claessens, Yann-Erick; Mira, Jean-Paul; Chiche, Jean-Daniel

2015-10-01

TLR2 has a prominent role in host defense against a wide variety of pathogens. Stimulation of TLR2 triggers MyD88-dependent signaling to induce NF-κB translocation, and activates a Rac1-PI 3-kinase dependent pathway that leads to transactivation of NF-κB through phosphorylation of the P65 NF-κB subunit. This transactivation pathway involves tyrosine phosphorylations. The role of the tyrosine kinases in TLR signaling is controversial, with discrepancies between studies using only chemical inhibitors and knockout mice. Here, we show the involvement of the tyrosine-kinase Lyn in TLR2-dependent activation of NF-κB in human cellular models, by using complementary inhibition strategies. Stimulation of TLR2 induces the formation of an activation cluster involving TLR2, CD14, PI 3-kinase and Lyn, and leads to the activation of AKT. Lyn-dependent phosphorylation of the p110 catalytic subunit of PI 3-kinase is essential to the control of PI 3-kinase biological activity upstream of AKT and thereby to the transactivation of NF-κB. Thus, Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells. © The Author(s) 2015.

The activation of directional stem cell motility by green light-emitting diode irradiation.

PubMed

Ong, Wei-Kee; Chen, How-Foo; Tsai, Cheng-Ting; Fu, Yun-Ju; Wong, Yi-Shan; Yen, Da-Jen; Chang, Tzu-Hao; Huang, Hsien-Da; Lee, Oscar Kuang-Sheng; Chien, Shu; Ho, Jennifer Hui-Chun

2013-03-01

Light-emitting diode (LED) irradiation is potentially a photostimulator to manipulate cell behavior by opsin-triggered phototransduction and thermal energy supply in living cells. Directional stem cell motility is critical for the efficiency and specificity of stem cells in tissue repair. We explored that green LED (530 nm) irradiation directed the human orbital fat stem cells (OFSCs) to migrate away from the LED light source through activation of extracellular signal-regulated kinases (ERK)/MAP kinase/p38 signaling pathway. ERK inhibitor selectively abrogated light-driven OFSC migration. Phosphorylation of these kinases as well as green LED irradiation-induced cell migration was facilitated by increasing adenosine triphosphate (ATP) production in OFSCs after green LED exposure, and which was thermal stress-independent mechanism. OFSCs, which are multi-potent mesenchymal stem cells isolated from human orbital fat tissue, constitutionally express three opsins, i.e. retinal pigment epithelium-derived rhodopsin homolog (RRH), encephalopsin (OPN3) and short-wave-sensitive opsin 1 (OPN1SW). However, only two non-visual opsins, i.e. RRH and OPN3, served as photoreceptors response to green LED irradiation-induced OFSC migration. In conclusion, stem cells are sensitive to green LED irradiation-induced directional cell migration through activation of ERK signaling pathway via a wavelength-dependent phototransduction. Copyright © 2012 Elsevier Ltd. All rights reserved.

ATM and KAT5 safeguard replicating chromatin against formaldehyde damage

PubMed Central

Ortega-Atienza, Sara; Wong, Victor C.; DeLoughery, Zachary; Luczak, Michal W.; Zhitkovich, Anatoly

2016-01-01

Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA. PMID:26420831

Activation of the NLRP3 inflammasome by proteins that signal for necroptosis.

PubMed

Kang, Tae-Bong; Yang, Seung-Hoon; Toth, Beata; Kovalenko, Andrew; Wallach, David

2014-01-01

Necroptosis-a form of programmed necrotic cell death-and its resulting release of damage-associated molecular patterns (DAMPs) are believed to participate in the triggering of inflammatory processes. To assess the relative contribution of this cell death mode to inflammation, we need to know what other cellular effects can be exerted by molecules shown to trigger necrotic death, and the extent to which those effects might themselves contribute to inflammation. Here, we describe the technical approaches that have been applied to assess the impact of the main signaling molecules known to mediate activation of necroptosis upon generation of inflammatory cytokines in LPS-treated mouse bone marrow-derived dendritic cells. The findings obtained by this assessment indicated that signaling molecules known to initiate necroptosis can also initiate activation of the NLRP3 inflammasome, thereby inducing inflammation independently of cell death by triggering the generation of proinflammatory cytokines such as IL-1β. © 2014 Elsevier Inc. All rights reserved.

BDE-99 (2,2',4,4',5-pentabromodiphenyl ether) triggers epithelial-mesenchymal transition in colorectal cancer cells via PI3K/Akt/Snail signaling pathway.

PubMed

Wang, Fei; Ruan, Xin-Jian; Zhang, Hong-Yan

2015-01-01

The gut is in direct contact with BDE-99 (2,2',4,4',5-pentabromodiphenyl ether), one of the most abundant PBDE congeners in the environment and in human tissues. The objective of the present study was to investigate the effects of BDE-99 on colorectal cancer (CRC) cells. The effects of BDE-99 on cell proliferation were measured by CCK-8 assay in the CRC cell line HCT-116. Wound healing and transwell migration/invasion assays were used to test the migration and invasion of CRC cells. Factors related to epithelial-to-mesenchymal transition (EMT) were measured by real-time PCR and Western blot analysis for mRNA and protein levels, respectively. BDE-99 was found to increase migration and invasion and trigger EMT in HCT-116 cells; EMT was characterized by cells acquiring mesenchymal spindle-like morphology and by increased expression of N-cadherin with a concomitant decrease in E-cadherin. BDE-99 treatment also increased the protein and mRNA levels of the transcription factor Snail, but not Slug, Twist, and ZEB1. Knockdown of Snail by siRNA significantly attenuated BDE-99-induced EMT in HCT-116 cells, suggesting that Snail plays a crucial role in BDE-99-induced EMT. The PI3K/Akt inhibitor LY294002 completely blocked BDE-99-induced Snail and invasion of HCT-116 cells. Our results revealed that BDE-99 can trigger the EMT of colon cancer cells via the PI3K/AKT/Snail signaling pathway. This study provides new insight into the tumorigenesis and metastasis of CRC stimulated by BDE-99 and possibly other PBDE congeners.

Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells.

PubMed

Ouyang, Weiming; Li, Jingxia; Ma, Qian; Huang, Chuanshu

2006-04-01

Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKbeta/NFkappaB signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K-->Akt/p70(S6k) signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70(S6k) and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of Deltap85 or DN-Akt blocked arsenite-induced IKK phosphorylation, IkappaBalpha degradation and cyclin D1 expression, indicating that IKK/NFkappaB is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKbeta/NFkappaB signal pathway by overexpression of its dominant negative mutant, IKKbeta-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKbeta/NFkappaB signal cascade which in turn plays essential roles in inducing cyclin D1 expression.

Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

PubMed Central

Kuo, Wen Ping; Amphornrat, Jesa; Thilemann, Sebastian; Saab, Aiman S.; Kirchhoff, Frank; Möbius, Wiebke; Goebbels, Sandra; Nave, Klaus-Armin; Schneider, Anja; Simons, Mikael; Klugmann, Matthias; Trotter, Jacqueline; Krämer-Albers, Eva-Maria

2013-01-01

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity. PMID:23874151

Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.

PubMed

Frühbeis, Carsten; Fröhlich, Dominik; Kuo, Wen Ping; Amphornrat, Jesa; Thilemann, Sebastian; Saab, Aiman S; Kirchhoff, Frank; Möbius, Wiebke; Goebbels, Sandra; Nave, Klaus-Armin; Schneider, Anja; Simons, Mikael; Klugmann, Matthias; Trotter, Jacqueline; Krämer-Albers, Eva-Maria

2013-07-01

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²⁺ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

The Central Role of cAMP in Regulating Plasmodium falciparum Merozoite Invasion of Human Erythrocytes

PubMed Central

More, Kunal R.; Siddiqui, Faiza Amber; Pachikara, Niseema; Ramdani, Ghania; Langsley, Gordon; Chitnis, Chetan E.

2014-01-01

All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria. PMID:25522250

Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells.

PubMed

Wang, Chun; Xu, Can-Xin; Alippe, Yael; Qu, Chao; Xiao, Jianqiu; Schipani, Ernestina; Civitelli, Roberto; Abu-Amer, Yousef; Mbalaviele, Gabriel

2017-07-07

Skeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.

Specification of functional cranial placode derivatives from human pluripotent stem cells.

PubMed

Dincer, Zehra; Piao, Jinghua; Niu, Lei; Ganat, Yosif; Kriks, Sonja; Zimmer, Bastian; Shi, Song-Hai; Tabar, Viviane; Studer, Lorenz

2013-12-12

Cranial placodes are embryonic structures essential for sensory and endocrine organ development. Human placode development has remained largely inaccessible despite the serious medical conditions caused by the dysfunction of placode-derived tissues. Here, we demonstrate the efficient derivation of cranial placodes from human pluripotent stem cells. Timed removal of the BMP inhibitor Noggin, a component of the dual-SMAD inhibition strategy of neural induction, triggers placode induction at the expense of CNS fates. Concomitant inhibition of fibroblast growth factor signaling disrupts placode derivation and induces surface ectoderm. Further fate specification at the preplacode stage enables the selective generation of placode-derived trigeminal ganglia capable of in vivo engraftment, mature lens fibers, and anterior pituitary hormone-producing cells that upon transplantation produce human growth hormone and adrenocorticotropic hormone in vivo. Our results establish a powerful experimental platform to study human cranial placode development and set the stage for the development of human cell-based therapies in sensory and endocrine disease. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Mind-controlled transgene expression by a wireless-powered optogenetic designer cell implant.

PubMed

Folcher, Marc; Oesterle, Sabine; Zwicky, Katharina; Thekkottil, Thushara; Heymoz, Julie; Hohmann, Muriel; Christen, Matthias; Daoud El-Baba, Marie; Buchmann, Peter; Fussenegger, Martin

2014-11-11

Synthetic devices for traceless remote control of gene expression may provide new treatment opportunities in future gene- and cell-based therapies. Here we report the design of a synthetic mind-controlled gene switch that enables human brain activities and mental states to wirelessly programme the transgene expression in human cells. An electroencephalography (EEG)-based brain-computer interface (BCI) processing mental state-specific brain waves programs an inductively linked wireless-powered optogenetic implant containing designer cells engineered for near-infrared (NIR) light-adjustable expression of the human glycoprotein SEAP (secreted alkaline phosphatase). The synthetic optogenetic signalling pathway interfacing the BCI with target gene expression consists of an engineered NIR light-activated bacterial diguanylate cyclase (DGCL) producing the orthogonal second messenger cyclic diguanosine monophosphate (c-di-GMP), which triggers the stimulator of interferon genes (STING)-dependent induction of synthetic interferon-β promoters. Humans generating different mental states (biofeedback control, concentration, meditation) can differentially control SEAP production of the designer cells in culture and of subcutaneous wireless-powered optogenetic implants in mice.

Memory effects on mechanically stimulated electric signal; diversification of stimuli impact on material memory and comments on the observed features

NASA Astrophysics Data System (ADS)

Kyriazis, Panagiotis; Stavrakas, Ilias; Anastasiadis, Cimon; Triantis, Dimos; Stonham, John

2010-05-01

Memory is defined as the ability of marble and generally of brittle geomaterials to retain 'imprints' from previous treatments and to reproduce information about these treatments under certain conditions, by analogy to the memory of human beings. Memory effects have been observed in the evolution of a variety of physical properties like the acoustic emissions of brittle materials during fracture. The existence of memory effects for the mechanically stimulated electric signal, either by Pressure (PSC) or by Bending (BSC), is examined in this work, alongside with an attempt to distinguish between the two different manifestations of 'memory' based on the electrification mechanism that is triggered at different levels of externally applied load on samples. Having identified two main mechanisms (i.e. the dynamic and the cracking) and following the human memory model, we suggest the separation of memory of a material specimen into two levels i.e. the short or temporary and long or permanent memory. For the observation and analysis of the short memory of brittle materials we have conducted experiments using the PSC technique in marble specimens. The materials are imposed to cyclic stepwise loading of the same level, scheme and direction (axial stress - unchanged position of material) in order to comply with the conditions that are proposed as suitable for memory effects study by other researchers. We have also conducted experimental tests of cyclic high level stepwise loading on amphibolite rock specimens in order to verify and study the existence of permanent memory effects. Modelling the signal recordings and studying the effects of memory on the signals, we have identified certain trends manifestation for the two types of memory that are summarised to the following points. (a) Both types of memory influence the PSC peaks evolution (exponential decrease) in cyclic loadings of the same level. (b) Permanent memory cannot be erased and affects PSC signal permanently and severely. (c) The short memory has temporary influence on the PSC signal and the impacts on the signal are milder. The main properties of the PSC signal, which are affected by the existence of memory, converge to an inertial attitude of the material to the same stimuli and they are quite common with the properties of other fracture induced signals (i.e. AE). Namely, they are the following: (a) The PSC peak evolution over loading cycles is a changing signal property either in the case of permanent or of temporary memory, with respect to the time interval between events, especially in the latter case. (b) The decrease of the dissipated electric energy during cyclic loading tests. (c) The PSC slower relaxation in each loading, quantified by the relaxation process parameters evolution. (d) The PSC signal response delay in each loading cycle increase The existence of memory effects on the mechanically stimulated electric signal is an indication that information about the deformation history (paleostresses) of the material reside inside the material. Under certain conditions such information can be revealed by analysis of the PSC signal response to specific external mechanical triggering.

Design and characterization of the PREC (Prototype Readout Electronics for Counting particles)

NASA Astrophysics Data System (ADS)

Assis, P.; Brogueira, P.; Ferreira, M.; Luz, R.; Mendes, L.

2016-08-01

The design, tests and performance of a novel, low noise, acquisition system—the PREC (Prototype Readout Electronics for Counting particles) is presented in this article. PREC is a system developed using discrete electronics for particle counting applications using RPCs (Resistive Plate Chamber) detectors. PREC can, however, be used with other kind of detectors that present fast pulses, e.g. Silicon Photomultipliers. The PREC system consists in several Front-End boards that transmit data to a purely digital Motherboard. The amplification and discrimination of the signal is performed in the Front-End boards, making them the critical component of the system. In this paper, the Front-End was tested extensively by measuring the gain, noise level, crosstalk, trigger efficiency, propagation time and power consumption. The gain shows a decrease with the working temperature and an increase with the power supply voltage. The Front-End board shows a low noise level (<= 1.6 mV at 3σ level) and no crosstalk is detected above this level. The s-curve of the trigger efficiency is characterized by a 3 mV gap from the region where most of the signals are triggered to almost no signal is triggered. The signal transit time between the Front-End input and the digital Motherboard is estimated to be 5.82 ns. The maximum power consumption is 3.372 W for the Motherboard and 3.576 W and 1.443 W for each Front-End analogue circuitry and digital part, respectively.

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

The miR9863 Family Regulates Distinct Mla Alleles in Barley to Attenuate NLR Receptor-Triggered Disease Resistance and Cell-Death Signaling

PubMed Central

Liu, Jie; Cheng, Xiliu; Liu, Da; Xu, Weihui; Wise, Roger; Shen, Qian-Hua

2014-01-01

Barley (Hordeum vulgare L.) Mla alleles encode coiled-coil (CC), nucleotide binding, leucine-rich repeat (NB-LRR) receptors that trigger isolate-specific immune responses against the powdery mildew fungus, Blumeria graminis f. sp. hordei (Bgh). How Mla or NB-LRR genes in grass species are regulated at post-transcriptional level is not clear. The microRNA family, miR9863, comprises four members that differentially regulate distinct Mla alleles in barley. We show that miR9863 members guide the cleavage of Mla1 transcripts in barley, and block or reduce the accumulation of MLA1 protein in the heterologous Nicotiana benthamiana expression system. Regulation specificity is determined by variation in a unique single-nucleotide-polymorphism (SNP) in mature miR9863 family members and two SNPs in the Mla miR9863-binding site that separates these alleles into three groups. Further, we demonstrate that 22-nt miR9863s trigger the biogenesis of 21-nt phased siRNAs (phasiRNAs) and together these sRNAs form a feed-forward regulation network for repressing the expression of group I Mla alleles. Overexpression of miR9863 members specifically attenuates MLA1, but not MLA10-triggered disease resistance and cell-death signaling. We propose a key role of the miR9863 family in dampening immune response signaling triggered by a group of MLA immune receptors in barley. PMID:25502438

HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration*

PubMed Central

Spear, Mark; Guo, Jia; Turner, Amy; Yu, Dongyang; Wang, Weifeng; Meltzer, Beatrix; He, Sijia; Hu, Xiaohua; Shang, Hong; Kuhn, Jeffrey; Wu, Yuntao

2014-01-01

The human immunodeficiency virus type 1 (HIV-1) initiates receptor signaling and early actin dynamics during viral entry. This process is required for viral infection of primary targets such as resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission. PMID:24415754

HIV-1 triggers WAVE2 phosphorylation in primary CD4 T cells and macrophages, mediating Arp2/3-dependent nuclear migration.

PubMed

Spear, Mark; Guo, Jia; Turner, Amy; Yu, Dongyang; Wang, Weifeng; Meltzer, Beatrix; He, Sijia; Hu, Xiaohua; Shang, Hong; Kuhn, Jeffrey; Wu, Yuntao

2014-03-07

The human immunodeficiency virus type 1 (HIV-1) initiates receptor signaling and early actin dynamics during viral entry. This process is required for viral infection of primary targets such as resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission.

Reconstruction of Micropattern Detector Signals using Convolutional Neural Networks

NASA Astrophysics Data System (ADS)

Flekova, L.; Schott, M.

2017-10-01

Micropattern gaseous detector (MPGD) technologies, such as GEMs or MicroMegas, are particularly suitable for precision tracking and triggering in high rate environments. Given their relatively low production costs, MPGDs are an exemplary candidate for the next generation of particle detectors. Having acknowledged these advantages, both the ATLAS and CMS collaborations at the LHC are exploiting these new technologies for their detector upgrade programs in the coming years. When MPGDs are utilized for triggering purposes, the measured signals need to be precisely reconstructed within less than 200 ns, which can be achieved by the usage of FPGAs. In this work, we present a novel approach to identify reconstructed signals, their timing and the corresponding spatial position on the detector. In particular, we study the effect of noise and dead readout strips on the reconstruction performance. Our approach leverages the potential of convolutional neural network (CNNs), which have recently manifested an outstanding performance in a range of modeling tasks. The proposed neural network architecture of our CNN is designed simply enough, so that it can be modeled directly by an FPGA and thus provide precise information on reconstructed signals already in trigger level.

Image Accumulation in Pixel Detector Gated by Late External Trigger Signal and its Application in Imaging Activation Analysis

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

Jakubek, J.; Cejnarova, A.; Platkevic, M.

Single quantum counting pixel detectors of Medipix type are starting to be used in various radiographic applications. Compared to standard devices for digital imaging (such as CCDs or CMOS sensors) they present significant advantages: direct conversion of radiation to electric signal, energy sensitivity, noiseless image integration, unlimited dynamic range, absolute linearity. In this article we describe usage of the pixel device TimePix for image accumulation gated by late trigger signal. Demonstration of the technique is given on imaging coincidence instrumental neutron activation analysis (Imaging CINAA). This method allows one to determine concentration and distribution of certain preselected element in anmore » inspected sample.« less

MicroRNA-155 Is Required for Mycobacterium bovis BCG-Mediated Apoptosis of Macrophages

PubMed Central

Ghorpade, Devram Sampat; Leyland, Rebecca; Kurowska-Stolarska, Mariola; Patil, Shripad A.

2012-01-01

Pathogenic mycobacteria, including Mycobacterium tuberculosis and Mycobacterium bovis, cause significant morbidity and mortality worldwide. However, the vaccine strain Mycobacterium bovis BCG, unlike virulent strains, triggers extensive apoptosis of infected macrophages, a step necessary for the elicitation of robust protective immunity. We here demonstrate that M. bovis BCG triggers Toll-like receptor 2 (TLR2)-dependent microRNA-155 (miR-155) expression, which involves signaling cross talk among phosphatidylinositol 3-kinase (PI3K), protein kinase Cδ (PKCδ), and mitogen-activated protein kinases (MAPKs) and recruitment of NF-κB and c-ETS to miR-155 promoter. Genetic and signaling perturbations presented the evidence that miR-155 regulates PKA signaling by directly targeting a negative regulator of PKA, protein kinase inhibitor alpha (PKI-α). Enhanced activation of PKA signaling resulted in the generation of PKA C-α; phosphorylation of MSK1, cyclic AMP response element binding protein (CREB), and histone H3; and recruitment of phospho-CREB to the apoptotic gene promoters. The miR-155-triggered activation of caspase-3, BAK1, and cytochrome c translocation involved signaling integration of MAPKs and epigenetic or posttranslational modification of histones or CREB. Importantly, M. bovis BCG infection-induced apoptosis was severely compromised in macrophages derived from miR-155 knockout mice. Gain-of-function and loss-of-function studies validated the requirement of miR-155 for M. bovis BCG's ability to trigger apoptosis. Overall, M. bovis BCG-driven miR-155 dictates cell fate decisions of infected macrophages, strongly implicating a novel role for miR-155 in orchestrating cellular reprogramming during immune responses to mycobacterial infection. PMID:22473996

Paracrine signaling in a bacterium.

PubMed

López, Daniel; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

2009-07-15

Cellular differentiation is triggered by extracellular signals that cause target cells to adopt a particular fate. Differentiation in bacteria typically involves autocrine signaling in which all cells in the population produce and respond to the same signal. Here we present evidence for paracrine signaling in bacterial populations-some cells produce a signal to which only certain target cells respond. Biofilm formation in Bacillus involves two centrally important signaling molecules, ComX and surfactin. ComX triggers the production of surfactin. In turn, surfactin causes a subpopulation of cells to produce an extracellular matrix. Cells that produced surfactin were themselves unable to respond to it. Likewise, once surfactin-responsive cells commenced matrix production, they no longer responded to ComX and could not become surfactin producers. Insensitivity to ComX was the consequence of the extracellular matrix as mutant cells unable to make matrix responded to both ComX and surfactin. Our results demonstrate that extracellular signaling was unidirectional, with one subpopulation producing a signal and a different subpopulation responding to it. Paracrine signaling in a bacterial population ensures the maintenance, over generations, of particular cell types even in the presence of molecules that would otherwise cause those cells to differentiate into other cell types.

Inflammatory Cell signaling following Exposures to Particulate Matter and Ozone

EPA Science Inventory

This review mainly focuses on major inflammatory cell signaling pathways triggered byexposure to PM and 03. The receptors covered in this review include the EGF receptor, toll like receptor,and NOD-like receptor. Intracellular signaling protein kinases depicted in this review are...

Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

PubMed Central

Sanman, Laura E; Qian, Yu; Eisele, Nicholas A; Ng, Tessie M; van der Linden, Wouter A; Monack, Denise M; Weerapana, Eranthie; Bogyo, Matthew

2016-01-01

When innate immune cells such as macrophages are challenged with environmental stresses or infection by pathogens, they trigger the rapid assembly of multi-protein complexes called inflammasomes that are responsible for initiating pro-inflammatory responses and a form of cell death termed pyroptosis. We describe here the identification of an intracellular trigger of NLRP3-mediated inflammatory signaling, IL-1β production and pyroptosis in primed murine bone marrow-derived macrophages that is mediated by the disruption of glycolytic flux. This signal results from a drop of NADH levels and induction of mitochondrial ROS production and can be rescued by addition of products that restore NADH production. This signal is also important for host-cell response to the intracellular pathogen Salmonella typhimurium, which can disrupt metabolism by uptake of host-cell glucose. These results reveal an important inflammatory signaling network used by immune cells to sense metabolic dysfunction or infection by intracellular pathogens. DOI: http://dx.doi.org/10.7554/eLife.13663.001 PMID:27011353

Extracellular signals that define distinct and coexisting cell fates in Bacillus subtilis.

PubMed

López, Daniel; Kolter, Roberto

2010-03-01

The soil-dwelling bacterium Bacillus subtilis differentiates into distinct subpopulations of specialized cells that coexist within highly structured communities. The coordination and interplay between these cell types requires extensive extracellular communication driven mostly by sensing self-generated secreted signals. These extracellular signals activate a set of sensor kinases, which respond by phosphorylating three major regulatory proteins, Spo0A, DegU and ComA. Each phosphorylated regulator triggers a specific differentiation program while at the same time repressing other differentiation programs. This allows a cell to differentiate in response to a specific cue, even in the presence of other, possibly conflicting, signals. The sensor kinases involved respond to an eclectic group of extracellular signals, such as quorum-sensing molecules, natural products, temperature, pH or scarcity of nutrients. This article reviews the cascades of cell differentiation pathways that are triggered by sensing extracellular signals. We also present a tentative developmental model in which the diverse cell types sequentially differentiate to achieve the proper development of the bacterial community.

Target-triggering multiple-cycle signal amplification strategy for ultrasensitive detection of DNA based on QCM and SPR.

PubMed

Song, Weiling; Yin, Wenshuo; Sun, Wenbo; Guo, Xiaoyan; He, Peng; Yang, Xiaoyan; Zhang, Xiaoru

2018-04-24

Detection of ultralow concentrations of nucleic acid sequences is a central challenge in the early diagnosis of genetic diseases. Herein, we developed a target-triggering cascade multiple cycle amplification for ultrasensitive DNA detection using quartz crystal microbalance (QCM) and surface plasmon resonance (SPR). It was based on the exonuclease Ⅲ (Exo Ⅲ)-assisted signal amplification and the hybridization chain reaction (HCR). The streptavidin-coated Au-NPs (Au-NPs-SA) were assembled on the HCR products as recognition element. Upon sensing of target DNA, the duplex DNA probe triggered the Exo Ⅲ cleavage process, accompanied by generating a new secondary target DNA and releasing target DNA. The released target DNA and the secondary target DNA were recycled. Simultaneously, numerous single strands were liberated and acted as the trigger of HCR to generate further signal amplification, resulting in the immobilization of abundant Au-NPs-SA on the gold substrate. The QCM sensor results were found to be comparable to that achieved using a SPR sensor platform. This method exhibited a high sensitivity toward target DNA with a detection limit of 0.70 fM. The high sensitivity and specificity make this method a great potential for detecting DNA with trace amounts in bioanalysis and clinical biomedicine. Copyright © 2018 Elsevier Inc. All rights reserved.

The Neutrophil Btk Signalosome Regulates Integrin Activation during Sterile Inflammation

PubMed Central

Volmering, Stephanie; Block, Helena; Boras, Mark; Lowell, Clifford A.; Zarbock, Alexander

2016-01-01

SUMMARY Neutrophils are recruited from the blood to sites of sterile inflammation, where they are involved in wound healing but can also cause tissue damage. During sterile inflammation, necrotic cells release pro-inflammatory molecules including formylated peptides. However, the signaling pathway triggered by formylated peptides to integrin activation and leukocyte recruitment is unknown. By using spinning-disk confocal intravital microscopy, we examined the molecular mechanisms of leukocyte recruitment to sites of focal hepatic necrosis in vivo. We demonstrated that the Bruton’s tyrosine kinase (Btk) was required for multiple Mac-1 activation events involved in neutrophil recruitment and functions during sterile inflammation triggered by fMLF. The Src family kinase Hck, Wiskott-Aldrich-syndrome protein, and phospholipase Cγ2 were also involved in this pathway required for fMLF-triggered Mac-1 activation and neutrophil recruitment. Thus, we have identified a neutrophil Btk signalosome that is involved in a signaling pathway triggered by formylated peptides leading to the selective activation of Mac-1 and neutrophil recruitment during sterile inflammation. PMID:26777396

Protection from feed-forward amplification in an amplified RNAi mechanism

PubMed Central

Pak, Julia; Maniar, Jay Mahesh; Mello, Cecilia Cabral; Fire, Andrew

2012-01-01

SUMMARY The effectiveness of RNA interference (RNAi) in many organisms is potentiated through the signal-amplifying activity of a targeted RNA directed RNA polymerase (RdRP) system that can convert a small population of exogenously-encountered dsRNA fragments into an abundant internal pool of small interfering RNA (siRNA). As for any biological amplification system, we expect an underlying architecture that will limit the ability of a randomly encountered trigger to produce an uncontrolled and self-escalating response. Investigating such limits in C. elegans, we find that feed-forward amplification is limited by a critical biosynthetic and structural distinction at the RNA level between (i) triggers that can produce amplification and (ii) siRNA products of the amplification reaction. By assuring that initial (primary) siRNAs can act as triggers but not templates for activation, and that the resulting (secondary) siRNAs can enforce gene silencing on additional targets without unbridled trigger amplification, the system achieves substantial but fundamentally limited signal amplification. PMID:23141544

Postsynaptic density scaffold SAP102 regulates cortical synapse development through EphB and PAK signaling pathway

PubMed Central

Murata, Yasunobu; Constantine-Paton, Martha

2013-01-01

Membrane associated guanylate kinases (MAGUKs), including SAP102, PSD-95, PSD-93 and SAP97, are scaffolding proteins for ionotropic glutamate receptors at excitatory synapses. MAGUKs play critical roles in synaptic plasticity; however, details of signaling roles for each MAGUK remain largely unknown. Here we report that SAP102 regulates cortical synapse development through the EphB and PAK signaling pathways. Using lentivirus-delivered shRNAs, we found that SAP102 and PSD-95, but not PSD-93, are necessary for excitatory synapse formation and synaptic AMPA receptor localization in developing mouse cortical neurons. SAP102 knockdown (KD) increased numbers of elongated dendritic filopodia, which is often observed in mouse models and human patients with mental retardation. Further analysis revealed that SAP102 co-immunoprecipitated the receptor tyrosine kinase EphB2 and RacGEF Kalirin-7 in neonatal cortex, and SAP102 KD reduced surface expression and dendritic localization of EphB. Moreover, SAP102 KD prevented reorganization of actin filaments, synapse formation and synaptic AMPAR trafficking in response to EphB activation triggered by its ligand ephrinB. Lastly, p21-activated kinases (PAKs) were down-regulated in SAP102 KD neurons. These results demonstrate that SAP102 has unique roles in cortical synapse development by mediating EphB and its downstream PAK signaling pathway. Both SAP102 and PAKs are associated with X-linked mental retardation in humans; thus, synapse formation mediated by EphB/SAP102/PAK signaling in the early postnatal brain may be crucial for cognitive development. PMID:23486974

FPGA-based trigger system for the LUX dark matter experiment

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

Akerib, D. S.; Araújo, H. M.; Bai, X.

LUX is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils resulting from interactions with dark matter particles. Signals from the detector are processed with an FPGA-based digital trigger system that analyzes the incoming data in real-time, with just a few microsecond latency. The system enables first pass selection of events of interest based on their pulse shape characteristics and 3D localization of the interactions. It has been shown to be >99% efficient in triggering on S2 signals induced by only few extracted liquid electrons. It is continuously and reliably operating since its full underground deployment inmore » early 2013. This document is an overview of the systems capabilities, its inner workings, and its performance.« less

FPGA-based trigger system for the LUX dark matter experiment

DOE PAGES

Akerib, D. S.; Araújo, H. M.; Bai, X.; ...

2016-02-17

We present that LUX is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils resulting from interactions with dark matter particles. Signals from the detector are processed with an FPGA-based digital trigger system that analyzes the incoming data in real-time, with just a few microsecond latency. The system enables first pass selection of events of interest based on their pulse shape characteristics and 3D localization of the interactions. It has been shown to be > 99% efficient in triggering on S2 signals induced by only few extracted liquid electrons. It is continuously and reliably operating since itsmore » full underground deployment in early 2013. Finally, this document is an overview of the systems capabilities, its inner workings, and its performance.« less

Remote shock sensing and notification system

DOEpatents

Muralidharan, Govindarajan [Knoxville, TN; Britton, Charles L [Alcoa, TN; Pearce, James [Lenoir City, TN; Jagadish, Usha [Knoxville, TN; Sikka, Vinod K [Oak Ridge, TN

2010-11-02

A low-power shock sensing system includes at least one shock sensor physically coupled to a chemical storage tank to be monitored for impacts, and an RF transmitter which is in a low-power idle state in the absence of a triggering signal. The system includes interface circuitry including or activated by the shock sensor, wherein an output of the interface circuitry is coupled to an input of the RF transmitter. The interface circuitry triggers the RF transmitter with the triggering signal to transmit an alarm message to at least one remote location when the sensor senses a shock greater than a predetermined threshold. In one embodiment the shock sensor is a shock switch which provides an open and a closed state, the open state being a low power idle state.

Remote shock sensing and notification system

DOEpatents

Muralidharan, Govindarajan; Britton, Charles L.; Pearce, James; Jagadish, Usha; Sikka, Vinod K.

2008-11-11

A low-power shock sensing system includes at least one shock sensor physically coupled to a chemical storage tank to be monitored for impacts, and an RF transmitter which is in a low-power idle state in the absence of a triggering signal. The system includes interference circuitry including or activated by the shock sensor, wherein an output of the interface circuitry is coupled to an input of the RF transmitter. The interface circuitry triggers the RF transmitting with the triggering signal to transmit an alarm message to at least one remote location when the sensor senses a shock greater than a predetermined threshold. In one embodiment the shock sensor is a shock switch which provides an open and a closed state, the open state being a low power idle state.

FPGA-based trigger system for the LUX dark matter experiment

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

Akerib, D. S.; Araújo, H. M.; Bai, X.

We present that LUX is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils resulting from interactions with dark matter particles. Signals from the detector are processed with an FPGA-based digital trigger system that analyzes the incoming data in real-time, with just a few microsecond latency. The system enables first pass selection of events of interest based on their pulse shape characteristics and 3D localization of the interactions. It has been shown to be > 99% efficient in triggering on S2 signals induced by only few extracted liquid electrons. It is continuously and reliably operating since itsmore » full underground deployment in early 2013. Finally, this document is an overview of the systems capabilities, its inner workings, and its performance.« less

CD45-mediated signaling pathway is involved in Rhizoctonia bataticola lectin (RBL)-induced proliferation and Th1/Th2 cytokine secretion in human PBMC

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

Pujari, Radha; Eligar, Sachin M.; Kumar, Natesh

2012-03-23

Highlights: Black-Right-Pointing-Pointer RBL, a potent mitogenic and complex N-glycan specific lectin binds to CD45 on PBMC. Black-Right-Pointing-Pointer RBL triggers CD45-mediated signaling involved in activation of p38MAPK and STAT-5. Black-Right-Pointing-Pointer Inhibition of CD45 PTPase signaling blocks RBL-induced ZAP70 phosphorylation. Black-Right-Pointing-Pointer RBL-CD45 mediated signaling is crucial for RBL-induced immunodulatory activities. -- Abstract: We earlier reported the mitogenic and immunostimulatory activities of Rhizoctonia bataticola lectin (RBL), purified from phytopathogenic fungus R. bataticola in human PBMC. The lectin demonstrates specificity towards glycoproteins containing complex N-glycans. Since CD45-protein tyrosine phosphatase that abundantly expresses N-glycans is important in T-cell signaling, the study aimed to investigate themore » involvement of CD45 in the immunomodulatory activities of RBL. Flowcytometry and confocal microscopy studies revealed that RBL exhibited binding to PBMC and colocalized with CD45. The binding was comparable in cells expressing different CD45 isoforms-RA, -RB and -RO. CD45 blocking antibody reduced the binding and proliferation of PBMC induced by RBL. CD45-PTPase inhibitor dephostatin inhibited RBL-induced proliferation, expression of CD25 and pZAP-70. RBL-induced secretion of Th1/Th2 cytokines were significantly inhibited in presence of dephostatin. Also, dephostatin blocked phosphorylation of p38MAPK and STAT-5 that was crucial for the biological functions of RBL. The study demonstrates the involvement of CD45-mediated signaling in RBL-induced PBMC proliferation and Th1/Th2 cytokine secretion through activation of p38MAPK and STAT-5.« less

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice.

PubMed

Xu, X; Ehdaie, B; Ohara, N; Yoshino, T; Deng, C-X

2010-02-04

Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

RAC1 regulate tumor necrosis factor-α-mediated impaired osteogenic differentiation of dental pulp stem cells.

PubMed

Feng, Guijuan; Shen, Qijie; Lian, Min; Gu, Zhifeng; Xing, Jing; Lu, Xiaohui; Huang, Dan; Li, Liren; Huang, Shen; Wang, Yi; Zhang, Jinlong; Shi, Jiahai; Zhang, Dongmei; Feng, Xingmei

2015-09-01

Human dental pulp contains a rapidly proliferative subpopulation of precursor cells termed dental pulp stem cells (DPSCs) that show self-renewal and multilineage differentiation, including neurogenic, chondrogenic, osteogenic and adipogenic. We previously reported that tomuor necrosis factor-α (TNF-α) (10 ng/mL) triggered osteogenic differentiation of human DPSCs via the nuclear factor-κB (NF-κB) signaling pathway. While previous studies showed that cells treated with TNF-α at higher concentrations showed decreased osteogenic differentiation capability. In this study we analyze the function of TNF-α (100 ng/mL) on osteogenic differentiation of human DPSCs for the first time and identify the underlying molecule mechanisms. Our data revealed that TNF-α with higher concentration significantly reduced mineralization and the expression of bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX2). Further, we revealed that TNF-α could suppress the osteogenic differentiation of DPSCs via increasing the expression of RAC1, which could activate the Wnt/β-catenin signaling pathway and liberate β-catenin to translocate into the nucleus. Genetic silencing of RAC1 expression using siRNA restored osteogenic differentiation of DPSCs. Our findings may provide a potential approach to bone regeneration in inflammatory microenvironments. © 2015 Japanese Society of Developmental Biologists.

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

PubMed Central

Ochi, Atsuo; Graffeo, Christopher S.; Zambirinis, Constantinos P.; Rehman, Adeel; Hackman, Michael; Fallon, Nina; Barilla, Rocky M.; Henning, Justin R.; Jamal, Mohsin; Rao, Raghavendra; Greco, Stephanie; Deutsch, Michael; Medina-Zea, Marco V.; Saeed, Usama Bin; Ego-Osuala, Melvin O.; Hajdu, Cristina; Miller, George

2012-01-01

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer. PMID:23023703

Human‐Like Sensing and Reflexes of Graphene‐Based Films

PubMed Central

Zhang, Qin; Tan, Lifang; Chen, Yunxu; Zhang, Tao; Wang, Wenjie; Liu, Zhongfan

2016-01-01

Humans have numerous senses, wherein vision, hearing, smell, taste, and touch are considered as the five conventionally acknowledged senses. Triggered by light, sound, or other physical stimulations, the sensory organs of human body are excited, leading to the transformation of the afferent energy into neural activity. Also converting other signals into electronical signals, graphene‐based film shows its inherent advantages in responding to the tiny stimulations. In this review, the human‐like senses and reflexes of graphene‐based films are presented. The review starts with the brief discussions about the preparation and optimization of graphene‐based film, as where as its new progress in synthesis method, transfer operation, film‐formation technologies and optimization techniques. Various human‐like senses of graphene‐based film and their recent advancements are then summarized, including light‐sensitive devices, acoustic devices, gas sensors, biomolecules and wearable devices. Similar to the reflex action of humans, graphene‐based film also exhibits reflex when under thermal radiation and light actuation. Finally, the current challenges associated with human‐like applications are discussed to help guide the future research on graphene films. At last, the future opportunities lie in the new applicable human‐like senses and the integration of multiple senses that can raise a revolution in bionic devices. PMID:27981005

Low-Dose Alkylphenol Exposure Promotes Mammary Epithelium Alterations and Transgenerational Developmental Defects, But Does Not Enhance Tumorigenic Behavior of Breast Cancer Cells

PubMed Central

Chamard-Jovenin, Clémence; Thiebaut, Charlène; Chesnel, Amand; Bresso, Emmanuel; Morel, Chloé; Smail-Tabbone, Malika; Devignes, Marie-Dominique; Boukhobza, Taha; Dumond, Hélène

2017-01-01

Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERα36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1–F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERα36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERα36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility. PMID:29109696

Emerging Players at the Intersection of Chondrocyte Loss of Maturational Arrest, Oxidative Stress, Senescence and Low-Grade Inflammation in Osteoarthritis.

PubMed

Minguzzi, Manuela; Cetrullo, Silvia; D'Adamo, Stefania; Silvestri, Ylenia; Flamigni, Flavio; Borzì, Rosa Maria

2018-01-01

The prevalence of Osteoarthritis (OA) is increasing because of the progressive aging and unhealthy lifestyle. These risk factors trigger OA by removing constraints that keep the tightly regulated low turnover of the extracellular matrix (ECM) of articular cartilage, the correct chondrocyte phenotype, and the functionality of major homeostatic mechanisms, such as mitophagy, that allows for the clearance of dysfunctional mitochondria, preventing increased production of reactive oxygen species, oxidative stress, and senescence. After OA onset, the presence of ECM degradation products is perceived as a "danger" signal by the chondrocytes and the synovial macrophages that release alarmins with autocrine/paracrine effects on the same cells. Alarmins trigger innate immunity in the joint, with important systemic crosstalks that explain the beneficial effects of dietary interventions and improved lifestyle. Alarmins also boost low-grade inflammation: the release of inflammatory molecules and chemokines sustained by continuous triggering of NF- κ B within an altered cellular setting that allows its higher transcriptional activity. Chemokines exert pleiotropic functions in OA, including the recruitment of inflammatory cells and the induction of ECM remodeling. Some chemokines have been successfully targeted to attenuate structural damage or pain in OA animal models. This represents a promising strategy for the future management of human OA.

Bovine lactoferrin and lactoferricin exert antitumor activities on human colorectal cancer cells (HT-29) by activating various signaling pathways.

PubMed

Jiang, Rulan; Lönnerdal, Bo

2017-02-01

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy.

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

Busch, Susann; Renaud, Stephen J.; Schleussner, Ekkehard

The intracellular signaling molecule mammalian target of rapamycin (mTOR) is essential for cell growth and proliferation. It is involved in mouse embryogenesis, murine trophoblast outgrowth and linked to tumor cell invasiveness. In order to assess the role of mTOR in human trophoblast invasion we analyzed the in vitro invasiveness of HTR-8/SVneo immortalized first-trimester trophoblast cells in conjunction with enzyme secretion upon mTOR inhibition and knockdown of mTOR protein expression. Additionally, we also tested the capability of mTOR to trigger signal transducer and activator of transcription (STAT)-3 by its phosphorylation status. Rapamycin inhibited mTOR kinase activity as demonstrated with a lowermore » phosphorylation level of the mTOR substrate p70 S6 kinase (S6K). With the use of rapamycin and siRNA-mediated mTOR knockdown we could show that cell proliferation, invasion and secretion of matrix-metalloproteinases (MMP)-2 and -9, urokinase-like plasminogen activator (uPA) and its major physiological uPA inhibitor (PAI)-1 were inhibited. While tyrosine phosphorylation of STAT3 was unaffected by mTOR inhibition and knockdown, serine phosphorylation was diminished. We conclude that mTOR signaling is one major mechanism in a tightly regulated network of intracellular signal pathways including the JAK/STAT system to regulate invasion in human trophoblast cells by secretion of enzymes that remodel the extra-cellular matrix (ECM) such as MMP-2, -9, uPA and PAI-1. Dysregulation of mTOR may contribute to pregnancy-related pathologies caused through impaired trophoblast invasion.« less

Cell-based assays in GPCR drug discovery.

PubMed

Siehler, Sandra

2008-04-01

G protein-coupled receptors (GPCRs) transmit extracellular signals into the intracellular space, and play key roles in the physiological regulation of virtually every cell and tissue. Characteristic for the GPCR superfamily of cell surface receptors are their seven transmembrane-spanning alpha-helices, an extracellular N terminus and intracellular C-terminal tail. Besides transmission of extracellular signals, their activity is modulated by cellular signals in an auto- or transregulatory fashion. The molecular complexity of GPCRs and their regulated signaling networks triggered the interest in academic research groups to explore them further, and their drugability and role in pathophysiology triggers pharmaceutical research towards small molecular weight ligands and therapeutic antibodies. About 30% of marketed drugs target GPCRs, which underlines the importance of this target class. This review describes current and emerging cellular assays for the ligand discovery of GPCRs.

Data processing method for a weak, moving telemetry signal

NASA Technical Reports Server (NTRS)

Kendall, W. B.; Levy, G. S.; Nixon, D. L.; Panson, P. L.

1969-01-01

Method of processing data from a spacecraft, where the carrier has a low signal-to-noise ratio and wide unpredictable frequency shifts, consists of analogue recording of the noisy signal along with a high-frequency tone that is used as a clock to trigger a digitizer.

Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage

PubMed Central

Pappas, Anthony C; Koide, Masayo

2016-01-01

Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting Gq-coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. PMID:27207166

Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage.

PubMed

Pappas, Anthony C; Koide, Masayo; Wellman, George C

2016-11-01

Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca 2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca 2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca 2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting G q -coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca 2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. © The Author(s) 2016.

Frequency-Domain Multiplexing Readout with a Self-Trigger System for Pulse Signals from Kinetic Inductance Detectors

NASA Astrophysics Data System (ADS)

Yamada, Y.; Ishino, H.; Kibayashi, A.; Kida, Y.; Hidehira, N.; Komatsu, K.; Hazumi, M.; Sato, N.; Sakai, K.; Yamamori, H.; Hirayama, F.; Kohjiro, S.

2018-04-01

We present the development of a frequency-domain multiplexing readout of kinetic inductance detectors (KIDs) for pulse signals with a self-trigger system. The KIDs consist of an array of superconducting resonators that have different resonant frequencies individually, allowing us to read out multiple channels in the frequency domain with a single wire using a microwave-frequency comb. The energy deposited to the resonators break Cooper pairs, changing the kinetic inductance and, hence, the amplitude and the phase of the probing microwaves. For some applications such as X-ray detections, the deposited energy is detected as a pulse signal shaped by the time constants of the quasiparticle lifetime, the resonator quality factor, and the ballistic phonon lifetime in the substrate, ranging from microseconds to milliseconds. A readout system commonly used converts the frequency-domain data to the time-domain data. For the short pulse signals, the data rate may exceed the data transfer bandwidth, as the short time constant pulses require us to have a high sampling rate. In order to overcome this circumstance, we have developed a KID readout system that contains a self-trigger system to extract relevant signal data and reduces the total data rate with a commercial off-the-shelf FPGA board. We have demonstrated that the system can read out pulse signals of 15 resonators simultaneously with about 10 Hz event rate by irradiating α particles from ^{241} Am to the silicon substrate on whose surface aluminum KID resonators are formed.

Functions of Calcium-Dependent Protein Kinases in Plant Innate Immunity

PubMed Central

Gao, Xiquan; Cox, Kevin L.; He, Ping

2014-01-01

An increase of cytosolic Ca2+ is generated by diverse physiological stimuli and stresses, including pathogen attack. Plants have evolved two branches of the immune system to defend against pathogen infections. The primary innate immune response is triggered by the detection of evolutionarily conserved pathogen-associated molecular pattern (PAMP), which is called PAMP-triggered immunity (PTI). The second branch of plant innate immunity is triggered by the recognition of specific pathogen effector proteins and known as effector-triggered immunity (ETI). Calcium (Ca2+) signaling is essential in both plant PTI and ETI responses. Calcium-dependent protein kinases (CDPKs) have emerged as important Ca2+ sensor proteins in transducing differential Ca2+ signatures, triggered by PAMPs or effectors and activating complex downstream responses. CDPKs directly transmit calcium signals by calcium binding to the elongation factor (EF)-hand domain at the C-terminus and substrate phosphorylation by the catalytic kinase domain at the N-terminus. Emerging evidence suggests that specific and overlapping CDPKs phosphorylate distinct substrates in PTI and ETI to regulate diverse plant immune responses, including production of reactive oxygen species, transcriptional reprogramming of immune genes, and the hypersensitive response. PMID:27135498

Muscle development and obesity

PubMed Central

2008-01-01

The formation of skeletal muscle from the epithelial somites involves a series of events triggered by temporally and spatially discrete signals resulting in the generation of muscle fibers which vary in their contractile and metabolic nature. The fiber type composition of muscles varies between individuals and it has now been found that there are differences in fiber type proportions between lean and obese animals and humans. Amongst the possible causes of obesity, it has been suggested that inappropriate prenatal environments may ‘program’ the fetus and may lead to increased risks for disease in adult life. The characteristics of muscle are both heritable and plastic, giving the tissue some ability to adapt to signals and stimuli both pre and postnatally. Given that muscle is a site of fatty acid oxidation and carbohydrate metabolism and that its development can be changed by prenatal events, it is interesting to examine the possible relationship between muscle development and the risk of obesity. PMID:19279728

GSL-enriched membrane microdomains in innate immune responses.

PubMed

Nakayama, Hitoshi; Ogawa, Hideoki; Takamori, Kenji; Iwabuchi, Kazuhisa

2013-06-01

Many pathogens target glycosphingolipids (GSLs), which, together with cholesterol, GPI-anchored proteins, and various signaling molecules, cluster on host cell membranes to form GSL-enriched membrane microdomains (lipid rafts). These GSL-enriched membrane microdomains may therefore be involved in host-pathogen interactions. Innate immune responses are triggered by the association of pathogens with phagocytes, such as neutrophils, macrophages and dendritic cells. Phagocytes express a diverse array of pattern-recognition receptors (PRRs), which sense invading microorganisms and trigger pathogen-specific signaling. PRRs can recognize highly conserved pathogen-associated molecular patterns expressed on microorganisms. The GSL lactosylceramide (LacCer, CDw17), which binds to various microorganisms, including Candida albicans, is expressed predominantly on the plasma membranes of human mature neutrophils and forms membrane microdomains together with the Src family tyrosine kinase Lyn. These LacCer-enriched membrane microdomains can mediate superoxide generation, migration, and phagocytosis, indicating that LacCer functions as a PRR in innate immunity. Moreover, the interactions of GSL-enriched membrane microdomains with membrane proteins, such as growth factor receptors, are important in mediating the physiological properties of these proteins. Similarly, we recently found that interactions between LacCer-enriched membrane microdomains and CD11b/CD18 (Mac-1, CR3, or αMβ2-integrin) are significant for neutrophil phagocytosis of non-opsonized microorganisms. This review describes the functional role of LacCer-enriched membrane microdomains and their interactions with CD11b/CD18.

Malate transported from chloroplast to mitochondrion triggers production of ROS and PCD in Arabidopsis thaliana.

PubMed

Zhao, Yannan; Luo, Lilan; Xu, Jiesi; Xin, Peiyong; Guo, Hongyan; Wu, Jian; Bai, Lin; Wang, Guodong; Chu, Jinfang; Zuo, Jianru; Yu, Hong; Huang, Xun; Li, Jiayang

2018-04-01

Programmed cell death (PCD) is a fundamental biological process. Deficiency in MOSAIC DEATH 1 (MOD1), a plastid-localized enoyl-ACP reductase, leads to the accumulation of reactive oxygen species (ROS) and PCD, which can be suppressed by mitochondrial complex I mutations, indicating a signal from chloroplasts to mitochondria. However, this signal remains to be elucidated. In this study, through cloning and analyzing a series of mod1 suppressors, we reveal a comprehensive organelle communication pathway that regulates the generation of mitochondrial ROS and triggers PCD. We show that mutations in PLASTIDIAL NAD-DEPENDENT MALATE DEHYDROGENASE (plNAD-MDH), chloroplastic DICARBOXYLATE TRANSPORTER 1 (DiT1) and MITOCHONDRIAL MALATE DEHYDROGENASE 1 (mMDH1) can each rescue the ROS accumulation and PCD phenotypes in mod1, demonstrating a direct communication from chloroplasts to mitochondria via the malate shuttle. Further studies demonstrate that these elements play critical roles in the redox homeostasis and plant growth under different photoperiod conditions. Moreover, we reveal that the ROS level and PCD are significantly increased in malate-treated HeLa cells, which can be dramatically attenuated by knockdown of the human gene MDH2, an ortholog of Arabidopsis mMDH1. These results uncover a conserved malate-induced PCD pathway in plant and animal systems, revolutionizing our understanding of the communication between organelles.

Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation

PubMed Central

Reinhardt, Christoph; von Brühl, Marie-Luise; Manukyan, Davit; Grahl, Lenka; Lorenz, Michael; Altmann, Berid; Dlugai, Silke; Hess, Sonja; Konrad, Ildiko; Orschiedt, Lena; Mackman, Nigel; Ruddock, Lloyd; Massberg, Steffen; Engelmann, Bernd

2008-01-01

The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased — and, under conditions of decreased platelet adhesion, PDI inhibition reduced — fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet–secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury. PMID:18274674

Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation.

PubMed

Reinhardt, Christoph; von Brühl, Marie-Luise; Manukyan, Davit; Grahl, Lenka; Lorenz, Michael; Altmann, Berid; Dlugai, Silke; Hess, Sonja; Konrad, Ildiko; Orschiedt, Lena; Mackman, Nigel; Ruddock, Lloyd; Massberg, Steffen; Engelmann, Bernd

2008-03-01

The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased - and, under conditions of decreased platelet adhesion, PDI inhibition reduced - fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet-secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury.

[Influence of human gastrointestinal tract bacterial pathogens on host cell apoptosis].

PubMed

Wronowska, Weronika; Godlewska, Renata; Jagusztyn-Krynicka, Elzbieta Katarzyna

2005-01-01

Several pathogenic bacteria are able to trigger apoptosis in the host cell, but the mechanisms by which it occurs differ, and the resulting pathology can take different courses. Induction and/or blockage of programmed cell death upon infection is a result of complex interaction of bacterial proteins with cellular proteins involved in signal transduction and apoptosis. In this review we focus on pro/anti-apoptotic activities exhibited by two enteric pathogens Salmonella enterica, Yersinia spp. and gastric pathogen Helicobacter pylori. We present current knowledge on how interaction between mammalian and bacterial cell relates to the molecular pathways of apoptosis, and what is the role of apoptosis in pathogenesis.

When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor.

PubMed

Su, Tsung-Ping; Hayashi, Teruo; Vaupel, D Bruce

2009-03-10

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine-associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.

When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor

PubMed Central

Su, Tsung-Ping; Hayashi, Teruo; Vaupel, D. Bruce

2011-01-01

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine–associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors. PMID:19278957

Heterologous expression of Homo sapiens alpha-folate receptors in E. coli by fusion with a trigger factor for enhanced solubilization.

PubMed

Miranda, Beatriz Nogueira Messias; Fotoran, Wesley Luzetti; Canduri, Fernanda; Souza, Dulce Helena Ferreira; Wunderlich, Gerhard; Carrilho, Emanuel

2018-02-01

The role of Alpha folate receptors (FRα) in folate metabolism and cancer development has been extensively studied. The reason for this is not only associated to its direct relation to disease development but also to its potential use as a highly sensitive and specific biomarker for cancers therapies. Over the recent years, the crystal structures of human FRα complexed with different ligands were described relying on an expensive and time-consuming production process. Here, we constructed an efficient system for the expression and purification of a human FRα in E. coli. Unlike a conventional expression method we used a specific protein fusion expressing the target protein together with a trigger factor (TF). This factor is a chaperone from E. coli that assists the correct folding of newly synthesized polypeptide chains. The activity of rTFFRα was comparable to glycosylphosphatidylinositol (GPI) anchored proteins extracted from HeLa tumor cells. Our work demonstrates a straightforward and versatile approach for the production of active human FRα by heterologous expression; this approach further enhances the development of inhibition studies and biotechnological applications. The purified product was then conjugated to liposomes, obtaining a 35% higher signal from densitometry measurement on the immunoblotting assay in the contruct containing the Ni-NTA tag, as a mimesis of an exosome, which is of vital importance to nanotherapeutic techniques associated to treatment and diagnosis of tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

PubMed

Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

2001-12-01

Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

Involvement of nuclear factor {kappa}B in platelet CD40 signaling

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

Hachem, Ahmed; Yacoub, Daniel; Centre Hospitalier Universite de Montreal, 264 boul. Rene-Levesque est, Montreal, Quebec, Canada H2X 1P1

Highlights: Black-Right-Pointing-Pointer sCD40L induces TRAF2 association to CD40 and NF-{kappa}B activation in platelets. Black-Right-Pointing-Pointer I{kappa}B{alpha} phosphorylation downstream of CD40L/CD40 signaling is independent of p38 MAPK phosphorylation. Black-Right-Pointing-Pointer I{kappa}B{alpha} is required for sCD40L-induced platelet activation and potentiation of aggregation. -- Abstract: CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to potentiate platelet activation and aggregation, in a CD40-dependent manner, via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In many cells, the CD40L/CD40 dyad also induces activation of nuclear factor kappa B (NF-{kappa}B). Givenmore » that platelets contain NF-{kappa}B, we hypothesized that it may be involved in platelet CD40 signaling and function. In human platelets, sCD40L induces association of CD40 with its adaptor protein the tumor necrosis factor receptor associated factor 2 and triggers phosphorylation of I{kappa}B{alpha}, which are abolished by CD40L blockade. Inhibition of I{kappa}B{alpha} phosphorylation reverses sCD40L-induced I{kappa}B{alpha} phosphorylation without affecting p38 MAPK phosphorylation. On the other hand, inhibition of p38 MAPK phosphorylation has no effect on I{kappa}B{alpha} phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. In functional studies, inhibition of I{kappa}B{alpha} phosphorylation reverses sCD40L-induced platelet activation and potentiation of platelet aggregation in response to a sub-threshold concentration of collagen. This study demonstrates that the sCD40L/CD40 axis triggers NF-{kappa}B activation in platelets. This signaling pathway plays a critical role in platelet activation and aggregation upon sCD40L stimulation and may represent an important target against thrombo-inflammatory disorders.« less

Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid‐induced muscle cell atrophy

PubMed Central

Cid‐Díaz, Tania; Santos‐Zas, Icía; González‐Sánchez, Jessica; Gurriarán‐Rodríguez, Uxía; Mosteiro, Carlos S.; Casabiell, Xesús; García‐Caballero, Tomás; Mouly, Vincent; Pazos, Yolanda

2017-01-01

Abstract Background Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid‐induced and wasting disorder‐related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid‐induced muscle cell atrophy. Methods In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes. Results The activation of the obestatin/GPR39 system protects from glucocorticoid‐induced atrophy by regulation of Akt, PKD/PKCμ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin–proteasome system and autophagy–lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post‐translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes. Conclusions Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions. PMID:28675664

Design and Application of a New Automated Fluidic Visceral Stimulation Device for Human fMRI Studies of Interoception

PubMed Central

Gassert, Roger; Wanek, Johann; Michels, Lars; Mehnert, Ulrich; Kollias, Spyros S.

2016-01-01

Mapping the brain centers that mediate the sensory-perceptual processing of visceral afferent signals arising from the body (i.e., interoception) is useful both for characterizing normal brain activity and for understanding clinical disorders related to abnormal processing of visceral sensation. Here, we report a novel closed-system, electrohydrostatically driven master–slave device that was designed and constructed for delivering controlled fluidic stimulations of visceral organs and inner cavities of the human body within the confines of a 3T magnetic resonance imaging (MRI) scanner. The design concept and performance of the device in the MRI environment are described. In addition, the device was applied during a functional MRI (fMRI) investigation of visceral stimulation related to detrusor distention in two representative subjects to verify its feasibility in humans. System evaluation tests demonstrate that the device is MR-compatible with negligible impact on imaging quality [static signal-to-noise ratio (SNR) loss <2.5% and temporal SNR loss <3.5%], and has an accuracy of 99.68% for flow rate and 99.27% for volume delivery. A precise synchronization of the stimulus delivery with fMRI slice acquisition was achieved by programming the proposed device to detect the 5 V transistor–transistor logic (TTL) trigger signals generated by the MRI scanner. The fMRI data analysis using the general linear model analysis with the standard hemodynamic response function showed increased activations in the network of brain regions that included the insula, anterior and mid-cingulate and lateral prefrontal cortices, and thalamus in response to increased distension pressure on viscera. The translation from manually operated devices to an MR-compatible and MR-synchronized device under automatic control represents a useful innovation for clinical neuroimaging studies of human interoception. PMID:27551646

R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/β-catenin signaling.

PubMed

Cui, Daming; Ren, Jie; Shi, Jinlong; Feng, Lijing; Wang, Ke; Zeng, Tao; Jin, Yi; Gao, Liang

2016-04-01

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene commonly occur in gliomas. Remarkably, the R132H mutation in IDH1 (IDH1-R132H) is associated with better prognosis and increased survival than patients lacking this mutation. The molecular mechanism underlying this phenomenon is largely unknown. In this study, we investigated potential cross-talk between IDH1-R132H and Wnt/β-catenin signaling in regulating the cellular properties of human glioma. Although aberrant nuclear accumulation of β-catenin is linked to the malignant progression of gliomas, its association with IDH1 remains unknown. We identified an inverse correlation between IDH1-R132H and the expression and activity of β-catenin in human gliomas. In addition, overexpression of IDH1-R132H in glioblastoma cell lines U87 and U251 led to reduced cell proliferation, migration and invasion, accompanied by increased apoptosis. At the molecular level, we detected a significant reduction in the expression, nuclear accumulation and activity of β-catenin following overexpression of IDH1-R132H. A microarray-based comparison of gene expression indicated that several mediators, effectors and targets of Wnt/β-catenin signaling are downregulated, while negative regulators are upregulated in IDH1-R132H gliomas. Further, overexpression of β-catenin in IDH1-R132H glioma cells restored the cellular phenotype induced by this mutation. Specifically, β-catenin abrogated the decrease in proliferation, invasion and migration, and the increase in apoptosis, triggered by overexpression of IDH1-R132H. Finally, we demonstrate that xenografts of IDH1-R132H overexpressing U87 cells can significantly decrease the growth of tumors in vivo. Altogether, our results strongly suggest that the R132H mutation in IDH1 serves a tumor suppressor function in human glioma by negatively regulating Wnt/β-catenin signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

Wired and Wireless Camera Triggering with Arduino

NASA Astrophysics Data System (ADS)

Kauhanen, H.; Rönnholm, P.

2017-10-01

Synchronous triggering is an important task that allows simultaneous data capture from multiple cameras. Accurate synchronization enables 3D measurements of moving objects or from a moving platform. In this paper, we describe one wired and four wireless variations of Arduino-based low-cost remote trigger systems designed to provide a synchronous trigger signal for industrial cameras. Our wireless systems utilize 315 MHz or 434 MHz frequencies with noise filtering capacitors. In order to validate the synchronization accuracy, we developed a prototype of a rotating trigger detection system (named RoTriDeS). This system is suitable to detect the triggering accuracy of global shutter cameras. As a result, the wired system indicated an 8.91 μs mean triggering time difference between two cameras. Corresponding mean values for the four wireless triggering systems varied between 7.92 and 9.42 μs. Presented values include both camera-based and trigger-based desynchronization. Arduino-based triggering systems appeared to be feasible, and they have the potential to be extended to more complicated triggering systems.

Remotely triggered microearthquakes and tremor in central California following the 2010 Mw 8.8 Chile earthquake

USGS Publications Warehouse

Peng, Zhigang; Hill, David P.; Shelly, David R.; Aiken, Chastity

2010-01-01

We examine remotely triggered microearthquakes and tectonic tremor in central California following the 2010 Mw 8.8 Chile earthquake. Several microearthquakes near the Coso Geothermal Field were apparently triggered, with the largest earthquake (Ml 3.5) occurring during the large-amplitude Love surface waves. The Chile mainshock also triggered numerous tremor bursts near the Parkfield-Cholame section of the San Andreas Fault (SAF). The locally triggered tremor bursts are partially masked at lower frequencies by the regionally triggered earthquake signals from Coso, but can be identified by applying high-pass or matched filters. Both triggered tremor along the SAF and the Ml 3.5 earthquake in Coso are consistent with frictional failure at different depths on critically-stressed faults under the Coulomb failure criteria. The triggered tremor, however, appears to be more phase-correlated with the surface waves than the triggered earthquakes, likely reflecting differences in constitutive properties between the brittle, seismogenic crust and the underlying lower crust.

Development of a novel scintillation-trigger detector for the MTV experiment using aluminum-metallized film tapes

NASA Astrophysics Data System (ADS)

Tanaka, S.; Ozaki, S.; Sakamoto, Y.; Tanuma, R.; Yoshida, T.; Murata, J.

2014-07-01

A new type of a trigger-scintillation counter array designed for the MTV experiment at TRIUMF-ISAC has been developed, which uses aluminum-metallized film tape for wrapping to achieve the required assembling precision of ±0.5 mm. The MTV experiment uses a cylindrical drift chamber (CDC) as the main electron-tracking detector. The barrel-type trigger counter is placed inside the CDC to generate a trigger signal using 1 mm thick, 300 mm long thin plastic scintillation counters. Detection efficiency and light attenuation compared with conventional wrapping materials are studied.

Low-power triggered data acquisition system and method

NASA Technical Reports Server (NTRS)

Champaigne, Kevin (Inventor); Sumners, Jonathan (Inventor)

2012-01-01

A low-power triggered data acquisition system and method utilizes low-powered circuitry, comparators, and digital logic incorporated into a miniaturized device interfaced with self-generating transducer sensor inputs to detect, identify and assess impact and damage to surfaces and structures wherein, upon the occurrence of a triggering event that produces a signal greater than a set threshold changes the comparator output and causes the system to acquire and store digital data representative of the incoming waveform on at least one triggered channel. The sensors may be disposed in an array to provide triangulation and location of the impact.

[Study on the application of pyroelectric infrared sensor to safety protection system].

PubMed

Wang, Song-de; Zhang, Shuan-ji; Zhu, Xiao-long; Yang, Jie-hui

2006-11-01

Using the infrared ray of human body, which is received and magnified by pyroelectric infrared sensor to form a certain voltage control signal, and using the control signal to trigger a voice recording-reproducing circuit, a pyroelectric infrared detector voice device with auto-control function designed. The circuit adopted new pyroelectric infrared detector assembly and voice recording-reproducing assembly. When someone is present in the detectable range of the pyroelectric infrared detector, first, the pyroelectric infrared sensor will transform the incepted radiation energy to a electric signal, which is then magnified and compared by an inside circuit, and an output control signal, touches off the voice recording-reproducing assembly with the reproducer sending out a beforehand transcribed caution voice to wise the man who does not know well the surrounding condition that the frontage is a danger zone and should not be approched. With the design of integrated structures, the distance-warning device has the advantages of strong anti-jamming ability, low temperature resistance, working stability and use-convenience, and it can be suitably installed and used in several locations which may endanger person safety, such as substation, high voltage switch panel, electric transformer, etc.

Recent advances in signal amplification strategy based on oligonucleotide and nanomaterials for microRNA detection-a review.

PubMed

Chen, Ying-Xu; Huang, Ke-Jing; Niu, Ke-Xin

2018-01-15

MicroRNAs (MiRNAs) play multiple crucial regulating roles in cell which can regulate one third of protein-coding genes. MiRNAs participate in the developmental and physiological processes of human body, while their aberrant adjustment will be more likely to trigger diseases such as cancers, kidney disease, central nervous system diseases, cardiovascular diseases, diabetes, viral infections and so on. What's worse, for the detection of miRNAs, their small size, high sequence similarity, low abundance and difficult extraction from cells impose great challenges in the analysis. Hence, it's necessary to fabricate accurate and sensitive biosensing platform for miRNAs detection. Up to now, researchers have developed many signal-amplification strategies for miRNAs detection, including hybridization chain reaction, nuclease amplification, rolling circle amplification, catalyzed hairpin assembly amplification and nanomaterials based amplification. These methods are typical, feasible and frequently used. In this review, we retrospect recent advances in signal amplification strategies for detecting miRNAs and point out the pros and cons of them. Furthermore, further prospects and promising developments of the signal-amplification strategies for detecting miRNAs are proposed. Copyright © 2017 Elsevier B.V. All rights reserved.

Towards mitigating the effect of sine-Gaussian noise transients on searches for gravitational waves from compact binary coalescences

NASA Astrophysics Data System (ADS)

Bose, Sukanta; Dhurandhar, Sanjeev; Gupta, Anuradha; Lundgren, Andrew

2016-12-01

Gravitational wave signals were recently detected directly by LIGO from the coalescences of two stellar mass black hole pairs. These detections have strengthened our long held belief that compact binary coalescences (CBCs) are the most promising gravitational wave detection prospects accessible to ground-based interferometric detectors. For detecting CBC signals, it is of vital importance to characterize and identify non-Gaussian and nonstationary noise in these detectors. In this work, we model two important classes of transient artifacts that contribute to this noise and adversely affect the detector sensitivity to CBC signals. One of them is the sine-Gaussian "glitch," characterized by a central frequency f0 and a quality factor Q and the other is the chirping sine-Gaussian glitch, which is characterized by f0, Q as well as a chirp parameter. We study the response that a bank of compact binary inspiral templates has to these two families of glitches when they are used to match filter data containing any of these glitches. Two important characteristics of this response are the distributions of the signal-to-noise ratio and the time lag (i.e., how long after the occurrence of a glitch the signal-to-noise ratio of a trigger arises from its matched filtering by a template peaks) of individual templates. We show how these distributions differ from those when the detector data has a real CBC signal instead of a glitch. We argue that these distinctions can be utilized to develop useful signal-artifact discriminators that add negligibly to the computational cost of a CBC search. Specifically, we show how the central frequency of a glitch can be used to set adaptive time windows around it so that any template trigger occurring in that window can be quarantined for further vetting of its supposed astrophysical nature. Second, we recommend focusing efforts on reducing the incidence of glitches with low central-frequency values because they create CBC triggers with the longest time lags. This work allows us to associate such triggers with the glitches that otherwise would have escaped attention.

Intracellular energy depletion triggers programmed cell death during petal senescence in tulip.

PubMed

Azad, A K; Ishikawa, Takayuki; Ishikawa, Takahiro; Sawa, Y; Shibata, H

2008-01-01

Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals.

Intracellular energy depletion triggers programmed cell death during petal senescence in tulip

PubMed Central

Azad, A. K.; Ishikawa, Takayuki; Ishikawa, Takahiro; Shibata, H.

2008-01-01

Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals. PMID:18515833

MyShake: Building a smartphone seismic network

NASA Astrophysics Data System (ADS)

Kong, Q.; Allen, R. M.; Schreier, L.

2014-12-01

We are in the process of building up a smartphone seismic network. In order to build this network, we did shake table tests to evaluate the performance of the smartphones as seismic recording instruments. We also conducted noise floor test to find the minimum earthquake signal we can record using smartphones. We added phone noises to the strong motion data from past earthquakes, and used these as an analogy dataset to test algorithms and to understand the difference of using the smartphone network and the traditional seismic network. We also built a prototype system to trigger the smartphones from our server to record signals which can be sent back to the server in near real time. The phones can also be triggered by our developed algorithm running locally on the phone, if there's an earthquake occur to trigger the phones, the signal recorded by the phones will be sent back to the server. We expect to turn the prototype system into a real smartphone seismic network to work as a supplementary network to the existing traditional seismic network.

The electronics, trigger and data acquisition system for the liquid argon time projection chamber of the DarkSide-50 search for dark matter

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

Agnes, P.; Albuquerque, I. F. M.; Alexander, T.

The DarkSide-50 experiment at the Laboratori Nazionali del Gran Sasso is a search for dark matter using a dual phase time projection chamber with 50 kg of low radioactivity argon as target. Light signals from interactions in the argon are detected by a system of 38 photo-multiplier tubes (PMTs), 19 above and 19 below the TPC volume inside the argon cryostat. We describe the electronics which processes the signals from the photo-multipliers, the trigger system which identifies events of interest, and the data-acquisition system which records the data for further analysis. The electronics include resistive voltage dividers on the PMTs,more » custom pre-amplifiers mounted directly on the PMT voltage dividers in the liquid argon, and custom amplifier/discriminators (at room temperature). After amplification, the PMT signals are digitized in CAEN waveform digitizers, and CAEN logic modules are used to construct the trigger, the data acquisition system for the TPC is based on the Fermilab "artdaq" software. The system has been in operation since early 2014.« less

Herpes simplex virus triggers activation of calcium-signaling pathways

PubMed Central

Cheshenko, Natalia; Del Rosario, Brian; Woda, Craig; Marcellino, Daniel; Satlin, Lisa M.; Herold, Betsy C.

2003-01-01

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy. PMID:14568989

The electronics, trigger and data acquisition system for the liquid argon time projection chamber of the DarkSide-50 search for dark matter

NASA Astrophysics Data System (ADS)

Agnes, P.; Albuquerque, I. F. M.; Alexander, T.; Alton, A. K.; Arisaka, K.; Asner, D. M.; Ave, M.; Back, H. O.; Baldin, B.; Biery, K.; Bocci, V.; Bonfini, G.; Bonivento, W.; Bossa, M.; Bottino, B.; Brigatti, A.; Brodsky, J.; Budano, F.; Bussino, S.; Cadeddu, M.; Cadoni, M.; Calaprice, F.; Canci, N.; Candela, A.; Cao, H.; Caravati, M.; Cariello, M.; Carlini, M.; Catalanotti, S.; Cataudella, V.; Cavalcante, P.; Chepurnov, A.; Cicaló, C.; Cocco, A. G.; Covone, G.; Crippa, L.; D'Angelo, D.; D'Incecco, M.; Davini, S.; de Candia, A.; De Cecco, S.; De Deo, M.; De Filippis, G.; De Rosa, G.; De Vincenzi, M.; Derbin, A.; Devoto, A.; Di Eusanio, F.; Dionisi, C.; Di Pietro, G.; Edkins, E.; Empl, A.; Fan, A.; Fiorillo, G.; Fomenko, K.; Forster, G.; Franco, D.; Gabriele, F.; Galbiati, C.; Giagu, S.; Giganti, C.; Giovanetti, G. K.; Goretti, A. M.; Granato, F.; Grandi, L.; Gromov, M.; Guan, M.; Guardincerri, Y.; Hackett, B. R.; Herner, K. R.; Hughes, D.; Humble, P.; Hungerford, E. V.; Ianni, A.; Ianni, A.; James, I.; Johnson, T. N.; Keeter, K.; Kendziora, C. L.; Kobychev, V.; Koh, G.; Korablev, D.; Korga, G.; Kubankin, A.; Li, X.; Lissia, M.; Loer, B.; Lombardi, P.; Longo, G.; Luitz, S.; Ma, Y.; Machado, A.; Machulin, I. N.; Mandarano, A.; Mari, S. M.; Maricic, J.; Marini, L.; Martoff, C. J.; Meyers, P. D.; Miletic, T.; Milincic, R.; Montanari, D.; Monte, A.; Montuschi, M.; Monzani, M. E.; Mosteiro, P.; Mount, B. J.; Muratova, V. N.; Musico, P.; Navrer Agasson, A.; Nelson, A.; Odrowski, S.; Oleinik, A.; Orsini, M.; Ortica, F.; Pagani, L.; Pallavicini, M.; Pantic, E.; Parmeggiano, S.; Pelczar, K.; Pelliccia, N.; Pocar, A.; Pordes, S.; Pugachev, D. A.; Qian, H.; Randle, K.; Ranucci, G.; Razeti, M.; Razeto, A.; Reinhold, B.; Renshaw, A. L.; Rescigno, M.; Riffard, Q.; Romani, A.; Rossi, B.; Rossi, N.; Rountree, S. D.; Sablone, D.; Saggese, P.; Saldanha, R.; Sands, W.; Sangiorgio, S.; Savarese, C.; Schlitzer, B.; Segreto, E.; Semenov, D. A.; Shields, E.; Singh, P. N.; Skorokhvatov, M. D.; Smirnov, O.; Sotnikov, A.; Stanford, C.; Suvorov, Y.; Tartaglia, R.; Tatarowicz, J.; Testera, G.; Tonazzo, A.; Trinchese, P.; Unzhakov, E. V.; Verducci, M.; Vishneva, A.; Vogelaar, R. B.; Wada, M.; Walker, S.; Wang, H.; Wang, Y.; Watson, A. W.; Westerdale, S.; Wojcik, M. M.; Xiang, X.; Xiao, X.; Xu, J.; Yang, C.; Yoo, J.; Zavatarelli, S.; Zec, A.; Zhong, W.; Zhu, C.; Zuzel, G.

2017-12-01

The DarkSide-50 experiment at the Laboratori Nazionali del Gran Sasso is a search for dark matter using a dual phase time projection chamber with 50 kg of low radioactivity argon as target. Light signals from interactions in the argon are detected by a system of 38 photo-multiplier tubes (PMTs), 19 above and 19 below the TPC volume inside the argon cryostat. We describe the electronics which processes the signals from the photo-multipliers, the trigger system which identifies events of interest, and the data-acquisition system which records the data for further analysis. The electronics include resistive voltage dividers on the PMTs, custom pre-amplifiers mounted directly on the PMT voltage dividers in the liquid argon, and custom amplifier/discriminators (at room temperature). After amplification, the PMT signals are digitized in CAEN waveform digitizers, and CAEN logic modules are used to construct the trigger; the data acquisition system for the TPC is based on the Fermilab artdaq software. The system has been in operation since early 2014.

Toll-like receptor-mediated inhibition of Gas6 and ProS expression facilitates inflammatory cytokine production in mouse macrophages

PubMed Central

Deng, Tingting; Zhang, Yue; Chen, Qiaoyuan; Yan, Keqin; Han, Daishu

2012-01-01

Activation of Toll-like receptors (TLRs) triggers rapid inflammatory cytokine production in various cell types. The exogenous product of growth-arrest-specific gene 6 (Gas6) and Protein S (ProS) inhibit the TLR-triggered inflammatory responses through the activation of Tyro3, Axl and Mer (TAM) receptors. However, regulation of the Gas6/ProS-TAM system remains largely unknown. In the current study, mouse macrophages are shown to constitutively express Gas6 and ProS, which synergistically suppress the basal and TLR-triggered production of inflammatory cytokines, including those of tumour necrosis factor-α, interleukin-6 and interleukin-1β, by the macrophages in an autocrine manner. Notably, TLR signalling markedly decreases Gas6 and ProS expression in macrophages through the activation of the nuclear factor-κB. Further, the down-regulation of Gas6 and ProS by TLR signalling facilitates the TLR-mediated inflammatory cytokine production in mouse macrophages. These results describe a self-regulatory mechanism of TLR signalling through the suppression of Gas6 and ProS expression. PMID:22043818

Observing the Next Galactic Supernova with the NOvA Detectors

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

Vasel, Justin A.; Sheshukov, Andrey; Habig, Alec

The next galactic core-collapse supernova will deliver a wealth of neutrinos which for the first time we are well-situated to measure. These explosions produce neutrinos with energies between 10 and 100 MeV over a period of tens of seconds. Galactic supernovae are relatively rare events, occurring with a frequency of just a few per century. It is therefore essential that all neutrino detectors capable of detecting these neutrinos are ready to trigger on this signal when it occurs. This poster describes a data-driven trigger which is designed to detect the neutrino signal from a galactic core-collapse supernova with the NOvAmore » detectors. The trigger analyzes 5ms blocks of detector activity and applies background rejection algorithms to detect the signal time structure over the background. This background reduction is an essential part of the process, as the NOvA detectors are designed to detect neutrinos from Fermilab's NuMI beam which have an average energy of 2GeV--well above the average energy of supernova neutrinos.« less

The electronics, trigger and data acquisition system for the liquid argon time projection chamber of the DarkSide-50 search for dark matter

DOE PAGES

Agnes, P.; Albuquerque, I. F. M.; Alexander, T.; ...

2017-12-01

The DarkSide-50 experiment at the Laboratori Nazionali del Gran Sasso is a search for dark matter using a dual phase time projection chamber with 50 kg of low radioactivity argon as target. Light signals from interactions in the argon are detected by a system of 38 photo-multiplier tubes (PMTs), 19 above and 19 below the TPC volume inside the argon cryostat. We describe the electronics which processes the signals from the photo-multipliers, the trigger system which identifies events of interest, and the data-acquisition system which records the data for further analysis. The electronics include resistive voltage dividers on the PMTs,more » custom pre-amplifiers mounted directly on the PMT voltage dividers in the liquid argon, and custom amplifier/discriminators (at room temperature). After amplification, the PMT signals are digitized in CAEN waveform digitizers, and CAEN logic modules are used to construct the trigger, the data acquisition system for the TPC is based on the Fermilab "artdaq" software. The system has been in operation since early 2014.« less

Seismology with Mermaids: Statistics from the Galapagos Experiment

NASA Astrophysics Data System (ADS)

Hello, Y.; Nolet, G.; Bonnieux, S.; Pazmino, A.; van der Lee, S.; Simons, F.; Chen, J.

2017-12-01

The operation of a small network of Mermaids for more than two years near the Galapagos Islands has provided with us the first experience of launching and following a mobile network of floating seismographs that transmit triggered signals by satellite (Rudics-Iridium).In mid 2014 we launched ten Mermaids of the first generation. The float that hosts the seismic instrumentation is an APEX float, the same as used by oceanographers in the Argo project.We lost contact with one of the floats after only one surfacing, in which it transmitted a time-depth history indicating a change of weight (leakage or fouling is suspected). The other nine surfaced on average 126 times before running out of power. They had an average lifespan of 616 days, with the longest lifespan 901 days. Earlier tests showed that power consumption is roughly divided equally between pump, CPU and transmission, and the large variety of lifespans indicate that unknown causes other than depletion of the battery may be at work, certainly in case of the one Mermaid that surfaced only 40 times.In total the nine Mermaids transmitted 1329 signals, of which 719 were associated with the arrival of an earthquake signal using our automatized data management software. Inspection by eye identified additional signals in the remaining records that are likely local earthquakes of small magnitude for which information in the catalogues is lacking, but most of them constitute false triggers.The success of a trigger depends very much on noise conditions that may be very local. The high frequency content of deep quakes makes them somewhat easier to identify than shallow ones. Teleseismic events with magnitudes higher than 5.5 can trigger successfully under quiet conditions, but even strong earthquakes can be missed during a storm. The experience with this first generation Mermaid has led us to develop the current version which has a larger battery capacity (expected lifespan 5 years) and the ability to recover missed triggers by commands via the satellite.

Multimodality of Ca2+ signaling in rat atrial myocytes.

PubMed

Morad, Martin; Javaheri, Ashkan; Risius, Tim; Belmonte, Steve

2005-06-01

It has been suggested that the multiplicity of Ca(2+) signaling pathways in atrial myocytes may contribute to the variability of its function. This article reports on a novel Ca(2+) signaling cascade initiated by mechanical forces induced by "puffing" of solution onto the myocytes. Ca(i) transients were measured in fura-2 acetoxymethyl (AM) loaded cells using alternating 340- and 410-nm excitation waves at 1.2 kHz. Pressurized puffs of bathing solutions, applied by an electronically controlled micro-barrel system, activated slowly (approximately 300 ms) developing Ca(i) transients that lasted 1,693 +/- 68 ms at room temperature. Subsequent second and third puffs, applied at approximately 20 s intervals activated significantly smaller or no Ca(i) transients. Puff-triggered Ca(i) transients could be reactivated once again following caffeine (10 mM)-induced release of Ca(2+) from sarcoplasmic reticulum (SR). Puff-triggered Ca(i) transients were independent of [Ca(2+)](o), and activation of voltage-gated Ca(2+) or cationic stretch channels or influx of Ca(2+) on Na(+)/Ca(2+)exchanger, because puffing solution containing no Ca(2+), 10 microM diltiazem, 1 mM Cd(2+), 5 mM Ni(2+), or 100 microM Gd(3+) failed to suppress them. Puff-triggered Ca(i) transients were enhanced in paced compared to quiescent myocytes. Electrically activated Ca(i) transients triggered during the time course of puff-induced transients were unaltered, suggesting functionally separate Ca(2+) pools. Contribution of inositol 1,4,5-triphosphate (IP(3))-gated or mitochondrial Ca(2+) pools or modulation of SR stores by nitric oxide/nitric oxide synthase (NO/NOS) signaling were evaluated using 0.5 to 500 microM 2-aminoethoxydiphenyl borate (2-APB) and 0.1 to 1 microM carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and 1 mM Nomega-Nitro-L-arginine methyl ester (L-NAME) and 7-nitroindizole, respectively. Only FCCP appeared to significantly suppress the puff-triggered Ca(i) transients. It was concluded that neither Ca(2+) influx nor depolarization was required for activation of this signaling pathway. These studies suggest that pressurized puffs of solutions activate a mechanically sensitive receptor, which signals in turn the release of Ca(2+) from a limited Ca(2+) store of mitochondria. How mechanical forces are sensed and transmitted to mitochondria to induce Ca(2+) release and what role such a Ca(2+) signaling pathway plays in the physiology or pathophysiology of the heart remain to be worked out.

Chemical signal activation of an organocatalyst enables control over soft material formation.

PubMed

Trausel, Fanny; Maity, Chandan; Poolman, Jos M; Kouwenberg, D S J; Versluis, Frank; van Esch, Jan H; Eelkema, Rienk

2017-10-12

Cells can react to their environment by changing the activity of enzymes in response to specific chemical signals. Artificial catalysts capable of being activated by chemical signals are rare, but of interest for creating autonomously responsive materials. We present an organocatalyst that is activated by a chemical signal, enabling temporal control over reaction rates and the formation of materials. Using self-immolative chemistry, we design a deactivated aniline organocatalyst that is activated by the chemical signal hydrogen peroxide and catalyses hydrazone formation. Upon activation of the catalyst, the rate of hydrazone formation increases 10-fold almost instantly. The responsive organocatalyst enables temporal control over the formation of gels featuring hydrazone bonds. The generic design should enable the use of a large range of triggers and organocatalysts, and appears a promising method for the introduction of signal response in materials, constituting a first step towards achieving communication between artificial chemical systems.Enzymes regulated by chemical signals are common in biology, but few such artificial catalysts exist. Here, the authors design an aniline catalyst that, when activated by a chemical trigger, catalyses formation of hydrazone-based gels, demonstrating signal response in a soft material.

Innate Immune Mechanisms in Transplant Allograft Vasculopathy

PubMed Central

Jane-wit, D; Fang, C; Goldstein, DR

2016-01-01

Purpose of Review Allograft vasculopathy (AV) is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury (IRI) and donor specific antibody (DSA)-induced complement activation confer heightened risk for AV via numerous innate immune mechanisms including MyD88, HMGB1, and complement induced non-canonical NF-kB signaling. Recent Findings The role of MyD88, a signal adaptor downstream of the toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced AV. Importantly, triggering receptor on myeloid receptor 1(Trem1), a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of AV in mice. HMGB1, a nuclear protein that activates TLRs, also enhanced the development of AV. Complement activation elicits assembly of membrane attack complexes (MAC) on endothelial cells which activate non-canonical NF-kB signaling, a novel complement effector pathway that induces pro-inflammatory genes and potentiates endothelial cell mediated alloimmune T cell activation, processes which enhance AV. Summary Innate immune mediators including HMGB1, MyD88, and non-canonical NFκB signaling via complement activation contribute to AV. These pathways represent potential therapeutic targets to reduce AV after solid organ transplantation. PMID:27077602

Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling.

PubMed

d'Hennezel, Eva; Abubucker, Sahar; Murphy, Leon O; Cullen, Thomas W

2017-01-01

Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immune stimulation generated by the microbiota such as the activation of Toll-like receptor 4 (TLR4) pathways by lipopolysaccharide (LPS). Indeed, gut microbial LPS is thought to be one of the most potent activators of innate immune signaling and an important mediator of the microbiome's influence on host physiology. In this study, we performed computational and experimental analyses of healthy human fecal samples to examine the TLR4 signaling capacity of the gut microbiota. These analyses revealed that an immunoinhibitory activity of LPS, conserved across the members of the order Bacteroidales and derived from an underacylated structural feature, silences TLR4 signaling for the entire consortium of organisms inhabiting the human gut. Comparative analysis of metagenomic data from the Human Microbiome Project and healthy-donor samples indicates that immune silencing via LPS is a microbe-intrinsic feature in all healthy adults. These findings challenge the current belief that robust TLR4 signaling is a feature of the microbiome and demonstrate that microbiome-derived LPS has the ability to facilitate host tolerance of gut microbes. These findings have broad implications for how we model host-microbe interactions and for our understanding of microbiome-linked disease. IMPORTANCE While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of intense research. This study shows that an important proinflammatory pathway that is commonly triggered by pathogenic bacteria upon interaction with the host is, in fact, actively repressed by the bacteria of the gut microbiome, supporting the idea that beneficial microbes themselves contribute to the immune tolerance in support of homeostasis. These findings are important for two reasons. First, many currently assume that proinflammatory signaling by lipopolysaccharide is a fundamental feature of the gut flora. This assumption influences greatly how host-microbiome interactions are theoretically modeled but also how they are experimentally studied, by using robust TLR signaling conditions to simulate commensals. Second, elucidation of the mechanisms that support host-microbe tolerance is key to the development of therapeutics for both intestinal and systemic inflammatory disorders.

Profilin-1 Is Expressed in Human Atherosclerotic Plaques and Induces Atherogenic Effects on Vascular Smooth Muscle Cells

PubMed Central

Caglayan, Evren; Romeo, Giulio R.; Kappert, Kai; Odenthal, Margarete; Südkamp, Michael; Body, Simon C.; Shernan, Stanton K.; Hackbusch, Daniel; Vantler, Marius; Kazlauskas, Andrius; Rosenkranz, Stephan

2010-01-01

Background Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo. Methodology Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans. Principal Findings In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10−6 M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70S6 kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group). Conclusions Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target. PMID:21049052

Modulation of occluding junctions alters the hematopoietic niche to trigger immune activation

PubMed Central

Khadilkar, Rohan J; Vogl, Wayne; Goodwin, Katharine

2017-01-01

Stem cells are regulated by signals from their microenvironment, or niche. During Drosophila hematopoiesis, a niche regulates prohemocytes to control hemocyte production. Immune challenges activate cell-signalling to initiate the cellular and innate immune response. Specifically, certain immune challenges stimulate the niche to produce signals that induce prohemocyte differentiation. However, the mechanisms that promote prohemocyte differentiation subsequent to immune challenges are poorly understood. Here we show that bacterial infection induces the cellular immune response by modulating occluding-junctions at the hematopoietic niche. Occluding-junctions form a permeability barrier that regulates the accessibility of prohemocytes to niche derived signals. The immune response triggered by infection causes barrier breakdown, altering the prohemocyte microenvironment to induce immune cell production. Moreover, genetically induced barrier ablation provides protection against infection by activating the immune response. Our results reveal a novel role for occluding-junctions in regulating niche-hematopoietic progenitor signalling and link this mechanism to immune cell production following infection. PMID:28841136

Aggressive reproductive competition among hopelessly queenless honeybee workers triggered by pheromone signaling

NASA Astrophysics Data System (ADS)

Malka, O.; Shnieor, S.; Katzav-Gozansky, T.; Hefetz, A.

2008-06-01

In the honeybee, Apis mellifera, the queen monopolizes reproduction, while the sterile workers cooperate harmoniously in nest maintenance. However, under queenless (QL) conditions, cooperation collapses and reproductive competition among workers ensues. This is mediated through aggression and worker oviposition, as well as shifts in pheromones, from worker to queen-like composition. Many studies suggest a dichotomy between conflict resolution through aggression or through pheromonal signaling. In this paper, we demonstrate that both phenomena comprise essential components of reproductive competition and that pheromone signaling actually triggers the onset of aggression. We kept workers as QL groups until first aggression was observed and subsequently determined the contestants’ reproductive status and content of the mandibular (MG) and Dufour’s glands (DG). In groups in which aggression occurred early, the attacked bee had consistently more queen-like pheromone in both the MG and DG, although both contestants had undeveloped ovaries. In groups with late aggression, the attacked bee had consistently larger oocytes and more queen-like pheromone in the DG, but not the MG. We suggest that at early stages of competition, the MG secretion is utilized to establish dominance and that the DG provides an honest fertility signal. We further argue that it is the higher amount of DG pheromone that triggers aggression.

A high power microwave triggered RF opening switch.

PubMed

Beeson, S; Dickens, J; Neuber, A

2015-03-01

A 4-port S-band waveguide structure was designed and fabricated such that a signal of any amplitude (less than 1 MW) can be switched from a normally closed state, <0.5 dB insertion loss (IL), to an open state >30 dB IL by initiating plasma in a gas cell situated at the junction of this waveguide and one propagating a megawatt level magnetron pulse. The 90/10 switching time is as low as 20 ns with a delay of ∼30 ns between the onset of the high power microwave pulse and the initial drop of the signal. Two ports of this device are for the high power triggering pulse while the other two ports are for the triggered signal in a Moreno-like coupler configuration. In order to maintain high isolation, these two sets of waveguides are rotated 90° from each other with a TE111 resonator/plasma cell located at the intersection. This manuscript describes the design and optimization of this structure using COMSOL 4.4 at the design frequency of 2.85 GHz, comparison of simulated scattering parameters with measured "cold tests" (testing without plasma), and finally the temporal waveforms of this device being used to successfully switch a low power CW signal from 2 W to <5 mW on a sub-microsecond timescale.

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

PubMed Central

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

Mobile Gibberellin Directly Stimulates Arabidopsis Hypocotyl Xylem Expansion[W][OA

PubMed Central

Ragni, Laura; Nieminen, Kaisa; Pacheco-Villalobos, David; Sibout, Richard; Schwechheimer, Claus; Hardtke, Christian S.

2011-01-01

Secondary growth of the vasculature results in the thickening of plant structures and continuously produces xylem tissue, the major biological carbon sink. Little is known about the developmental control of this quantitative trait, which displays two distinct phases in Arabidopsis thaliana hypocotyls. The later phase of accelerated xylem expansion resembles the secondary growth of trees and is triggered upon flowering by an unknown, shoot-derived signal. We found that flowering-dependent hypocotyl xylem expansion is a general feature of herbaceous plants with a rosette growth habit. Flowering induction is sufficient to trigger xylem expansion in Arabidopsis. By contrast, neither flower formation nor elongation of the main inflorescence is required. Xylem expansion also does not depend on any particular flowering time pathway or absolute age. Through analyses of natural genetic variation, we found that ERECTA acts locally to restrict xylem expansion downstream of the gibberellin (GA) pathway. Investigations of mutant and transgenic plants indicate that GA and its signaling pathway are both necessary and sufficient to directly trigger enhanced xylogenesis. Impaired GA signaling did not affect xylem expansion systemically, suggesting that it acts downstream of the mobile cue. By contrast, the GA effect was graft transmissible, suggesting that GA itself is the mobile shoot-derived signal. PMID:21498678

Protons Trigger Mitochondrial Flashes.

PubMed

Wang, Xianhua; Zhang, Xing; Huang, Zhanglong; Wu, Di; Liu, Beibei; Zhang, Rufeng; Yin, Rongkang; Hou, Tingting; Jian, Chongshu; Xu, Jiejia; Zhao, Yan; Wang, Yanru; Gao, Feng; Cheng, Heping

2016-07-26

Emerging evidence indicates that mitochondrial flashes (mitoflashes) are highly conserved elemental mitochondrial signaling events. However, which signal controls their ignition and how they are integrated with other mitochondrial signals and functions remain elusive. In this study, we aimed to further delineate the signal components of the mitoflash and determine the mitoflash trigger mechanism. Using multiple biosensors and chemical probes as well as label-free autofluorescence, we found that the mitoflash reflects chemical and electrical excitation at the single-organelle level, comprising bursting superoxide production, oxidative redox shift, and matrix alkalinization as well as transient membrane depolarization. Both electroneutral H(+)/K(+) or H(+)/Na(+) antiport and matrix proton uncaging elicited immediate and robust mitoflash responses over a broad dynamic range in cardiomyocytes and HeLa cells. However, charge-uncompensated proton transport, which depolarizes mitochondria, caused the opposite effect, and steady matrix acidification mildly inhibited mitoflashes. Based on a numerical simulation, we estimated a mean proton lifetime of 1.42 ns and diffusion distance of 2.06 nm in the matrix. We conclude that nanodomain protons act as a novel, to our knowledge, trigger of mitoflashes in energized mitochondria. This finding suggests that mitoflash genesis is functionally and mechanistically integrated with mitochondrial energy metabolism. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Fast, externally triggered, digital phase controller for an optical lattice

NASA Astrophysics Data System (ADS)

Sadgrove, Mark; Nakagawa, Ken'ichi

2011-11-01

We present a method to control the phase of an optical lattice according to an external trigger signal. The method has a latency of less than 30 μs. Two phase locked digital synthesizers provide the driving signal for two acousto-optic modulators which control the frequency and phase of the counter-propagating beams which form a standing wave (optical lattice). A micro-controller with an external interrupt function is connected to the desired external signal, and updates the phase register of one of the synthesizers when the external signal changes. The standing wave (period λ/2 = 390 nm) can be moved by units of 49 nm with a mean jitter of 28 nm. The phase change is well known due to the digital nature of the synthesizer, and does not need calibration. The uses of the scheme include coherent control of atomic matter-wave dynamics.

Phosphorylation of Nephrin Triggers Its Internalization by Raft-Mediated Endocytosis

PubMed Central

Qin, Xiao-Song; Shono, Akemi; Yamamoto, Akitsugu; Kurihara, Hidetake; Doi, Toshio

2009-01-01

Proper localization of nephrin determines integrity of the glomerular slit diaphragm. Slit diaphragm proteins assemble into functional signaling complexes on a raft-based platform, but how the trafficking of these proteins coordinates with their signaling function is unknown. Here, we demonstrate that a raft-mediated endocytic (RME) pathway internalizes nephrin. Nephrin internalization was slower with raft-mediated endocytosis than with classic clathrin-mediated endocytosis. Ultrastructurally, the RME pathway consisted of noncoated invaginations and was dependent on cholesterol and dynamin. Nephrin constituted a stable, signaling-competent microdomain through interaction with Fyn, a Src kinase, and podocin, a scaffold protein. Tyrosine phosphorylation of nephrin triggered its own RME-mediated internalization. Protamine-induced hyperphosphorylation of nephrin led to noncoated invaginations predominating over coated pits. These results demonstrate that an RME pathway couples nephrin internalization to its own signaling, suggesting that RME promotes proper spatiotemporal assembly of slit diaphragms during podocyte development or injury. PMID:19850954

Small Leucine-Rich Proteoglycans in Renal Inflammation: Two Sides of the Coin.

PubMed

Nastase, Madalina V; Janicova, Andrea; Roedig, Heiko; Hsieh, Louise Tzung-Harn; Wygrecka, Malgorzata; Schaefer, Liliana

2018-04-01

It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.

Synchronization trigger control system for flow visualization

NASA Technical Reports Server (NTRS)

Chun, K. S.

1987-01-01

The use of cinematography or holographic interferometry for dynamic flow visualization in an internal combustion engine requires a control device that globally synchronizes camera and light source timing at a predefined shaft encoder angle. The device is capable of 0.35 deg resolution for rotational speeds of up to 73 240 rpm. This was achieved by implementing the shaft encoder signal addressed look-up table (LUT) and appropriate latches. The developed digital signal processing technique achieves 25 nsec of high speed triggering angle detection by using direct parallel bit comparison of the shaft encoder digital code with a simulated angle reference code, instead of using angle value comparison which involves more complicated computation steps. In order to establish synchronization to an AC reference signal whose magnitude is variant with the rotating speed, a dynamic peak followup synchronization technique has been devised. This method scrutinizes the reference signal and provides the right timing within 40 nsec. Two application examples are described.

Missing pulse detector for a variable frequency source

DOEpatents

Ingram, Charles B.; Lawhorn, John H.

1979-01-01

A missing pulse detector is provided which has the capability of monitoring a varying frequency pulse source to detect the loss of a single pulse or total loss of signal from the source. A frequency-to-current converter is used to program the output pulse width of a variable period retriggerable one-shot to maintain a pulse width slightly longer than one-half the present monitored pulse period. The retriggerable one-shot is triggered at twice the input pulse rate by employing a frequency doubler circuit connected between the one-shot input and the variable frequency source being monitored. The one-shot remains in the triggered or unstable state under normal conditions even though the source period is varying. A loss of an input pulse or single period of a fluctuating signal input will cause the one-shot to revert to its stable state, changing the output signal level to indicate a missing pulse or signal.

Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages

PubMed Central

Graziano, Francesca; Desdouits, Marion; Garzetti, Livia; Podini, Paola; Alfano, Massimo; Rubartelli, Anna; Furlan, Roberto; Benaroch, Philippe; Poli, Guido

2015-01-01

HIV type 1 (HIV-1) infects CD4+ T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are believed to act as “Trojan horses” carrying infectious particles to be released on cell necrosis or functional stimulation. Here we explored the hypothesis that extracellular ATP (eATP) could represent a microenvironmental signal potentially affecting virion release from VCC of infected macrophages. Indeed, eATP triggered the rapid release of infectious HIV-1 from primary human monocyte-derived macrophages (MDM) acutely infected with the CCR5-dependent HIV-1 strain. A similar phenomenon was observed in chronically infected promonocytic U1 cells differentiated to macrophage-like cells (D-U1) by costimulation with phorbol esters and urokinase-type plasminogen activator. Worthy of note, eATP did not cause necrotic, apoptotic, or pyroptotic cell death, and its effect on HIV-1 release was suppressed by Imipramine (an antidepressant agent known to inhibit microvesicle formation by interfering with membrane-associated acid sphingomyelinase). Virion release was not triggered by oxidized ATP, whereas the effect of eATP was inhibited by a specific inhibitor of the P2X7 receptor (P2X7R). Thus, eATP triggered the discharge of virions actively accumulating in VCC of infected macrophages via interaction with the P2X7R in the absence of significant cytopathicity. These findings suggest that the microvesicle pathway and P2X7R could represent exploitable targets for interfering with the VCC-associated reservoir of infectious HIV-1 virions in tissue macrophages. PMID:26056317

Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages.

PubMed

Graziano, Francesca; Desdouits, Marion; Garzetti, Livia; Podini, Paola; Alfano, Massimo; Rubartelli, Anna; Furlan, Roberto; Benaroch, Philippe; Poli, Guido

2015-06-23

HIV type 1 (HIV-1) infects CD4(+) T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are believed to act as "Trojan horses" carrying infectious particles to be released on cell necrosis or functional stimulation. Here we explored the hypothesis that extracellular ATP (eATP) could represent a microenvironmental signal potentially affecting virion release from VCC of infected macrophages. Indeed, eATP triggered the rapid release of infectious HIV-1 from primary human monocyte-derived macrophages (MDM) acutely infected with the CCR5-dependent HIV-1 strain. A similar phenomenon was observed in chronically infected promonocytic U1 cells differentiated to macrophage-like cells (D-U1) by costimulation with phorbol esters and urokinase-type plasminogen activator. Worthy of note, eATP did not cause necrotic, apoptotic, or pyroptotic cell death, and its effect on HIV-1 release was suppressed by Imipramine (an antidepressant agent known to inhibit microvesicle formation by interfering with membrane-associated acid sphingomyelinase). Virion release was not triggered by oxidized ATP, whereas the effect of eATP was inhibited by a specific inhibitor of the P2X7 receptor (P2X7R). Thus, eATP triggered the discharge of virions actively accumulating in VCC of infected macrophages via interaction with the P2X7R in the absence of significant cytopathicity. These findings suggest that the microvesicle pathway and P2X7R could represent exploitable targets for interfering with the VCC-associated reservoir of infectious HIV-1 virions in tissue macrophages.

Signalling of Arabidopsis thaliana response to Pieris brassicae eggs shares similarities with PAMP-triggered immunity

PubMed Central

Reymond, Philippe

2013-01-01

Insect egg deposition activates plant defence, but very little is known about signalling events that control this response. In Arabidopsis thaliana, oviposition by Pieris brassicae triggers salicylic acid (SA) accumulation and induces the expression of defence genes. This is similar to the recognition of pathogen-associated molecular patterns (PAMPs), which are involved in PAMP-triggered immunity (PTI). Here, the involvement of known signalling components of PTI in response to oviposition was studied. Treatment with P. brassicae egg extract caused a rapid induction of early PAMP-responsive genes. In addition, expression of the defence gene PR-1 required EDS1, SID2, and, partially, NPR1, thus implicating the SA pathway downstream of egg recognition. PR-1 expression was triggered by a non-polar fraction of egg extract and by an oxidative burst modulated through the antagonistic action of EDS1 and NUDT7, but which did not depend on the NADPH oxidases RBOHD and RBOHF. Searching for receptors of egg-derived elicitors, a receptor-like kinase mutant, lecRK-I.8, was identified which shows a much reduced induction of PR-1 in response to egg extract treatment. These results demonstrate the importance of the SA pathway in response to egg-derived elicitor(s) and unravel intriguing similarities between the detection of insect eggs and PTI in Arabidopsis. PMID:23264520

Transcriptome analysis supports viral infection and fluoride toxicity as contributors to chronic kidney disease of unknown etiology (CKDu) in Sri Lanka.

PubMed

Sayanthooran, Saravanabavan; Gunerathne, Lishanthe; Abeysekera, Tilak D J; Magana-Arachchi, Dhammika N

2018-05-28

Chronic kidney disease of unknown etiology (CKDu), having epidemic characteristics, is being diagnosed increasingly in certain tropical regions of the world, mainly Latin America and Sri Lanka. They have been observed primarily in farming communities and current hypotheses point toward many environmental and occupational triggers. CKDu does not have common etiologies of chronic kidney disease (CKD) such as hypertension, diabetes, or autoimmune disease. We aimed to understand the molecular processes underlying CKDu in Sri Lanka using transcriptome analysis. RNA extracted from whole blood was reverse transcribed and used for microarray analysis using the Human HT-12 v.4 array (Illumina). Pathway analysis was carried out using ingenuity pathway analysis (IPA-Qiagen). Microarray results were validated using real-time PCR of five selected genes. Pathways related to innate immune response, including interferon signaling, inflammasome signaling and TREM1 signaling had the most significant positive activation z scores, where as EIF2 signaling and mTOR signaling had the most significant negative activation z scores. Pathways previously linked to fluoride toxicity; G-protein activation, Cdc42 signaling, Rac signaling and RhoA signaling were activated in CKDu patients. The most significantly activated biological functions were cell death, cell movement and antimicrobial response. Significant toxicological functions were mitochondrial dysfunction, oxidative stress and apoptosis. Based on the molecular pathway analysis in CKDu patients and review of literature, viral infections and fluoride toxicity appear to be contributing to the molecular mechanisms underlying CKDu.

Aberrant Epithelial-Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

PubMed Central

Wang, David H.; Clemons, Nicholas J.; Miyashita, Tomoharu; Dupuy, Adam J.; Zhang, Wei; Szczepny, Anette; Corcoran-Schwartz, Ian M.; Wilburn, Daniel L.; Montgomery, Elizabeth A.; Wang, Jean S.; Jenkins, Nancy A.; Copeland, Neal A.; Harmon, John W.; Phillips, Wayne A.; Watkins, D. Neil

2010-01-01

Background & Aims The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. Methods Immunohistochemistry, immunofluorescence, and quantitative real-time PCR were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. Results Marked upregulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of DMBT1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9 and columnar cytokeratins. Conclusions Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype. PMID:20138038

FITPix COMBO—Timepix detector with integrated analog signal spectrometric readout

NASA Astrophysics Data System (ADS)

Holik, M.; Kraus, V.; Georgiev, V.; Granja, C.

2016-02-01

The hybrid semiconductor pixel detector Timepix has proven a powerful tool in radiation detection and imaging. Energy loss and directional sensitivity as well as particle type resolving power are possible by high resolution particle tracking and per-pixel energy and quantum-counting capability. The spectrometric resolving power of the detector can be further enhanced by analyzing the analog signal of the detector common sensor electrode (also called back-side pulse). In this work we present a new compact readout interface, based on the FITPix readout architecture, extended with integrated analog electronics for the detector's common sensor signal. Integrating simultaneous operation of the digital per-pixel information with the common sensor (called also back-side electrode) analog pulse processing circuitry into one device enhances the detector capabilities and opens new applications. Thanks to noise suppression and built-in electromagnetic interference shielding the common hardware platform enables parallel analog signal spectroscopy on the back side pulse signal with full operation and read-out of the pixelated digital part, the noise level is 600 keV and spectrometric resolution around 100 keV for 5.5 MeV alpha particles. Self-triggering is implemented with delay of few tens of ns making use of adjustable low-energy threshold of the particle analog signal amplitude. The digital pixelated full frame can be thus triggered and recorded together with the common sensor analog signal. The waveform, which is sampled with frequency 100 MHz, can be recorded in adjustable time window including time prior to the trigger level. An integrated software tool provides control, on-line display and read-out of both analog and digital channels. Both the pixelated digital record and the analog waveform are synchronized and written out by common time stamp.

Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling

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

Chiang, Jo-Hua; Yang, Jai-Sing; Lu, Chi-Cheng

The current study aims to investigate the antiangiogenic responses and apoptotic death of human umbilical vein endothelial cells (HUVECs) by a newly synthesized compound named 2-(3′-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38). This work attempted to not only explore the effects of angiogenesis on in vivo and ex vivo studies but also hypothesize the implications for HUVECs (an ideal cell model for angiogenesis in vitro) and further undermined apoptotic experiments to verify the underlying molecular signaling by HMJ-38. Our results demonstrated that HMJ-38 significantly inhibited blood vessel growth and microvessel formation by the mouse Matrigel plug assay of angiogenesis, and the suppression of microsprouting frommore » the rat aortic ring assay was observed after HMJ-38 exposure. In addition, HMJ-38 disrupted the tube formation and blocked the ability of HUVECs to migrate in response to VEGF. We also found that HMJ-38 triggered cell apoptosis of HUVECs in vitro. HMJ-38 concentration-dependently suppressed viability and induced apoptotic damage in HUVECs. HMJ-38-influenced HUVECs were performed by determining the oxidative stress (ROS production) and ATM/p53-modulated Fas and DR4/DR5 signals that were examined by flow cytometry, Western blotting, siRNA and real-time RT-PCR analyses, respectively. Our findings demonstrate that p53-regulated extrinsic pathway might fully contribute to HMJ-38-provoked apoptotic death in HUVECs. In view of these observations, we conclude that HMJ-38 reduces angiogenesis in vivo and ex vivo as well as induces apoptosis of HUVECs in vitro. Overall, HMJ-38 has a potent anti-neovascularization effect and could warrant being a vascular targeting agent in the future. - Highlights: • HMJ-38 suppresses angiogenic actions in vivo and ex vivo. • Inhibitions of blood vessel and microvessel formation by HMJ-38 are acted. • Cytotoxic effects of HUVECs occur by HMJ-38 challenge. • p53-modulated extrinsic pathway contributes to HMJ-38-provoked apoptosis in HUVECs. • Novel HMJ-38 possesses anti-angiogenic properties and pro-apoptotic processes.« less

Synchronized operation by field programmable gate array based signal controller for the Thomson scattering diagnostic system in KSTAR.

PubMed

Lee, W R; Kim, H S; Park, M K; Lee, J H; Kim, K H

2012-09-01

The Thomson scattering diagnostic system is successfully installed in the Korea Superconducting Tokamak Advanced Research (KSTAR) facility. We got the electron temperature and electron density data for the first time in 2011, 4th campaign using a field programmable gate array (FPGA) based signal control board. It operates as a signal generator, a detector, a controller, and a time measuring device. This board produces two configurable trigger pulses to operate Nd:YAG laser system and receives a laser beam detection signal from a photodiode detector. It allows a trigger pulse to be delivered to a time delay module to make a scattered signal measurement, measuring an asynchronous time value between the KSTAR timing board and the laser system injection signal. All functions are controlled by the embedded processor running on operating system within a single FPGA. It provides Ethernet communication interface and is configured with standard middleware to integrate with KSTAR. This controller has operated for two experimental campaigns including commissioning and performed the reconfiguration of logic designs to accommodate varying experimental situation without hardware rebuilding.

Modular Activating Receptors in Innate and Adaptive Immunity.

PubMed

Berry, Richard; Call, Matthew E

2017-03-14

Triggering of cell-mediated immunity is largely dependent on the recognition of foreign or abnormal molecules by a myriad of cell surface-bound receptors. Many activating immune receptors do not possess any intrinsic signaling capacity but instead form noncovalent complexes with one or more dimeric signaling modules that communicate with a common set of kinases to initiate intracellular information-transfer pathways. This modular architecture, where the ligand binding and signaling functions are detached from one another, is a common theme that is widely employed throughout the innate and adaptive arms of immune systems. The evolutionary advantages of this highly adaptable platform for molecular recognition are visible in the variety of ligand-receptor interactions that can be linked to common signaling pathways, the diversification of receptor modules in response to pathogen challenges, and the amplification of cellular responses through incorporation of multiple signaling motifs. Here we provide an overview of the major classes of modular activating immune receptors and outline the current state of knowledge regarding how these receptors assemble, recognize their ligands, and ultimately trigger intracellular signal transduction pathways that activate immune cell effector functions.

The tomato calcium sensor Cbl10 and its interacting protein kinase Cipk6 define a signaling pathway in plant immunity.

PubMed

de la Torre, Fernando; Gutiérrez-Beltrán, Emilio; Pareja-Jaime, Yolanda; Chakravarthy, Suma; Martin, Gregory B; del Pozo, Olga

2013-07-01

Ca(2+) signaling is an early and necessary event in plant immunity. The tomato (Solanum lycopersicum) kinase Pto triggers localized programmed cell death (PCD) upon recognition of Pseudomonas syringae effectors AvrPto or AvrPtoB. In a virus-induced gene silencing screen in Nicotiana benthamiana, we independently identified two components of a Ca(2+)-signaling system, Cbl10 (for calcineurin B-like protein) and Cipk6 (for calcineurin B-like interacting protein kinase), as their silencing inhibited Pto/AvrPto-elicited PCD. N. benthamiana Cbl10 and Cipk6 are also required for PCD triggered by other plant resistance genes and virus, oomycete, and nematode effectors and for host susceptibility to two P. syringae pathogens. Tomato Cipk6 interacts with Cbl10 and its in vitro kinase activity is enhanced in the presence of Cbl10 and Ca(2+), suggesting that tomato Cbl10 and Cipk6 constitute a Ca(2+)-regulated signaling module. Overexpression of tomato Cipk6 in N. benthamiana leaves causes accumulation of reactive oxygen species (ROS), which requires the respiratory burst homolog RbohB. Tomato Cbl10 and Cipk6 interact with RbohB at the plasma membrane. Finally, Cbl10 and Cipk6 contribute to ROS generated during effector-triggered immunity in the interaction of P. syringae pv tomato DC3000 and N. benthamiana. We identify a role for the Cbl/Cipk signaling module in PCD, establishing a mechanistic link between Ca(2+) and ROS signaling in plant immunity.

NRG1-Fc improves metabolic health via dual hepatic and central action.

PubMed

Zhang, Peng; Kuang, Henry; He, Yanlin; Idiga, Sharon O; Li, Siming; Chen, Zhimin; Yang, Zhao; Cai, Xing; Zhang, Kezhong; Potthoff, Matthew J; Xu, Yong; Lin, Jiandie D

2018-03-08

Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.

NRG1-Fc improves metabolic health via dual hepatic and central action

PubMed Central

Kuang, Henry; Idiga, Sharon O.; Li, Siming; Chen, Zhimin; Cai, Xing; Zhang, Kezhong; Potthoff, Matthew J.; Xu, Yong; Lin, Jiandie D.

2018-01-01

Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat–enriched secreted factor NRG4 protects mice from high-fat diet–induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake. PMID:29515030

Human Mut T Homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS.

PubMed

Rai, Priyamvada

2012-01-01

Oncogenic RAS-induced reactive oxygen species (ROS) trigger barriers to cell transformation and cancer progression through tumor-suppressive responses such as cellular senescence or cell death. We have recently shown that oncogenic RAS-induced DNA damage and attendant premature senescence can be prevented by overexpressing human MutT Homolog 1 (MTH1), the major mammalian detoxifier of the oxidized DNA precursor, 8-oxo-dGTP. Paradoxically, RAS-induced ROS are also able to participate in tumor progression via transformative processes such as mitogenic signaling, the epithelial-mesenchymal transition (EMT), anoikis inhibition, and PI3K/Akt-mediated survival signaling. Here we provide a preliminary insight into the influence of MTH1 levels on the EMT phenotype and Akt activation in RAS-transformed HMLE breast epithelial cells. Within this context, we will discuss the implications of MTH1 upregulation in oncogenic RAS-sustaining cells as a beneficial adaptive change that inhibits ROS-mediated cell senescence and participates in the maintenance of ROS-associated tumor-promoting mechanisms. Accordingly, targeting MTH1 in RAS-transformed tumor cells will not only induce proliferative defects but also potentially enhance therapeutic cytotoxicity by shifting cellular response away from pro-survival mechanisms.

The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling

PubMed Central

Klein, Theo; Fung, Shan-Yu; Renner, Florian; Blank, Michael A.; Dufour, Antoine; Kang, Sohyeong; Bolger-Munro, Madison; Scurll, Joshua M.; Priatel, John J.; Schweigler, Patrick; Melkko, Samu; Gold, Michael R.; Viner, Rosa I.; Régnier, Catherine H.; Turvey, Stuart E.; Overall, Christopher M.

2015-01-01

Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1mut/mut patient with healthy MALT1+/mut family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway—first promoting activation via the CBM—then triggering HOIL1-dependent negative-feedback termination, preventing reactivation. PMID:26525107

Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

PubMed Central

Robles, Eloy F.; Mena-Varas, Maria; Barrio, Laura; Merino-Cortes, Sara V.; Balogh, Péter; Du, Ming-Qing; Akasaka, Takashi; Parker, Anton; Roa, Sergio; Panizo, Carlos; Martin-Guerrero, Idoia; Siebert, Reiner; Segura, Victor; Agirre, Xabier; Macri-Pellizeri, Laura; Aldaz, Beatriz; Vilas-Zornoza, Amaia; Zhang, Shaowei; Moody, Sarah; Calasanz, Maria Jose; Tousseyn, Thomas; Broccardo, Cyril; Brousset, Pierre; Campos-Sanchez, Elena; Cobaleda, Cesar; Sanchez-Garcia, Isidro; Fernandez-Luna, Jose Luis; Garcia-Muñoz, Ricardo; Pena, Esther; Bellosillo, Beatriz; Salar, Antonio; Baptista, Maria Joao; Hernandez-Rivas, Jesús Maria; Gonzalez, Marcos; Terol, Maria Jose; Climent, Joan; Ferrandez, Antonio; Sagaert, Xavier; Melnick, Ari M.; Prosper, Felipe; Oscier, David G.; Carrasco, Yolanda R.; Dyer, Martin J. S.; Martinez-Climent, Jose A.

2016-01-01

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas. PMID:27297662

78 FR 66666 - Airworthiness Directives; Diamond Aircraft Industries GmbH Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-06

... available in the AD docket shortly after receipt. FOR FURTHER INFORMATION CONTACT: Mike Kiesov, Aerospace... Invited We invite you to send any written relevant data, views, or arguments about this proposed AD. Send... trigger by using the G1000 ampere-meter signals. The trigger is set once an alternator provides less than...

Latency study of the High Performance Time to Digital Converter for the ATLAS Muon Spectrometer trigger upgrade

NASA Astrophysics Data System (ADS)

Meng, X. T.; Levin, D. S.; Chapman, J. W.; Li, D. C.; Yao, Z. E.; Zhou, B.

2017-02-01

The High Performance Time to Digital Converter (HPTDC), a multi-channel ASIC designed by the CERN Microelectronics group, has been proposed for the digitization of the thin-Resistive Plate Chambers (tRPC) in the ATLAS Muon Spectrometer Phase-1 upgrade project. These chambers, to be staged for higher luminosity LHC operation, will increase trigger acceptance and reduce or eliminate the fake muon trigger rates in the barrel-endcap transition region, corresponding to pseudo-rapidity range 1<|η|<1.3. Low level trigger candidates must be flagged within a maximum latency of 1075 ns, thus imposing stringent signal processing time performance requirements on the readout system in general, and on the digitization electronics in particular. This paper investigates the HPTDC signal latency performance based on a specially designed evaluation board coupled with an external FPGA evaluation board, when operated in triggerless mode, and under hit rate conditions expected in Phase-I. This hardware based study confirms previous simulations and demonstrates that the HPTDC in triggerless operation satisfies the digitization timing requirements in both leading edge and pair modes.

More About The Video Event Trigger

NASA Technical Reports Server (NTRS)

Williams, Glenn L.

1996-01-01

Report presents additional information about system described in "Video Event Trigger" (LEW-15076). Digital electronic system processes video-image data to generate trigger signal when image shows significant change, such as motion, or appearance, disappearance, change in color, brightness, or dilation of object. Potential uses include monitoring of hallways, parking lots, and other areas during hours when supposed unoccupied, looking for fires, tracking airplanes or other moving objects, identification of missing or defective parts on production lines, and video recording of automobile crash tests.

Human rhinovirus-induced ISG15 selectively modulates epithelial antiviral immunity

PubMed Central

Zaheer, R S; Wiehler, S; Hudy, M H; Traves, S L; Pelikan, J B; Leigh, R; Proud, D

2014-01-01

Human rhinovirus (HRV) infections trigger exacerbations of lower airway diseases. HRV infects human airway epithelial cells and induces proinflammatory and antiviral molecules that regulate the response to HRV infection. Interferon (IFN)-stimulated gene of 15 kDa (ISG15) has been shown to regulate other viruses. We now show that HRV-16 infection induces both intracellular epithelial ISG15 expression and ISG15 secretion in vitro. Moreover, ISG15 protein levels increased in nasal secretions of subjects with symptomatic HRV infections. HRV-16-induced ISG15 expression is transcriptionally regulated via an IFN regulatory factor pathway. ISG15 does not directly alter HRV replication but does modulate immune signaling via the viral sensor protein RIG-I to impact production of CXCL10, which has been linked to innate immunity to viruses. Extracellular ISG15 also alters CXCL10 production. We conclude that ISG15 has a complex role in host defense against HRV infection, and that additional studies are needed to clarify the role of this molecule. PMID:24448099

Human intraepithelial lymphocytes.

PubMed

Mayassi, Toufic; Jabri, Bana

2018-04-20

The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ + CD8αβ + IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ + CD8αα + and adaptively induced TCRαβ + CD8αβ + IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.

47 CFR 2.1505 - Test instrumentation and equipment.

Code of Federal Regulations, 2010 CFR

2010-10-01

... instrument is to be DC coupled and capable of manually triggered single sweeps. (d) Frequency counter. A... frequency. (e) Signal generator. A calibrated signal generator with an output of at least 75 mW at 121.5 and...

Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells.

PubMed

Zogovic, Nevena; Tovilovic-Kovacevic, Gordana; Misirkic-Marjanovic, Maja; Vucicevic, Ljubica; Janjetovic, Kristina; Harhaji-Trajkovic, Ljubica; Trajkovic, Vladimir

2015-04-01

We explored the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and autophagy in phorbol myristate acetate (PMA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells. PMA-triggered expression of neuronal markers (dopamine transporter, microtubule-associated protein 2, β-tubulin) was associated with an autophagic response, measured by the conversion of microtubule-associated protein light chain 3 (LC3)-I to autophagosome-bound LC3-II, increase in autophagic flux, and expression of autophagy-related (Atg) proteins Atg7 and beclin-1. This coincided with the transient activation of AMPK and sustained activation of ERK. Pharmacological inhibition or RNA interference-mediated silencing of AMPK suppressed PMA-induced expression of neuronal markers, as well as ERK activation and autophagy. A selective pharmacological blockade of ERK prevented PMA-induced neuronal differentiation and autophagy induction without affecting AMPK phosphorylation. Conversely, the inhibition of autophagy downstream of AMPK/ERK, either by pharmacological agents or LC3 knockdown, promoted the expression of neuronal markers, thus indicating a role of autophagy in the suppression of PMA-induced differentiation of SH-SY5Y cells. Therefore, PMA-induced neuronal differentiation of SH-SY5Y cells depends on a complex interplay between AMPK, ERK, and autophagy, in which the stimulatory effects of AMPK/ERK signaling are counteracted by the coinciding autophagic response. Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process. © 2014 International Society for Neurochemistry.

Study of a novel ultrasonically triggered drug vehicle with magnetic resonance properties.

PubMed

Liu, Tse-Ying; Huang, Hsin-Hui; Chen, Yen-Ju; Chen, Yu-Jen

2011-02-01

We developed a novel ultrasonically triggered drug vehicle with magnetic resonance (MR) properties by encapsulating superparamagnetic iron oxide (SPIO) nanoparticles in hydroxyapatite (HA)-coated liposomes. The effects of HA coating on the background leakage, ultrasound response and MR signal were investigated. HA coating of liposomes significantly reduced the background leakage of liposome. It also enhanced their sensitivity to ultrasound regardless of HA thickness or ultrasound frequency, even under sonication conditions of high frequency (1 and 3 MHz) and low power density (0.2-0.4 Wcm(-2)) used for diagnosis. However, it was found that the ultrasonically triggered vehicle could exhibit T(2) contrast in MR images by encapsulating SPIO. However, HA coating reduced the r(2) value of SPIO encapsulated in liposomes, but had no significant effect on the r(2)(∗) value, implying that MR images of HA-coated liposomes encapsulating SPIO could be probed by the T(2)(∗) signal. Most importantly, the r(2)(∗)-r(2) value of HA-coated liposomes encapsulating SPIO decreased after sonication, suggesting that the proposed vehicle could be used not only as a MR-guided drug vehicle capable of ultrasonically triggered release but also as a MR reporter to probe ultrasonic triggering. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Transcriptional Regulation of Pattern-Triggered Immunity in Plants.

PubMed

Li, Bo; Meng, Xiangzong; Shan, Libo; He, Ping

2016-05-11

Perception of microbe-associated molecular patterns (MAMPs) by cell-surface-resident pattern recognition receptors (PRRs) induces rapid, robust, and selective transcriptional reprogramming, which is central for launching effective pattern-triggered immunity (PTI) in plants. Signal relay from PRR complexes to the nuclear transcriptional machinery via intracellular kinase cascades rapidly activates primary immune response genes. The coordinated action of gene-specific transcription factors and the general transcriptional machinery contribute to the selectivity of immune gene activation. In addition, PRR complexes and signaling components are often transcriptionally upregulated upon MAMP perception to ensure the robustness and sustainability of PTI outputs. In this review, we discuss recent advances in deciphering the signaling pathways and regulatory mechanisms that coordinately lead to timely and accurate MAMP-induced gene expression in plants. Copyright © 2016 Elsevier Inc. All rights reserved.

Upgrade of Tile Calorimeter of the ATLAS Detector for the High Luminosity LHC.

NASA Astrophysics Data System (ADS)

Valdes Santurio, Eduardo; Tile Calorimeter System, ATLAS

2017-11-01

The Tile Calorimeter (TileCal) is the hadronic calorimeter of ATLAS covering the central region of the ATLAS experiment. TileCal is a sampling calorimeter with steel as absorber and scintillators as active medium. The scintillators are read out by wavelength shifting fibers coupled to photomultiplier tubes (PMT). The analogue signals from the PMTs are amplified, shaped and digitized by sampling the signal every 25 ns. The High Luminosity Large Hadron Collider (HL-LHC) will have a peak luminosity of 5 × 1034 cm -2 s -1, five times higher than the design luminosity of the LHC. TileCal will undergo a major replacement of its on- and off-detector electronics for the high luminosity programme of the LHC in 2026. The calorimeter signals will be digitized and sent directly to the off-detector electronics, where the signals are reconstructed and shipped to the first level of trigger at a rate of 40 MHz. This will provide a better precision of the calorimeter signals used by the trigger system and will allow the development of more complex trigger algorithms. Three different options are presently being investigated for the front-end electronic upgrade. Extensive test beam studies will determine which option will be selected. Field Programmable Gate Arrays (FPGAs) are extensively used for the logic functions of the off- and on-detector electronics. One hybrid demonstrator prototype module with the new calorimeter module electronics, but still compatible with the present system, may be inserted in ATLAS at the end of 2016.

Signal-on fluorescence biosensor for microRNA-21 detection based on DNA strand displacement reaction and Mg2+-dependent DNAzyme cleavage.

PubMed

Yin, Huan-Shun; Li, Bing-Chen; Zhou, Yun-Lei; Wang, Hai-Yan; Wang, Ming-Hui; Ai, Shi-Yun

2017-10-15

MicroRNAs have been involved into many biological processes and are regarded as disease biomarkers. Simple, rapid, sensitive and selective method for microRNA detection is crucial for early diagnosis and therapy of diseases. In this work, sensitive fluorescence assay was developed for microRNA-21 detection based on DNA polymerase induced strand displacement amplification reaction, Mg 2+ -dependent DNAzyme catalysis reaction, and magnetic separation. In the presence of target microRNA-21, amounts of trigger DNA could be produced with DNA polymerase induced strand displacement amplification reaction, and the trigger DNA could be further hybridized with signal DNA, which was labeled with biotin and AMCA dye. After introduction of Mg 2+ , trigger DNA could form DNAzyme to cleave signal DNA. After magnetic separation, the DNA fragment with AMCA dye could give fluorescence signal, which was related to microRNA-21 concentration. Based on the two efficient signal amplifications, the developed method showed high detection sensitivity with low detection limit of 0.27fM (3σ). In addition, this fluorescence strategy also possessed excellent detection specificity, and could be applied to analyze microRNA-21 expression level in serum of cancer patient. According to the obtained results, the developed fluorescence method might be a promising detection platform for microRNA-21 quantitative analysis in biomedical research and clinical diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Dynamic compaction of human mesenchymal stem/precursor cells (MSC) into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6 and STC1)

PubMed Central

Bazhanov, Nikolay; Kuhlman, Jessica; Prockop, Darwin J.

2013-01-01

Human mesenchymal stem/precursor cells (MSC) are similar to some other stem/progenitor cells in that they compact into spheres when cultured in hanging drops or on non-adherent surfaces. Assembly of MSC into spheres alters many of their properties, including enhanced secretion of factors that mediate inflammatory and immune responses. Here we demonstrated that MSC spontaneously aggregated into sphere-like structures after injection into a subcutaneous air pouch or the peritoneum of mice. The structures were similar to MSC spheres formed in cultures demonstrated by the increased expression of genes for inflammation-modulating factors TSG6, STC1, and COX2, a key enzyme in production of PGE2. To identify the signaling pathways involved, hanging drop cultures were used to follow the time-dependent changes in the cells as they compacted into spheres. Among the genes up-regulated were genes for the stress-activated signaling pathway for IL1α/β, and the contact-dependent signaling pathway for Notch. An inhibitor of caspases reduced the up-regulation of IL1A/B expression, and inhibitors of IL1 signaling decreased production of PGE2, TSG6 and STC1. Also, inhibition of IL1A/B expression and secretion of PGE2 negated the anti-inflammatory effects of MSC spheres on stimulated macrophages. Experiments with γ-secretase inhibitors suggested that Notch signaling was also required for production of PGE2 but not TSG6 or STC1. The results indicated that assembly of MSC into spheres triggers caspase-dependent IL1 signaling and the secretion of modulators of inflammation and immunity. Similar aggregation in vivo may account for some of the effects observed with administration of the cells in animal models. PMID:23922312

Acoustic Response of Microbubbles Derived from Phase-Change Nanodroplet

NASA Astrophysics Data System (ADS)

Kawabata, Ken-ichi; Asami, Rei; Azuma, Takashi; Umemura, Shin-ichiro

2010-07-01

An in vitro feasibility test for a novel ultrasound therapy using a type of superheated perfluorocarbon droplet, phase-change nanodroplet (PCND), was performed in gel phantoms with the goal of high selectivity and low invasiveness. Measurements of broadband signal emission revealed that a triggering ultrasound pulse (peak negative pressure of 2.4 MPa) reduces the pressure threshold for cavitation induced by a subsequent ultrasound exposure at an order of magnitude from 2.4 to 0.2 MPa. The maximum allowed interval between the two ultrasound exposures for inducing cavitation with 100- and 1,000-cycle triggering ultrasound was about 100 and 500 ms, respectively. The echo signal increases induced by the triggering ultrasound with 100- and 1000-cycles were enhanced and suppressed by the subsequent ultrasound exposure, respectively. This different behavior seemed to be due to the presence of enlarged free bubbles, which should be avoided for the localization of therapeutic effects.

Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor.

PubMed

Monaco-Shawver, Linda; Schwartz, Lynnae; Tuluc, Florin; Guo, Chang-Jiang; Lai, Jian Ping; Gunnam, Satya M; Kilpatrick, Laurie E; Banerjee, Pinaki P; Douglas, Steven D; Orange, Jordan S

2011-01-01

SP is a potent neuroimmunomodulator that functions through ligating members of the neurokinin receptor family, one of which, NK1R, is widely expressed in immune cells. As in humans, circulating SP levels are increased in pathologic states associated with impairment of NK cell functions, such as depression and HIV infection, we hypothesized that SP has a direct, inhibitory effect upon NK cells. We have studied a clonal human NK cell line (YTS) as well as ex vivo human NK cells and have determined that truncated and full-length NK1R isoforms are expressed in and SP bound by ex vivo NK cells and the YTS NK cell line. Incubation of YTS cells with 10⁻⁶ M SP and ex vivo NK cells with 10⁻⁵ M SP inhibited cytotoxic ability by ∼20% and reduced degranulation. This inhibitory effect upon cytotoxicity was partially prevented by the NK1R antagonist CP96,345. The treatment of YTS or ex vivo NK cells with SP neither down-modulated NCR expression nor affected triggering receptor-induced NF-κB activation. Preincubation of YTS cells with SP, however, did abbreviate the typically prolonged intracellular calcium increase induced by target cell engagement and reduced triggering receptor-induced pERK. Thus, SP has the potential to regulate NK cell functions and acts downstream from neurokinin receptors to modulate NK cell activation signaling. This mechanism may contribute to impairment of NK cell function in certain disease states associated with increased circulating SP. Antagonism of this system may present an opportunity to augment NK cell function therapeutically in selected human diseases.

Hypo-responsiveness of interleukin-8 production in human embryonic epithelial intestine 407 cells independent of NF-{kappa}B pathway: New lessons from endotoxin and ribotoxic deoxynivalenol

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

Moon, Yuseok; Yang, Hyun; Park, Seung-Hwan

Mucosal epithelium senses external toxic insults and transmits the danger signals into the epithelial cells in order to activate a broad range of inflammatory responses. However, pre-exposure to the commensal endotoxins can induce inflammatory tolerance and maintain the homeostasis without excessive immune responses. We recently reported that ribotoxin deoxynivalenol (DON) and its derivatives elicited the pro-inflammatory response as the mucosal insults in human epithelial cells. Taking the knowledge into consideration, we tested the hypothesis that endotoxin pre-exposure can attenuate ribotoxin-induced epithelial interleukin-8 (IL-8) production via a tolerance mechanism. Pre-exposure to endotoxin repressed IL-8 release and its gene expression. However, inflammatorymore » tolerance was not mediated by the attenuated NF-{kappa}B activation which has been generally recognized as the major mediator of LPS-mediated toll-like receptor (TLR) signaling pathway. Instead, pre-exposure to endotoxin was observed to trigger the delayed induction of peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) which contributed to the diminished IL-8 production in the human epithelial cells. Moreover, endogenous PPAR-{gamma} agonist suppressed toxicant-mediated interleukin-8 production and IL-8 mRNA stability. Taken together, endotoxin induced hypo-production of pro-inflammatory cytokine IL-8 in the human epithelial cells, which was associated with the delayed activation of PPAR-{gamma} expression by pre-existing endotoxin.« less

Excitation-transcription coupling via calcium/calmodulin-dependent protein kinase/ERK1/2 signaling mediates the coordinate induction of VGLUT2 and Narp triggered by a prolonged increase in glutamatergic synaptic activity.

PubMed

Doyle, Sukhjeevan; Pyndiah, Slovénie; De Gois, Stéphanie; Erickson, Jeffrey D

2010-05-07

Homeostatic scaling of glutamatergic and GABAergic transmission is triggered by prolonged alterations in synaptic neuronal activity. We have previously described a presynaptic mechanism for synaptic homeostasis and plasticity that involves scaling the level of vesicular glutamate (VGLUT1) and gamma-aminobutyric acid (GABA) (VGAT) transporter biosynthesis. These molecular determinants of vesicle filling and quantal size are regulated by neuronal activity in an opposite manner and bi-directionally. Here, we report that a striking induction of VGLUT2 mRNA and synaptic protein is triggered by a prolonged increase in glutamatergic synaptic activity in mature neocortical neuronal networks in vitro together with two determinants of inhibitory synaptic strength, the neuronal activity-regulated pentraxin (Narp), and glutamate decarboxylase (GAD65). Activity-dependent induction of VGLUT2 and Narp exhibits a similar intermediate-early gene response that is blocked by actinomycin D and tetrodotoxin, by inhibitors of ionotropic glutamate receptors and L-type voltage-gated calcium channels, and is dependent on downstream signaling via calmodulin, calcium/calmodulin-dependent protein kinase (CaMK) and extracellular signal-regulated kinase 1/2 (ERK1/2). The co-induction of VGLUT2 and Narp triggered by prolonged gamma-aminobutyric acid type A receptor blockade is independent of brain-derived nerve growth factor and TrkB receptor signaling. VGLUT2 protein induction occurs on a subset of cortically derived synaptic vesicles in excitatory synapses on somata and dendritic processes of multipolar GABAergic interneurons, recognized sites for the clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptors by Narp. We propose that VGLUT2 and Narp induction by excitation-transcription coupling leads to increased glutamatergic transmission at synapses on GABAergic inhibitory feedback neurons as part of a coordinated program of Ca(2+)-signal transcription involved in mechanisms of homeostatic plasticity after prolonged hyperactivity.

Evaluation of optimal DNA staining for triggering by scanning fluorescence microscopy (SFM)

NASA Astrophysics Data System (ADS)

Mittag, Anja; Marecka, Monika; Pierzchalski, Arkadiusz; Malkusch, Wolf; Bocsi, József; Tárnok, Attila

2009-02-01

In imaging and flow cytometry, DNA staining is a common trigger signal for cell identification. Selection of the proper DNA dye is restricted by the hardware configuration of the instrument. The Zeiss Imaging Solutions GmbH (München, Germany) introduced a new automated scanning fluorescence microscope - SFM (Axio Imager.Z1) which combines fluorescence imaging with cytometric parameters measurement. The aim of the study was to select optimal DNA dyes as trigger signal in leukocyte detection and subsequent cytometric analysis of double-labeled leukocytes by SFM. Seven DNA dyes (DAPI, Hoechst 33258, Hoechst 33342, POPO-3, PI, 7-AAD, and TOPRO-3) were tested and found to be suitable for the implemented filtersets (fs) of the SFM (fs: 49, fs: 44, fs: 20). EDTA blood was stained after erythrocyte lysis with DNA dye. Cells were transferred on microscopic slides and embedded in fluorescent mounting medium. Quality of DNA fluorescence signal as well as spillover signals were analyzed by SFM. CD45-APC and CD3-PE as well as CD4-FITC and CD8-APC were selected for immunophenotyping and used in combination with Hoechst. Within the tested DNA dyes DAPI showed relatively low spillover and the best CV value. Due to the low spillover of UV DNA dyes a triple staining of Hoechst and APC and PE (or APC and FITC, respectively) could be analyzed without difficulty. These results were confirmed by FCM measurements. DNA fluorescence is applicable for identifying and triggering leukocytes in SFM analyses. Although some DNA dyes exhibit strong spillover in other fluorescence channels, it was possible to immunophenotype leukocytes. DAPI seems to be best suitable for use in the SFM system and will be used in protocol setups as primary parameter.

The retrospective binning method improves the consistency of phase binning in respiratory-gated PET/CT

NASA Astrophysics Data System (ADS)

Didierlaurent, D.; Ribes, S.; Batatia, H.; Jaudet, C.; Dierickx, L. O.; Zerdoud, S.; Brillouet, S.; Caselles, O.; Courbon, F.

2012-12-01

This study assesses the accuracy of prospective phase-gated PET/CT data binning and presents a retrospective data binning method that improves image quality and consistency. Respiratory signals from 17 patients who underwent 4D PET/CT were analysed to evaluate the reproducibility of temporal triggers used for the standard phase-based gating method. Breathing signals were reprocessed to implement retrospective PET data binning. The mean and standard deviation of time lags between automatic triggers provided by the Real-time Position Management (RPM, Varian) gating device and inhalation peaks derived from respiratory curves were computed for each patient. The total number of respiratory cycles available for 4D PET/CT according to the binning mode (prospective versus retrospective) was compared. The maximum standardized uptake value (SUVmax), biological tumour volume (BTV) and tumour trajectory measures were determined from the PET/CT images of five patients. Compared to retrospective binning (RB), prospective gating approach led to (i) a significant loss in breathing cycles (15%) and (ii) the inconsistency of data binning due to temporal dispersion of triggers (average 396 ms). Consequently, tumour characterization could be impacted. In retrospective mode, SUVmax was up to 27% higher, where no significant difference appeared in BTV. In addition, prospective mode gave an inconsistent spatial location of the tumour throughout the bins. Improved consistency with breathing patterns and greater motion amplitude of the tumour centroid were observed with retrospective mode. The detection of the tumour motion and trajectory was improved also for small temporal dispersion of triggers. This study shows that the binning mode could have a significant impact on 4D PET images. The consistency of triggers with breathing signals should be checked before clinical use of gated PET/CT images, and our RB method improves 4D PET/CT image quantification.

Tremors Triggered along the Queen Charlotte Fault

NASA Astrophysics Data System (ADS)

Aiken, C.; Peng, Z.; Chao, K.

2012-12-01

In the past decade, deep tectonic tremors have been observed in numerous tectonic environments surrounding the Pacific and Caribbean plates. In these regions, tremors triggered by both regional and distant earthquakes have also been observed. Despite the ubiquitous observations of triggered tremors, tremors triggered in differing strike-slip environments are less understood. Here, we conduct a preliminary search of tremors triggered by teleseismic earthquakes along the transpressive Queen Charlotte Fault (QCF) located between the Cascadia subduction zone and Alaska. Tectonic tremors have not been previously reported along the QCF. We select teleseismic earthquakes during the 1990-2012 period as having magnitude M ≥ 6.5 and occurring at least 1,000 km away from the region. We reduce the number of mainshocks by selecting those that generate greater than 1 kPa dynamic stress estimated from surface-wave magnitude equations [e.g. van der Elst and Brodsky, 2010]. Our mainshock waveforms are retrieved from the Canadian National Seismograph Network (CNSN), processed, and filtered for triggered tremor observations. We characterize triggered tremors as high-frequency signals visible among several stations and coincident with broadband surface wave peaks. So far, we have found tremors triggered along the QCF by surface waves of five great earthquakes - the 2002/11/03 Mw7.9 Denali Fault, 2004/12/26 Mw9.0 Sumatra, 2010/02/27 Mw8.8 Chile, 2011/03/11 Mw9.0 Japan, and 2012/04/11 Mw8.6 Sumatra earthquakes. We compare our results to tremors triggered by teleseismic earthquakes on strike-slip faults in central and southern California, as well as Cuba [Peng et al., 2012]. Among strike-slip faults in these regions, we also compare triggered tremor amplitudes to peak ground velocities from the mainshocks and compute dynamic stresses to determine a triggering threshold for the QCF. We find that in most cases tremors in the QCF are triggered primarily by the Love waves, and additional tremors are triggered by the subsequent Rayleigh waves. This is consistent with the near strike-parallel incidence for many triggering earthquakes, which tends to produce maximum triggering potential for vertical strike-slip faults. These results suggest a shear faulting mechanism is responsible for the triggered tremor on the QCF. The triggering threshold of dynamic stress is higher than that found at the Parkfield-Cholame section of the San Andreas Fault (2-3 KPa). This could be due to the sparse network coverage in the QCF, which may miss weak tremor signals triggered by smaller-size events. Our observations suggest that triggered tremor could occur in many places on major strike-slip faults around the world, although the necessary conditions for tremor generation are still not clear at this stage.

Universal, colorimetric microRNA detection strategy based on target-catalyzed toehold-mediated strand displacement reaction

NASA Astrophysics Data System (ADS)

Park, Yeonkyung; Lee, Chang Yeol; Kang, Shinyoung; Kim, Hansol; Park, Ki Soo; Park, Hyun Gyu

2018-02-01

In this work, we developed a novel, label-free, and enzyme-free strategy for the colorimetric detection of microRNA (miRNA), which relies on a target-catalyzed toehold-mediated strand displacement (TMSD) reaction. The system employs a detection probe that specifically binds to the target miRNA and sequentially releases a catalyst strand (CS) intended to trigger the subsequent TMSD reaction. Thus, the presence of target miRNA releases the CS that mediates the formation of an active G-quadruplex DNAzyme which is initially caged and inactivated by a blocker strand. In addition, a fuel strand that is supplemented for the recycling of the CS promotes another TMSD reaction, consequently generating a large number of active G-quadruplex DNAzymes. As a result, a distinct colorimetric signal is produced by the ABTS oxidation promoted by the peroxidase mimicking activity of the released G-quadruplex DNAzymes. Based on this novel strategy, we successfully detected miR-141, a promising biomarker for human prostate cancer, with high selectivity. The diagnostic capability of this system was also demonstrated by reliably determining target miR-141 in human serum, showing its great potential towards real clinical applications. Importantly, the proposed approach is composed of separate target recognition and signal transduction modules. Thus, it could be extended to analyze different target miRNAs by simply redesigning the detection probe while keeping the same signal transduction module as a universal signal amplification unit, which was successfully demonstrated by analyzing another target miRNA, let-7d.

Universal, colorimetric microRNA detection strategy based on target-catalyzed toehold-mediated strand displacement reaction.

PubMed

Park, Yeonkyung; Lee, Chang Yeol; Kang, Shinyoung; Kim, Hansol; Park, Ki Soo; Park, Hyun Gyu

2018-02-23

In this work, we developed a novel, label-free, and enzyme-free strategy for the colorimetric detection of microRNA (miRNA), which relies on a target-catalyzed toehold-mediated strand displacement (TMSD) reaction. The system employs a detection probe that specifically binds to the target miRNA and sequentially releases a catalyst strand (CS) intended to trigger the subsequent TMSD reaction. Thus, the presence of target miRNA releases the CS that mediates the formation of an active G-quadruplex DNAzyme which is initially caged and inactivated by a blocker strand. In addition, a fuel strand that is supplemented for the recycling of the CS promotes another TMSD reaction, consequently generating a large number of active G-quadruplex DNAzymes. As a result, a distinct colorimetric signal is produced by the ABTS oxidation promoted by the peroxidase mimicking activity of the released G-quadruplex DNAzymes. Based on this novel strategy, we successfully detected miR-141, a promising biomarker for human prostate cancer, with high selectivity. The diagnostic capability of this system was also demonstrated by reliably determining target miR-141 in human serum, showing its great potential towards real clinical applications. Importantly, the proposed approach is composed of separate target recognition and signal transduction modules. Thus, it could be extended to analyze different target miRNAs by simply redesigning the detection probe while keeping the same signal transduction module as a universal signal amplification unit, which was successfully demonstrated by analyzing another target miRNA, let-7d.

Transcriptional response to muscarinic acetylcholine receptor stimulation: regulation of Egr-1 biosynthesis by ERK, Elk-1, MKP-1, and calcineurin in carbachol-stimulated human neuroblastoma cells.

PubMed

Rössler, Oliver G; Henss, Isabell; Thiel, Gerald

2008-02-01

Carbachol-mediated activation of type M(3) muscarinic acetylcholine receptors induces the biosynthesis of the transcription factor Egr-1 in human SH-SY5Y neuroblastoma cells involving an activation of extracellular signal-regulated protein kinase. Carbachol triggered the phosphorylation of the ternary complex factor Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, and strikingly enhanced the transcriptional activation potential of Elk-1. Chromatin immunoprecipitation experiments revealed that Elk-1 binds in vivo to the 5'-upstream region of the Egr-1 gene in carbachol-stimulated neuroblastoma cells. Together, these data indicate that Elk-1 connects the intracellular signaling cascade elicited by activation of M(3) muscarinic acetylcholine receptors with the transcription of the Egr-1 gene. Lentiviral-mediated expression of either MAP kinase phosphatase-1 (MKP-1) or a constitutively active mutant of calcineurin A inhibited Egr-1 biosynthesis following carbachol stimulation, indicating that these phosphatases function as shut-off devices of muscarinic acetylcholine receptor signaling. Additionally, carbachol stimulation increased transcription of a chromatin-embedded collagenase promoter/reporter gene, showing that AP-1 activity is enhanced in carbachol-stimulated neuroblastoma. Expression experiments revealed that both MKP-1 and a constitutively active mutant of calcineurin A impaired carbachol-induced upregulation of AP-1 activity. The fact that carbachol stimulation of neuroblastoma cells activates the transcription factors Egr-1 and AP-1 suggests that changes in the gene expression pattern are an integral part of muscarinic acetylcholine receptor signaling.

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.

PubMed

Iborra, Salvador; Martínez-López, María; Cueto, Francisco J; Conde-Garrosa, Ruth; Del Fresno, Carlos; Izquierdo, Helena M; Abram, Clare L; Mori, Daiki; Campos-Martín, Yolanda; Reguera, Rosa María; Kemp, Benjamin; Yamasaki, Sho; Robinson, Matthew J; Soto, Manuel; Lowell, Clifford A; Sancho, David

2016-10-18

C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c + cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self. Copyright © 2016 Elsevier Inc. All rights reserved.

Insights into the Evolution of Host Association through the Isolation and Characterization of a Novel Human Periodontal Pathobiont, Desulfobulbus oralis.

PubMed

Cross, Karissa L; Chirania, Payal; Xiong, Weili; Beall, Clifford J; Elkins, James G; Giannone, Richard J; Griffen, Ann L; Guss, Adam M; Hettich, Robert L; Joshi, Snehal S; Mokrzan, Elaine M; Martin, Roman K; Zhulin, Igor B; Leys, Eugene J; Podar, Mircea

2018-03-13

The human oral microbiota encompasses representatives of many bacterial lineages that have not yet been cultured. Here we describe the isolation and characterization of previously uncultured Desulfobulbus oralis , the first human-associated representative of its genus. As mammalian-associated microbes rarely have free-living close relatives, D. oralis provides opportunities to study how bacteria adapt and evolve within a host. This sulfate-reducing deltaproteobacterium has adapted to the human oral subgingival niche by curtailing its physiological repertoire, losing some biosynthetic abilities and metabolic independence, and by dramatically reducing environmental sensing and signaling capabilities. The genes that enable free-living Desulfobulbus to synthesize the potent neurotoxin methylmercury were also lost by D. oralis , a notably positive outcome of host association. However, horizontal gene acquisitions from other members of the microbiota provided novel mechanisms of interaction with the human host, including toxins like leukotoxin and hemolysins. Proteomic and transcriptomic analysis revealed that most of those factors are actively expressed, including in the subgingival environment, and some are secreted. Similar to other known oral pathobionts, D. oralis can trigger a proinflammatory response in oral epithelial cells, suggesting a direct role in the development of periodontal disease. IMPORTANCE Animal-associated microbiota likely assembled as a result of numerous independent colonization events by free-living microbes followed by coevolution with their host and other microbes. Through specific adaptation to various body sites and physiological niches, microbes have a wide range of contributions, from beneficial to disease causing. Desulfobulbus oralis provides insights into genomic and physiological transformations associated with transition from an open environment to a host-dependent lifestyle and the emergence of pathogenicity. Through a multifaceted mechanism triggering a proinflammatory response, D. oralis is a novel periodontal pathobiont. Even though culture-independent approaches can provide insights into the potential role of the human microbiome "dark matter," cultivation and experimental characterization remain important to studying the roles of individual organisms in health and disease.

Early dissemination seeds metastasis in breast cancer

PubMed Central

Hosseini, Hedayatollah; Obradović, Milan M.S.; Hoffmann, Martin; Harper, Kathryn; Sosa, Maria Soledad; Werner-Klein, Melanie; Nanduri, Lahiri Kanth; Werno, Christian; Ehrl, Carolin; Maneck, Matthias; Patwary, Nina; Haunschild, Gundula; Gužvić, Miodrag; Reimelt, Christian; Grauvogl, Michael; Eichner, Norbert; Weber, Florian; Hartkopf, Andreas; Taran, Florin-Andrei; Brucker, Sara Y.; Fehm, Tanja; Rack, Brigitte; Buchholz, Stefan; Spang, Rainer; Meister, Gunter; Aguirre-Ghiso, Julio A.; Klein, Christoph A.

2016-01-01

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation but the mechanisms of early metastatic spread have not yet been addressed. Here, we studied metastasis in a HER2-driven mouse breast cancer model and found that progesterone-induced signalling triggered migration of cancer cells from early lesions shortly after HER2 activation, but promoted proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by elevated HER2 expression and increased tumour cell density involving miRNA-mediated progesterone receptor (PGR) down-regulation and was reversible. Cells from early, low-density lesions displayed more stemness features than cells from dense, advanced tumours, migrated more and founded more metastases. Strikingly, we found that at least 80% of metastases were derived from early disseminated cancer cells (DCC). Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination. PMID:27974799

Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia▿

PubMed Central

Bell, Eric L.; Klimova, Tatyana A.; Eisenbart, James; Schumacker, Paul T.; Chandel, Navdeep S.

2007-01-01

Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span. PMID:17562866

Toll-Like Receptors in the Pathogenesis of Autoimmune Diseases

PubMed Central

Mohammad Hosseini, Akbar; Majidi, Jafar; Baradaran, Behzad; Yousefi, Mehdi

2015-01-01

Human Toll-like receptors (TLRs) are a family of transmembrane receptors, which play a key role in both innate and adaptive immune responses. Beside of recognizing specific molecular patterns that associated with different types of pathogens, TLRs may also detect a number of self-proteins and endogenous nucleic acids. Activating TLRs lead to the heightened expression of various inflammatory genes, which have a protective role against infection. Data rising predominantly from human patients and animal models of autoimmune disease indicate that, inappropriate triggering of TLR pathways by exogenous or endogenous ligands may cause the initiation and/or perpetuation of autoimmune reactions and tissue damage. Given their important role in infectious and non-infectious disease process, TLRs and its signaling pathways emerge as appealing targets for therapeutics. In this review, we demonstrate how TLRs pathways could be involved in autoimmune disorders and their therapeutic application. PMID:26793605

Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps.

PubMed

Loures, Flávio V; Röhm, Marc; Lee, Chrono K; Santos, Evelyn; Wang, Jennifer P; Specht, Charles A; Calich, Vera L G; Urban, Constantin F; Levitz, Stuart M

2015-02-01

Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors contributing to hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2, but not Dectin-1, participates in A. fumigatus hyphal recognition, TNF-α and IFN-α release, and antifungal activity. Moreover, Dectin-2 acts in cooperation with the FcRγ chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. These structures closely resembled those of neutrophil extracellular traps (NETs). The microarray analysis of the pDC transcriptome upon A. fumigatus infection also demonstrated up-regulated expression of genes associated with apoptosis as well as type I interferon-induced genes. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2; this interaction results in cytokine release and antifungal activity. Moreover, hyphal stimulation of pDCs triggers a distinct pattern of pDC gene expression and leads to pET formation.

ToxCast Profiling in a Human Stem Cell Assay for ...

EPA Pesticide Factsheets

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox)

Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production

PubMed Central

Costa, Pedro A. C.; Leoratti, Fabiana M. S.; Figueiredo, Maria M.; Tada, Mauro S.; Pereira, Dhelio B.; Junqueira, Caroline; Soares, Irene S.; Barber, Daniel L.; Gazzinelli, Ricardo T.; Antonelli, Lis R. V.

2015-01-01

The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4+ and CD8+ T cells. Higher frequencies of CD4+ express more than 1 regulatory molecule compared to CD8+ T cells. Moreover, lower proportions of CD4+ T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin–3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function. PMID:26019284

Staphylococcus aureus lipoproteins trigger human corneal epithelial innate response through toll-like receptor-2.

PubMed

Li, Qiong; Kumar, Ashok; Gui, Jian-Fang; Yu, Fu-Shin X

2008-05-01

Bacterial lipoproteins (LP) are a family of cell wall components found in a wide variety of bacteria. In this study, we characterized the response of HUCL, a telomerase-immortalized human corneal epithelial cell (HCEC) line, to LP isolated from Staphylococcus (S) aureus. S. aureus LP (saLP) prepared by Triton X-114 extraction stimulated the activation of NF-kappaB, JNK, and P38 signaling pathways in HUCL cells. The extracts failed to stimulate NF-kappaB activation in HUCL cells after lipoprotein lipase treatment and in cell lines expressing TLR4 or TLR9, but not TLR2, indicating lipoprotein nature of the extracts. saLP induced the up-regulation of a variety of inflammatory cytokines and chemokines (IL-6, IL-8, ICAM-1), antimicrobial molecules (hBD-2, LL-37, and iNOS), and homeostasis genes (Mn-SOD) at both the mRNA level and protein level. Similar inflammatory response to saLP was also observed in primarily cultured HCECs using the production of IL-6 as readout. Moreover, TLR2 neutralizing antibody blocked the saLP-induced secretion of IL-6, IL-8 and hBD2 in HUCL cells. Our findings suggest that saLP activates TLR2 and triggers innate immune response in the cornea to S. aureus infection via production of proinflammatory cytokines and defense molecules.

Deregulation of the CEACAM expression pattern causes undifferentiated cell growth in human lung adenocarcinoma cells.

PubMed

Singer, Bernhard B; Scheffrahn, Inka; Kammerer, Robert; Suttorp, Norbert; Ergun, Suleyman; Slevogt, Hortense

2010-01-18

CEACAM1, CEA/CEACAM5, and CEACAM6 are cell adhesion molecules (CAMs) of the carcinoembryonic antigen (CEA) family that have been shown to be deregulated in lung cancer and in up to 50% of all human cancers. However, little is known about the functional impact of these molecules on undifferentiated cell growth and tumor progression. Here we demonstrate that cell surface expression of CEACAM1 on confluent A549 human lung adenocarcinoma cells plays a critical role in differentiated, contact-inhibited cell growth. Interestingly, CEACAM1-L, but not CEACAM1-S, negatively regulates proliferation via its ITIM domain, while in proliferating cells no CEACAM expression is detectable. Furthermore, we show for the first time that CEACAM6 acts as an inducer of cellular proliferation in A549 cells, likely by interfering with the contact-inhibiting signal triggered by CEACAM1-4L, leading to undifferentiated anchorage-independent cell growth. We also found that A549 cells expressed significant amounts of non-membrane anchored variants of CEACAM5 and CEACAM6, representing a putative source for the increased CEACAM5/6 serum levels frequently found in lung cancer patients. Taken together, our data suggest that post-confluent contact inhibition is established and maintained by CEACAM1-4L, but disturbances of CEACAM1 signalling by CEACAM1-4S and other CEACAMs lead to undifferentiated cell growth and malignant transformation.

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

PubMed Central

Lehmann, Geniece M.; Xi, Xia; Kulkarni, Ajit A.; Olsen, Keith C.; Pollock, Stephen J.; Baglole, Carolyn J.; Gupta, Shikha; Casey, Ann E.; Huxlin, Krystel R.; Sime, Patricia J.; Feldon, Steven E.; Phipps, Richard P.

2011-01-01

Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-β1 (TGFβ1). In this study, we demonstrate that TGFβ1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFβ1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFβ1-driven myofibroblast differentiation in AhR−/− fibroblasts: Its ability to inhibit TGFβ1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent. PMID:21406171

BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells.

PubMed

Combes, Alexis; Camosseto, Voahirana; N'Guessan, Prudence; Argüello, Rafael J; Mussard, Julie; Caux, Christophe; Bendriss-Vermare, Nathalie; Pierre, Philippe; Gatti, Evelina

2017-10-13

Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1 + late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3 +/ LAMP2 +/ LAMP1 - endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression. BAD-LAMP-silencing enhances TLR9 retention in this compartment and consequent downstream signalling events. Conversely, sustained BAD-LAMP expression in pDCs contributes to their lack of type I interferon production after exposure to a TGF-β-positive microenvironment or isolation from human breast tumours. Hence, BAD-LAMP limits interferon expression in pDCs indirectly, by promoting TLR9 sorting to late endosome compartments at steady state and in response to immunomodulatory cues.TLR9 is highly expressed by plasmacytoid dendritic cells and detects nucleic acids, but to discriminate between host and microbial nucleic acids TLR9 is sorted into different endosomal compartments. Here the authors show that BAD-LAMP limits type 1 interferon responses by sorting TLR9 to late endosomal compartments.

The transcriptome of Legionella pneumophila-infected human monocyte-derived macrophages.

PubMed

Price, Christopher T D; Abu Kwaik, Yousef

2014-01-01

Legionella pneumophila is an intracellular bacterial pathogen that invades and replicates within alveolar macrophages through injection of ∼ 300 effector proteins by its Dot/Icm type IV translocation apparatus. The bona fide F-box protein, AnkB, is a nutritional virulence effector that triggers macrophages to generate a surplus of amino acids, which is essential for intravacuolar proliferation. Therefore, the ankB mutant represents a novel genetic tool to determine the transcriptional response of human monocyte-derived macrophages (hMDMs) to actively replicating L. pneumophila. Here, we utilized total human gene microarrays to determine the global transcriptional response of hMDMs to infection by wild type or the ankB mutant of L. pneumophila. The transcriptomes of hMDMs infected with either actively proliferating wild type or non-replicative ankB mutant bacteria were remarkably similar. The transcriptome of infected hMDMs was predominated by up-regulation of inflammatory pathways (IL-10 anti-inflammatory, interferon signaling and amphoterin signaling), anti-apoptosis, and down-regulation of protein synthesis pathways. In addition, L. pneumophila modulated diverse metabolic pathways, particularly those associated with bio-active lipid metabolism, and SLC amino acid transporters expression. Taken together, the hMDM transcriptional response to L. pneumophila is independent of intra-vacuolar replication of the bacteria and primarily involves modulation of the immune response and metabolic as well as nutritional pathways.

Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα).

PubMed

Tsai, Chia-Lung; Wu, Hsien-Ming; Lin, Chiao-Yun; Lin, Yi-Jun; Chao, Angel; Wang, Tzu-Hao; Hsueh, Swei; Lai, Chyong-Huey; Wang, Hsin-Shih

2013-01-01

Estrogens and tamoxifen (an antiestrogen) exert their actions by activation of estrogen receptor (ER) through genomic and non-genomic mechanisms and are implicated in the development of endometrial cancer. Previous reports have demonstrated that estradiol and tamoxifen induce proliferation of human endometrial cancer cells through GPR30 (non-genomic ER) signaling pathway. Herein, we demonstrate that phosphorylation of focal adhesion kinase (FAK) is involved in cell migration induced by estradiol, tamoxifen and G1 (a GPR30 agonist) through the transmembrane ER (GPR30) in endometrial cancer cell lines with or without ERα (Ishikawa and RL95-2). Additionally, the GPR30-mediated cell migration was further abolished by administration of either specific RNA interference targeting GPR30 or an FAK inhibitor. Moreover, we have validated that the signaling between GPR30 and phosphorylated FAK is indeed mediated by the EGFR/PI3K/ERK pathway. Clinically, a significant correlation between levels of GPR30 and phophorylated FAK (pFAK) observed in human endometrial cancer tissues with low or without ERα further suggested that estrogen-induced phosphorylation of FAK and cell migration were most likely triggered by GPR30 activation. These results provided new insights for understanding the pathophysiological functions of GPR30 in human endometrial cancers.

Mobile phone electromagnetic radiation activates MAPK signaling and regulates viability in Drosophila.

PubMed

Lee, Kyu-Sun; Choi, Jong-Soon; Hong, Sae-Yong; Son, Tae-Ho; Yu, Kweon

2008-07-01

Mobile phones are widely used in the modern world. However, biological effects of electromagnetic radiation produced by mobile phones are largely unknown. In this report, we show biological effects of the mobile phone 835 MHz electromagnetic field (EMF) in the Drosophila model system. When flies were exposed to the specific absorption rate (SAR) 1.6 W/kg, which is the proposed exposure limit by the American National Standards Institute (ANSI), more than 90% of the flies were viable even after the 30 h exposure. However, in the SAR 4.0 W/kg strong EMF exposure, viability dropped from the 12 h exposure. These EMF exposures triggered stress response and increased the production of reactive oxygen species. The EMF exposures also activated extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling, but not p38 kinase signaling. Interestingly, SAR 1.6 W/kg activated mainly ERK signaling and expression of an anti-apoptotic gene, whereas SAR 4.0 W/kg strongly activated JNK signaling and expression of apoptotic genes. In addition, SAR 4.0 W/kg amplified the number of apoptotic cells in the fly brain. These findings demonstrate that the exposure limit on electromagnetic radiation proposed by ANSI triggered ERK-survival signaling but the strong electromagnetic radiation activated JNK-apoptotic signaling in Drosophila.

A negative feedback signal that is triggered by peril curbs honey bee recruitment.

PubMed

Nieh, James C

2010-02-23

Decision making in superorganisms such as honey bee colonies often uses self-organizing behaviors, feedback loops that allow the colony to gather information from multiple individuals and achieve reliable and agile solutions. Honey bees use positive feedback from the waggle dance to allocate colony foraging effort. However, the use of negative feedback signals by superorganisms is poorly understood. I show that conspecific attacks at a food source lead to the production of stop signals, communication that was known to reduce waggle dancing and recruitment but lacked a clear natural trigger. Signalers preferentially targeted nestmates visiting the same food source, on the basis of its odor. During aggressive food competition, attack victims increased signal production by 43 fold. Foragers that attacked competitors or experienced no aggression did not alter signal production. Biting ambush predators also attack foragers at flowers. Simulated biting of foragers or exposure to bee alarm pheromone also elicited signaling (88-fold and 14-fold increases, respectively). This provides the first clear evidence of a negative feedback signal elicited by foraging peril to counteract the positive feedback of the waggle dance. As in intra- and intercellular communication, negative feedback may play an important, though currently underappreciated, role in self-organizing behaviors within superorganisms. Copyright 2010 Elsevier Ltd. All rights reserved.

Muscarinic Receptors as Targets for Metronomic Therapy in Breast Cancer.

PubMed

Sales, María Elena

2016-01-01

It is actually known that acetylcholine works as a signaling molecule in non-neuronal cells and tissues, in addition to its neuronal function as neurotransmitter. It can act on two types of receptors nicotinic and muscarinic receptors (mAChRs). The latter belong to the G protein coupled receptor family and there are five subtypes genetically cloned. Their activation triggers classical and non-classical intracellular signals that could be linked to the proliferation of normal and/or transformed cells. The M3 subtype was identified in different types of tumors and its stimulation with agonists triggers cell proliferation, migration, invasion and metastasis. Our laboratory has extensively investigated the expression and function of mAChRs in breast tumors from animal and human origins. We found a profuse expression of mAChRs in breast tumors, but opposite to this, an absence of these receptors in normal breast cells and tissues. The stimulation of mAChRs with the cholinergic agonist carbachol for 20 h increased tumor cell death. Moreover, the combination of subthreshold concentrations of the agonist with paclitaxel potentiates cell death. The usage of low dose chemotherapy with short drug free intervals was named metronomic therapy and it has emerged as a novel regimen for cancer treatment with very low incidence of side effects. Our work and that of others indicate that mAChRs that are over-expressed in different types of tumor cells could be a useful target for metronomic therapy in cancer treatment.

Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus.

PubMed

Stenqvist, Ann-Christin; Nagaeva, Olga; Baranov, Vladimir; Mincheva-Nilsson, Lucia

2013-12-01

Apoptosis is crucially important in mediating immune privilege of the fetus during pregnancy. We investigated the expression and in vitro apoptotic activity of two physiologically relevant death messengers, the TNF family members Fas ligand (FasL) and TRAIL in human early and term placentas. Both molecules were intracellularly expressed, confined to the late endosomal compartment of the syncytiotrophoblast, and tightly associated to the generation and secretion of placental exosomes. Using immunoelectron microscopy, we show that FasL and TRAIL are expressed on the limiting membrane of multivesicular bodies where, by membrane invagination, intraluminal microvesicles carrying membranal bioactive FasL and TRAIL are formed and released in the extracellular space as exosomes. Analyzing exosomes secreted from placental explant cultures, to our knowledge, we demonstrate for the first time that FasL and TRAIL are clustered on the exosomal membrane as oligomerized aggregates ready to form death-inducing signaling complex. Consistently, placental FasL- and TRAIL-carrying exosomes triggered apoptosis in Jurkat T cells and activated PBMC in a dose-dependent manner. Limiting the expression of functional FasL and TRAIL to exosomes comprise a dual benefit: 1) storage of exosomal FasL and TRAIL in multivesicular bodies is protected from proteolytic cleavage and 2) upon secretion, delivery of preformed membranal death molecules by exosomes rapidly triggers apoptosis. Our results suggest that bioactive FasL- and TRAIL-carrying exosomes, able to convey apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its exosome-secreting ability.

Simple Fall Criteria for MEMS Sensors: Data Analysis and Sensor Concept

PubMed Central

Ibrahim, Alwathiqbellah; Younis, Mohammad I.

2014-01-01

This paper presents a new and simple fall detection concept based on detailed experimental data of human falling and the activities of daily living (ADLs). Establishing appropriate fall algorithms compatible with MEMS sensors requires detailed data on falls and ADLs that indicate clearly the variations of the kinematics at the possible sensor node location on the human body, such as hip, head, and chest. Currently, there is a lack of data on the exact direction and magnitude of each acceleration component associated with these node locations. This is crucial for MEMS structures, which have inertia elements very close to the substrate and are capacitively biased, and hence, are very sensitive to the direction of motion whether it is toward or away from the substrate. This work presents detailed data of the acceleration components on various locations on the human body during various kinds of falls and ADLs. A two-degree-of-freedom model is used to help interpret the experimental data. An algorithm for fall detection based on MEMS switches is then established. A new sensing concept based on the algorithm is proposed. The concept is based on employing several inertia sensors, which are triggered simultaneously, as electrical switches connected in series, upon receiving a true fall signal. In the case of everyday life activities, some or no switches will be triggered resulting in an open circuit configuration, thereby preventing false positive. Lumped-parameter model is presented for the device and preliminary simulation results are presented illustrating the new device concept. PMID:25006997

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

PubMed Central

Leonhard, Wouter N.; Zandbergen, Malu; Veraar, Kimberley; van den Berg, Susan; van der Weerd, Louise; Breuning, Martijn; de Heer, Emile

2015-01-01

In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could be explained by increased PKD-related signaling in not only cystic epithelial cells but also, healthy-appearing tubules near cysts. In the majority of mice, these changes preceded a rapid and massive onset of severe PKD that was remarkably similar to human ADPKD. Our data suggest that initial cysts are the principal trigger for a snowball effect driving the formation of new cysts, leading to the progression of severe PKD. In addition, this approach is a suitable model for mimicking human ADPKD and can be used for preclinical testing. PMID:25361818

The solid state detector technology for picosecond laser ranging

NASA Technical Reports Server (NTRS)

Prochazka, Ivan

1993-01-01

We developed an all solid state laser ranging detector technology, which makes the goal of millimeter accuracy achievable. Our design and construction philosophy is to combine the techniques of single photon ranging, ultrashort laser pulses, and fast fixed threshold discrimination while avoiding any analog signal processing within the laser ranging chain. The all solid state laser ranging detector package consists of the START detector and the STOP solid state photon counting module. Both the detectors are working in an optically triggered avalanche switching regime. The optical signal is triggering an avalanche current buildup which results in the generation of a uniform, fast risetime output pulse.

Pulse transmission receiver with higher-order time derivative pulse generator

DOEpatents

Dress, Jr., William B.; Smith, Stephen F.

2003-08-12

Systems and methods for pulse-transmission low-power communication modes are disclosed. A pulse transmission receiver includes: a front-end amplification/processing circuit; a synchronization circuit coupled to the front-end amplification/processing circuit; a clock coupled to the synchronization circuit; a trigger signal generator coupled to the clock; and at least one higher-order time derivative pulse generator coupled to the trigger signal generator. The systems and methods significantly reduce lower-frequency emissions from pulse transmission spread-spectrum communication modes, which reduces potentially harmful interference to existing radio frequency services and users and also simultaneously permit transmission of multiple data bits by utilizing specific pulse shapes.

Bcr-Abl and inhibition of apoptosis in chronic myelogenous leukemia cells.

PubMed

Fernandez-Luna, J L

2000-10-01

Chronic myelogenous leukemia (CML) cells are highly resistant to apoptosis induced by chemotherapeutic drugs. The observation that production of Bcr-Abl is the initiating event in CML has focussed attention on the survival signals triggered by this oncogene. A number of signal transducers and transcription factors have been associated with the antiapoptotic phenotype of CML cells, some of which lead to the expression and/or activation of members of the Bcl-2 family of apoptosis modulators, such as Bcl-xL and Bad. In this article, recent advances in understanding the antiapoptotic pathways triggered by Bcr-Abl in CML cells, are discussed.

Design, characterization, and sensitivity of the supernova trigger system at Daya Bay

NASA Astrophysics Data System (ADS)

Wei, Hanyu; Lebanowski, Logan; Li, Fei; Wang, Zhe; Chen, Shaomin

2016-02-01

Providing an early warning of galactic supernova explosions from neutrino signals is important in studying supernova dynamics and neutrino physics. A dedicated supernova trigger system has been designed and installed in the data acquisition system at Daya Bay and integrated into the worldwide Supernova Early Warning System (SNEWS). Daya Bay's unique feature of eight identically-designed detectors deployed in three separate experimental halls makes the trigger system naturally robust against cosmogenic backgrounds, enabling a prompt analysis of online triggers and a tight control of the false-alert rate. The trigger system is estimated to be fully sensitive to 1987A-type supernova bursts throughout most of the Milky Way. The significant gain in sensitivity of the eight-detector configuration over a mass-equivalent single detector is also estimated. The experience of this online trigger system is applicable to future projects with spatially distributed detectors.

Signal-on electrochemiluminescence biosensor for microRNA-319a detection based on two-stage isothermal strand-displacement polymerase reaction.

PubMed

Wang, Minghui; Zhou, Yunlei; Yin, Huanshun; Jiang, Wenjing; Wang, Haiyan; Ai, Shiyun

2018-06-01

MicroRNAs play crucial role in regulating gene expression in organism, thus it is very necessary to exploit an efficient method for the sensitive and specific detection of microRNA. Herein, a signal-on electrochemiluminescence biosensor was fabricated for microRNA-319a detection based on two-stage isothermal strand-displacement polymerase reaction (ISDPR). In the presence of target microRNA, amounts of trigger DNA could be generated by the first ISDPR. Then, the trigger DNA and the primer hybridized simultaneously with the hairpin probe to open the stem of the probe, and then the ECL signal will be emitted. In the presence of phi29 DNA polymerase and dNTPs, the trigger DNA could be displaced to initiate a new cycle which was the second ISDPR. Due to the two-stage amplification, this method presented excellent detection sensitivity with a low detection limit of 0.14 fM. Moreover, the applicability of the developed method was demonstrated by detecting the change of microRNA-319a content in the leaves of rice seedlings after the rice seeds were incubated with chemical mutagen of ethyl methanesulfonate. Copyright © 2018 Elsevier B.V. All rights reserved.

Readout, first- and second-level triggers of the new Belle silicon vertex detector

NASA Astrophysics Data System (ADS)

Friedl, M.; Abe, R.; Abe, T.; Aihara, H.; Asano, Y.; Aso, T.; Bakich, A.; Browder, T.; Chang, M. C.; Chao, Y.; Chen, K. F.; Chidzik, S.; Dalseno, J.; Dowd, R.; Dragic, J.; Everton, C. W.; Fernholz, R.; Fujii, H.; Gao, Z. W.; Gordon, A.; Guo, Y. N.; Haba, J.; Hara, K.; Hara, T.; Harada, Y.; Haruyama, T.; Hasuko, K.; Hayashi, K.; Hazumi, M.; Heenan, E. M.; Higuchi, T.; Hirai, H.; Hitomi, N.; Igarashi, A.; Igarashi, Y.; Ikeda, H.; Ishino, H.; Itoh, K.; Iwaida, S.; Kaneko, J.; Kapusta, P.; Karawatzki, R.; Kasami, K.; Kawai, H.; Kawasaki, T.; Kibayashi, A.; Koike, S.; Korpar, S.; Križan, P.; Kurashiro, H.; Kusaka, A.; Lesiak, T.; Limosani, A.; Lin, W. C.; Marlow, D.; Matsumoto, H.; Mikami, Y.; Miyake, H.; Moloney, G. R.; Mori, T.; Nakadaira, T.; Nakano, Y.; Natkaniec, Z.; Nozaki, S.; Ohkubo, R.; Ohno, F.; Okuno, S.; Onuki, Y.; Ostrowicz, W.; Ozaki, H.; Peak, L.; Pernicka, M.; Rosen, M.; Rozanska, M.; Sato, N.; Schmid, S.; Shibata, T.; Stamen, R.; Stanič, S.; Steininger, H.; Sumisawa, K.; Suzuki, J.; Tajima, H.; Tajima, O.; Takahashi, K.; Takasaki, F.; Tamura, N.; Tanaka, M.; Taylor, G. N.; Terazaki, H.; Tomura, T.; Trabelsi, K.; Trischuk, W.; Tsuboyama, T.; Uchida, K.; Ueno, K.; Ueno, K.; Uozaki, N.; Ushiroda, Y.; Vahsen, S.; Varner, G.; Varvell, K.; Velikzhanin, Y. S.; Wang, C. C.; Wang, M. Z.; Watanabe, M.; Watanabe, Y.; Yamada, Y.; Yamamoto, H.; Yamashita, Y.; Yamashita, Y.; Yamauchi, M.; Yanai, H.; Yang, R.; Yasu, Y.; Yokoyama, M.; Ziegler, T.; Žontar, D.

2004-12-01

A major upgrade of the Silicon Vertex Detector (SVD 2.0) of the Belle experiment at the KEKB factory was installed along with new front-end and back-end electronics systems during the summer shutdown period in 2003 to cope with higher particle rates, improve the track resolution and meet the increasing requirements of radiation tolerance. The SVD 2.0 detector modules are read out by VA1TA chips which provide "fast or" (hit) signals that are combined by the back-end FADCTF modules to coarse, but immediate level 0 track trigger signals at rates of several tens of a kHz. Moreover, the digitized detector signals are compared to threshold lookup tables in the FADCTFs to pass on hit information on a single strip basis to the subsequent level 1.5 trigger system, which reduces the rate below the kHz range. Both FADCTF and level 1.5 electronics make use of parallel real-time processing in Field Programmable Gate Arrays (FPGAs), while further data acquisition and event building is done by PC farms running Linux. The new readout system hardware is described and the first results obtained with cosmics are shown.

Kobuvirus VP3 protein restricts the IFN-β-triggered signaling pathway by inhibiting STAT2-IRF9 and STAT2-STAT2 complex formation

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

Peng, Qianqian; Lan, Xi; Wang, Chen

Emerged porcine kobuvirus (PKV) has adversely affected the global swine industry since 2008, but the etiological biology of PKV is unclear. Screening PKV-encoded structural and non-structural proteins with a type I IFN-responsive luciferase reporter showed that PKV VP3 protein inhibited the IFN-β-triggered signaling pathway, resulting in the decrease of VSV-GFP replication. QPCR data showed that IFN-β downstream cytokine genes were suppressed without cell-type specificity as well. The results from biochemical experiments indicated that PKV VP3 associated with STAT2 and IRF9, and interfered with the formation of the STAT2-IRF9 and STAT2-STAT2 complex, impairing nuclear translocation of STAT2 and IRF9. Taken together,more » these data reveal a new mechanism for immune evasion of PKV. - Highlights: •PKV VP3 inhibits the IFN-β-triggered signaling pathway. •VP3 associates with STAT2 and IRF9. •VP3 blocks the STAT2-IRF9 nuclear translocation. •VP3 utilizes a novel strategy for innate immune evasion.« less

Role of thrombin signalling in platelets in haemostasis and thrombosis

NASA Astrophysics Data System (ADS)

Sambrano, Gilberto R.; Weiss, Ethan J.; Zheng, Yao-Wu; Huang, Wei; Coughlin, Shaun R.

2001-09-01

Platelets are critical in haemostasis and in arterial thrombosis, which causes heart attacks and other events triggered by abnormal clotting. The coagulation protease thrombin is a potent activator of platelets ex vivo. However, because thrombin also mediates fibrin deposition and because multiple agonists can trigger platelet activation, the relative importance of platelet activation by thrombin in haemostasis and thrombosis is unknown. Thrombin triggers cellular responses at least in part through protease-activated receptors (PARs). Mouse platelets express PAR3 and PAR4 (ref. 9). Here we show that platelets from PAR4-deficient mice failed to change shape, mobilize calcium, secrete ATP or aggregate in response to thrombin. This result demonstrates that PAR signalling is necessary for mouse platelet activation by thrombin and supports the model that mouse PAR3 (mPAR3) does not by itself mediate transmembrane signalling but instead acts as a cofactor for thrombin cleavage and activation of mPAR4 (ref. 10). Importantly, PAR4-deficient mice had markedly prolonged bleeding times and were protected in a model of arteriolar thrombosis. Thus platelet activation by thrombin is necessary for normal haemostasis and may be an important target in the treatment of thrombosis.

γCaMKII shuttles Ca2+/CaM to the nucleus to trigger CREB phosphorylation and gene expression

PubMed Central

Ma, Huan; Groth, Rachel D.; Cohen, Samuel M.; Emery, John F.; Li, Bo-Xing; Hoedt, Esthelle; Zhang, Guo-An; Neubert, Thomas A.; Tsien, Richard W.

2014-01-01

SUMMARY Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events but how information is relayed onward to the nucleus remains unclear. Here we report a novel mechanism that mediates long-distance communication within cells: a shuttle that transports Ca2+/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, that its phosphorylation at Thr287 by βCaMKII protects the Ca2+/CaM signal, and that CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, while γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca2+/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves longstanding puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII and CaN in multiple neuropsychiatric disorders. PMID:25303525

General-purpose readout electronics for white neutron source at China Spallation Neutron Source

NASA Astrophysics Data System (ADS)

Wang, Q.; Cao, P.; Qi, X.; Yu, T.; Ji, X.; Xie, L.; An, Q.

2018-01-01

The under-construction White Neutron Source (WNS) at China Spallation Neutron Source is a facility for accurate measurements of neutron-induced cross section. Seven spectrometers are planned at WNS. As the physical objectives of each spectrometer are different, the requirements for readout electronics are not the same. In order to simplify the development of the readout electronics, this paper presents a general method for detector signal readout. This method has advantages of expansibility and flexibility, which makes it adaptable to most detectors at WNS. In the WNS general-purpose readout electronics, signals from any kinds of detectors are conditioned by a dedicated signal conditioning module corresponding to this detector, and then digitized by a common waveform digitizer with high speed and high precision (1 GSPS at 12-bit) to obtain the full waveform data. The waveform digitizer uses a field programmable gate array chip to process the data stream and trigger information in real time. PXI Express platform is used to support the functionalities of data readout, clock distribution, and trigger information exchange between digitizers and trigger modules. Test results show that the performance of the WNS general-purpose readout electronics can meet the requirements of the WNS spectrometers.

Combined Electrocardiography- and Respiratory-Triggered CT of the Lung to Reduce Respiratory Misregistration Artifacts between Imaging Slabs in Free-Breathing Children: Initial Experience.

PubMed

Goo, Hyun Woo; Allmendinger, Thomas

2017-01-01

Cardiac and respiratory motion artifacts degrade the image quality of lung CT in free-breathing children. The aim of this study was to evaluate the effect of combined electrocardiography (ECG) and respiratory triggering on respiratory misregistration artifacts on lung CT in free-breathing children. In total, 15 children (median age 19 months, range 6 months-8 years; 7 boys), who underwent free-breathing ECG-triggered lung CT with and without respiratory-triggering were included. A pressure-sensing belt of a respiratory gating system was used to obtain the respiratory signal. The degree of respiratory misregistration artifacts between imaging slabs was graded on a 4-point scale (1, excellent image quality) on coronal and sagittal images and compared between ECG-triggered lung CT studies with and without respiratory triggering. A p value < 0.05 was considered significant. Lung CT with combined ECG and respiratory triggering showed significantly less respiratory misregistration artifacts than lung CT with ECG triggering only (1.1 ± 0.4 vs. 2.2 ± 1.0, p = 0.003). Additional respiratory-triggering reduces respiratory misregistration artifacts on ECG-triggered lung CT in free-breathing children.

Integration of reward signalling and appetite regulating peptide systems in the control of food‐cue responses

PubMed Central

Westbrook, R F; Morris, M J

2015-01-01

Understanding the neurobiological substrates that encode learning about food‐associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food‐associated cues can promote over‐consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food‐associated cues can promote cravings and food‐seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self‐administration. Preventing cue‐triggered eating may therefore reduce the over‐consumption seen in obesity and binge‐eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward‐based feeding behaviours and the potential involvement of appetite‐regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti‐obesity therapeutics is to reduce non‐homeostatic, reward driven eating behaviour, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods. PMID:26403657

Tests with beam setup of the TileCal phase-II upgrade electronics

NASA Astrophysics Data System (ADS)

Reward Hlaluku, Dingane

2017-09-01

The LHC has planned a series of upgrades culminating in the High Luminosity LHC which will have an average luminosity 5-7 times larger than the nominal Run-2 value. The ATLAS Tile calorimeter plans to introduce a new readout architecture by completely replacing the back-end and front-end electronics for the High Luminosity LHC. The photomultiplier signals will be fully digitized and transferred for every bunch crossing to the off-detector Tile PreProcessor. The Tile PreProcessor will further provide preprocessed digital data to the first level of trigger with improved spatial granularity and energy resolution in contrast to the current analog trigger signals. A single super-drawer module commissioned with the phase-II upgrade electronics is to be inserted into the real detector to evaluate and qualify the new readout and trigger concepts in the overall ATLAS data acquisition system. This new super-drawer, so-called hybrid Demonstrator, must provide analog trigger signals for backward compatibility with the current system. This Demonstrator drawer has been inserted into a Tile calorimeter module prototype to evaluate the performance in the lab. In parallel, one more module has been instrumented with two other front-end electronics options based on custom ASICs (QIE and FATALIC) which are under evaluation. These two modules together with three other modules composed of the current system electronics were exposed to different particles and energies in three test-beam campaigns during 2015 and 2016.

Integration of reward signalling and appetite regulating peptide systems in the control of food-cue responses.

PubMed

Reichelt, A C; Westbrook, R F; Morris, M J

2015-11-01

Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over-consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over-consumption seen in obesity and binge-eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviours and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti-obesity therapeutics is to reduce non-homeostatic, reward driven eating behaviour, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods. © 2015 The British Pharmacological Society.

Convergent Evolution of Pathogen Effectors toward Reactive Oxygen Species Signaling Networks in Plants.

PubMed

Jwa, Nam-Soo; Hwang, Byung Kook

2017-01-01

Microbial pathogens have evolved protein effectors to promote virulence and cause disease in host plants. Pathogen effectors delivered into plant cells suppress plant immune responses and modulate host metabolism to support the infection processes of pathogens. Reactive oxygen species (ROS) act as cellular signaling molecules to trigger plant immune responses, such as pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity. In this review, we discuss recent insights into the molecular functions of pathogen effectors that target multiple steps in the ROS signaling pathway in plants. The perception of PAMPs by pattern recognition receptors leads to the rapid and strong production of ROS through activation of NADPH oxidase Respiratory Burst Oxidase Homologs (RBOHs) as well as peroxidases. Specific pathogen effectors directly or indirectly interact with plant nucleotide-binding leucine-rich repeat receptors to induce ROS production and the hypersensitive response in plant cells. By contrast, virulent pathogens possess effectors capable of suppressing plant ROS bursts in different ways during infection. PAMP-triggered ROS bursts are suppressed by pathogen effectors that target mitogen-activated protein kinase cascades. Moreover, pathogen effectors target vesicle trafficking or metabolic priming, leading to the suppression of ROS production. Secreted pathogen effectors block the metabolic coenzyme NADP-malic enzyme, inhibiting the transfer of electrons to the NADPH oxidases (RBOHs) responsible for ROS generation. Collectively, pathogen effectors may have evolved to converge on a common host protein network to suppress the common plant immune system, including the ROS burst and cell death response in plants.

Adjuvant gonadotrophin-releasing hormone agonist trigger with human chorionic gonadotrophin to enhance ooplasmic maturity.

PubMed

Pereira, Nigel; Elias, Rony T; Neri, Queenie V; Gerber, Rachel S; Lekovich, Jovana P; Palermo, Gianpiero D; Rosenwaks, Zev

2016-11-01

This study investigates whether an adjuvant gonadotrophin-releasing hormone agonist (GnRHa) trigger with human chorionic gonadotrophin (HCG) improves fresh intracytoplasmic sperm injection (ICSI) cycle outcomes in patients with poor fertilization history after standard HCG trigger alone. This study compared 156 patients with <40% fertilization rate in a prior ICSI cycle with standard HCG trigger who underwent another ICSI cycle with a combined 2 mg GnRHa and 1500 IU HCG ovulatory trigger. There was no difference in the baseline demographics, ovarian stimulation outcomes or sperm parameters of the groups. More mature oocytes were retrieved in the combined trigger group compared with the HCG trigger group: 12 (9-14) versus 10 (7-12); P = 0.01. The fertilization rate in the combined trigger group (59.2%) was higher than the HCG group (35.3%); P = 0.01. The odds of clinical pregnancy and live birth were 1.8 and 1.7 times higher, respectively, when comparing the former group to the latter; P = 0.03. The results suggest that combined GnRHa and HCG trigger in ICSI cycles is a reasonable approach to increase oocyte maturity, specifically ooplasmic maturity, thereby increasing fertilization and improving ICSI cycle outcomes in patients with a history of poor fertilization after standard HCG trigger alone. Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Natural Variation in Small Molecule–Induced TIR-NB-LRR Signaling Induces Root Growth Arrest via EDS1- and PAD4-Complexed R Protein VICTR in Arabidopsis[C][W

PubMed Central

Kim, Tae-Houn; Kunz, Hans-Henning; Bhattacharjee, Saikat; Hauser, Felix; Park, Jiyoung; Engineer, Cawas; Liu, Amy; Ha, Tracy; Parker, Jane E.; Gassmann, Walter; Schroeder, Julian I.

2012-01-01

In a chemical genetics screen we identified the small-molecule [5-(3,4-dichlorophenyl)furan-2-yl]-piperidine-1-ylmethanethione (DFPM) that triggers rapid inhibition of early abscisic acid signal transduction via PHYTOALEXIN DEFICIENT4 (PAD4)- and ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1)-dependent immune signaling mechanisms. However, mechanisms upstream of EDS1 and PAD4 in DFPM-mediated signaling remain unknown. Here, we report that DFPM generates an Arabidopsis thaliana accession-specific root growth arrest in Columbia-0 (Col-0) plants. The genetic locus responsible for this natural variant, VICTR (VARIATION IN COMPOUND TRIGGERED ROOT growth response), encodes a TIR-NB-LRR (for Toll-Interleukin1 Receptor–nucleotide binding–Leucine-rich repeat) protein. Analyses of T-DNA insertion victr alleles showed that VICTR is necessary for DFPM-induced root growth arrest and inhibition of abscisic acid–induced stomatal closing. Transgenic expression of the Col-0 VICTR allele in DFPM-insensitive Arabidopsis accessions recapitulated the DFPM-induced root growth arrest. EDS1 and PAD4, both central regulators of basal resistance and effector-triggered immunity, as well as HSP90 chaperones and their cochaperones RAR1 and SGT1B, are required for the DFPM-induced root growth arrest. Salicylic acid and jasmonic acid signaling pathway components are dispensable. We further demonstrate that VICTR associates with EDS1 and PAD4 in a nuclear protein complex. These findings show a previously unexplored association between a TIR-NB-LRR protein and PAD4 and identify functions of plant immune signaling components in the regulation of root meristematic zone-targeted growth arrest. PMID:23275581

Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

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

Kovalova, Natalia, E-mail: kovalova@msu.edu

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12 h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized thatmore » TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes. - Highlights: • Kovalova TAAP Highlights Nov. 2016 • RNA-Seq identified TCDD-induced gene expression in PWM-activated primary B cells. • TCDD elicited differential expression of 515 human, 2371 mouse and 712 rat orthologs. • 28 orthologs were differentially expressed in response to TCDD in all three species. • TCDD elicits mostly species-specific gene expression changes in activated B cells.« less

Event-triggered decentralized adaptive fault-tolerant control of uncertain interconnected nonlinear systems with actuator failures.

PubMed

Choi, Yun Ho; Yoo, Sung Jin

2018-06-01

This paper investigates the event-triggered decentralized adaptive tracking problem of a class of uncertain interconnected nonlinear systems with unexpected actuator failures. It is assumed that local control signals are transmitted to local actuators with time-varying faults whenever predefined conditions for triggering events are satisfied. Compared with the existing control-input-based event-triggering strategy for adaptive control of uncertain nonlinear systems, the aim of this paper is to propose a tracking-error-based event-triggering strategy in the decentralized adaptive fault-tolerant tracking framework. The proposed approach can relax drastic changes in control inputs caused by actuator faults in the existing triggering strategy. The stability of the proposed event-triggering control system is analyzed in the Lyapunov sense. Finally, simulation comparisons of the proposed and existing approaches are provided to show the effectiveness of the proposed theoretical result in the presence of actuator faults. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of ALS through activation of c-Abl signaling.

PubMed

Rojas, Fabiola; Gonzalez, David; Cortes, Nicole; Ampuero, Estibaliz; Hernández, Diego E; Fritz, Elsa; Abarzua, Sebastián; Martinez, Alexis; Elorza, Alvaro A; Alvarez, Alejandra; Court, Felipe; van Zundert, Brigitte

2015-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1(G93A) (ACM-hSOD1(G93A)) quickly enhances Nav channel-mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1(G93A), but not ACM-hSOD1(WT), increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1(G93A)-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1(G86R) or TDP43(A315T). We further find that co-application of ACM-SOD1(G93A) with blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1(G93A) induces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.

Powered ankle-foot prosthesis to assist level-ground and stair-descent gaits.

PubMed

Au, Samuel; Berniker, Max; Herr, Hugh

2008-05-01

The human ankle varies impedance and delivers net positive work during the stance period of walking. In contrast, commercially available ankle-foot prostheses are passive during stance, causing many clinical problems for transtibial amputees, including non-symmetric gait patterns, higher gait metabolism, and poorer shock absorption. In this investigation, we develop and evaluate a myoelectric-driven, finite state controller for a powered ankle-foot prosthesis that modulates both impedance and power output during stance. The system employs both sensory inputs measured local to the external prosthesis, and myoelectric inputs measured from residual limb muscles. Using local prosthetic sensing, we first develop two finite state controllers to produce biomimetic movement patterns for level-ground and stair-descent gaits. We then employ myoelectric signals as control commands to manage the transition between these finite state controllers. To transition from level-ground to stairs, the amputee flexes the gastrocnemius muscle, triggering the prosthetic ankle to plantar flex at terminal swing, and initiating the stair-descent state machine algorithm. To transition back to level-ground walking, the amputee flexes the tibialis anterior muscle, triggering the ankle to remain dorsiflexed at terminal swing, and initiating the level-ground state machine algorithm. As a preliminary evaluation of clinical efficacy, we test the device on a transtibial amputee with both the proposed controller and a conventional passive-elastic control. We find that the amputee can robustly transition between the finite state controllers through direct muscle activation, allowing rapid transitioning from level-ground to stair walking patterns. Additionally, we find that the proposed finite state controllers result in a more biomimetic ankle response, producing net propulsive work during level-ground walking and greater shock absorption during stair descent. The results of this study highlight the potential of prosthetic leg controllers that exploit neural signals to trigger terrain-appropriate, local prosthetic leg behaviors.

cGMP signalling in pre- and post-conditioning: the role of mitochondria.

PubMed

Costa, Alexandre D T; Pierre, Sandrine V; Cohen, Michael V; Downey, James M; Garlid, Keith D

2008-01-15

Much of cell death from ischaemia/reperfusion in heart and other tissues is generally thought to arise from mitochondrial permeability transition (MPT) in the first minutes of reperfusion. In ischaemic pre-conditioning, agonist binding to G(i) protein-coupled receptors prior to ischaemia triggers a signalling cascade that protects the heart from MPT. We believe that the cytosolic component of this trigger pathway terminates in activation of guanylyl cyclase resulting in increased production of cGMP and subsequent activation of protein kinase G (PKG). PKG phosphorylates a protein on the mitochondrial outer membrane (MOM), which then causes the mitochondrial K(ATP) channel (mitoK(ATP)) on the mitochondrial inner membrane to open, leading to increased production of reactive oxygen species (ROS) by the mitochondria. This implies that the protective signal is somehow transmitted from the MOM to its inner membrane. This is accomplished by a series of intermembrane signalling steps that includes protein kinase C (PKCepsilon) activation. The resulting ROS then activate a second PKC pool which, through another signal transduction pathway termed the mediator pathway, causes inhibition of MPT and reduction in cell death.

[Recent Advances of Researches on Expression, Function and Regulation of CD22].

PubMed

Wu, Xiao-Jing; Shao, Zong-Hong

2015-04-01

CD22 is a type I transmembrane protein expressed on most mature B lymphocyte, and plays a significant role in signal transduction pathways. CD22 acts as a co-receptor of the B-cell receptor (BCR) that inhibits the BCR signaling by antigen-receptor interaction. The phosphorylation of CD22 can be triggered by cross-linking of CD22 with the BCR through antigen, then predominantly triggers the dephosphorylation and inactivation of downstream proteins and inhibit the BCR signaling. Autoimmune disease could be caused by the abnormal expression or dysfunction of CD22 which interrupts BCR signaling and then influences the quantity and function of B cells. The further study of the function and regulation of CD22 would help us understanding the pathogenesis of autoimmune disease and setting theoretical basis for its targeting treatment. In this article, the structure and expression of CD22, the ligands of CD22, the regulation of BCR and transmenbrane signaling, the effect of CD22 on B cells, and CD22 and autoimmune diseases were reviewed.

Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species.

PubMed

Liu, Yuanyuan; Fan, Chenghe; Pu, Lv; Wei, Cui; Jin, Haiqiang; Teng, Yuming; Zhao, Mingming; Yu, Albert Cheung Hoi; Jiang, Feng; Shu, Junlong; Li, Fan; Peng, Qing; Kong, Jian; Pan, Bing; Zheng, Lemin; Huang, Yining

2016-06-01

Phloretin, a flavonoid present in various plants, has been reported to exert anticarcinogenic effects. However, the mechanism of its chemo-preventive effect on human glioblastoma cells is not fully understood. This study aimed to investigate the molecular mechanism of phloretin and its associated chemo-preventive effect in human glioblastoma cells. The results indicate that phloretin inhibited cell proliferation by inducing cell cycle arrest at the G0-G1 phase and induced apoptosis of human glioblastoma cells. Phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclinD and cyclinE. Moreover, the PI3K/AKT/mTOR signaling cascades were suppressed by phloretin in a dose-dependent manner. In addition, phloretin triggered the mitochondrial apoptosis pathway and generated reactive oxygen species (ROS). This was accompanied by the up-regulation of Bax, Bak and c-PARP and the down-regulation of Bcl-2. The antioxidant agents N-acetyl-L-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts potent chemo-preventive activity in human glioblastoma cells through the generation of ROS.

Real-time implementation of an interactive jazz accompaniment system

NASA Astrophysics Data System (ADS)

Deshpande, Nikhil

Modern computational algorithms and digital signal processing (DSP) are able to combine with human performers without forced or predetermined structure in order to create dynamic and real-time accompaniment systems. With modern computing power and intelligent algorithm layout and design, it is possible to achieve more detailed auditory analysis of live music. Using this information, computer code can follow and predict how a human's musical performance evolves, and use this to react in a musical manner. This project builds a real-time accompaniment system to perform together with live musicians, with a focus on live jazz performance and improvisation. The system utilizes a new polyphonic pitch detector and embeds it in an Ableton Live system - combined with Max for Live - to perform elements of audio analysis, generation, and triggering. The system also relies on tension curves and information rate calculations from the Creative Artificially Intuitive and Reasoning Agent (CAIRA) system to help understand and predict human improvisation. These metrics are vital to the core system and allow for extrapolated audio analysis. The system is able to react dynamically to a human performer, and can successfully accompany the human as an entire rhythm section.

Beyond Chemical Triggers: Evidence for Sound-Evoked Physiological Reactions in Plants

PubMed Central

Jung, Jihye; Kim, Seon-Kyu; Kim, Joo Y.; Jeong, Mi-Jeong; Ryu, Choong-Min

2018-01-01

Sound is ubiquitous in nature. Recent evidence supports the notion that naturally occurring and artificially generated sound waves contribute to plant robustness. New information is emerging about the responses of plants to sound and the associated downstream signaling pathways. Here, beyond chemical triggers which can improve plant health by enhancing plant growth and resistance, we provide an overview of the latest findings, limitations, and potential applications of sound wave treatment as a physical trigger to modulate physiological traits and to confer an adaptive advantage in plants. We believe that sound wave treatment is a new trigger to help protect plants against unfavorable conditions and to maintain plant fitness. PMID:29441077

Wnt signaling: Ig-norrin the dogma.

PubMed

Clevers, Hans

2004-06-08

Secreted Wnt proteins trigger the intracellular Wnt signaling cascade upon engagement of dedicated Frizzled-Lrp receptor complexes. Unexpectedly, a non-Wnt ligand for this receptor complex has now been discovered. This novel ligand, Norrin, is mutated in the hereditary ocular Norrie syndrome. Copyright 2004 Elsevier Ltd.

The Drosophila homologue of SRF acts as a boosting mechanism to sustain FGF-induced terminal branching in the tracheal system.

PubMed

Gervais, Louis; Casanova, Jordi

2011-04-01

Recent data have demonstrated a crucial role for the transcription factor SRF (serum response factor) downstream of VEGF and FGF signalling during branching morphogenesis. This is the case for sprouting angiogenesis in vertebrates, axonal branching in mammals and terminal branching of the Drosophila tracheal system. However, the specific functions of SRF in these processes remain unclear. Here, we establish the relative contributions of the Drosophila homologues of FGF [Branchless (BNL)] and SRF [Blistered (BS)] in terminal tracheal branching. Conversely to an extended view, we show that BNL triggers terminal branching initiation in a DSRF-independent mechanism and that DSRF transcription induced by BNL signalling is required to maintain terminal branch elongation. Moreover, we report that increased and continuous FGF signalling can trigger tracheal cells to develop full-length terminal branches in the absence of DSRF transcription. Our results indicate that DSRF acts as an amplifying step to sustain the progression of terminal branch elongation even in the wild-type conditions of FGF signalling.

Low-Latency Digital Signal Processing for Feedback and Feedforward in Quantum Computing and Communication

NASA Astrophysics Data System (ADS)

Salathé, Yves; Kurpiers, Philipp; Karg, Thomas; Lang, Christian; Andersen, Christian Kraglund; Akin, Abdulkadir; Krinner, Sebastian; Eichler, Christopher; Wallraff, Andreas

2018-03-01

Quantum computing architectures rely on classical electronics for control and readout. Employing classical electronics in a feedback loop with the quantum system allows us to stabilize states, correct errors, and realize specific feedforward-based quantum computing and communication schemes such as deterministic quantum teleportation. These feedback and feedforward operations are required to be fast compared to the coherence time of the quantum system to minimize the probability of errors. We present a field-programmable-gate-array-based digital signal processing system capable of real-time quadrature demodulation, a determination of the qubit state, and a generation of state-dependent feedback trigger signals. The feedback trigger is generated with a latency of 110 ns with respect to the timing of the analog input signal. We characterize the performance of the system for an active qubit initialization protocol based on the dispersive readout of a superconducting qubit and discuss potential applications in feedback and feedforward algorithms.

Spatiotemporally and Mechanically Controlled Triggering of Mast Cells using Atomic Force Microscopy

PubMed Central

Hu, Kenneth K.; Bruce, Marc A.; Butte, Manish J.

2014-01-01

Mast cells are thought to be sensitive to mechanical forces, for example, coughing in asthma or pressure in “physical urticarias”. Conversion of mechanical forces to biochemical signals could potentially augment antigenic signaling. Studying the combined effects of mechanical and antigenic cues on mast cells and other hematopoietic cells has been elusive. Here, we present an approach using a modified atomic force microscope cantilever to deliver antigenic signals to mast cells while simultaneously applying mechanical forces. We developed a strategy to concurrently record degranulation events by fluorescence microscopy during antigenic triggering. Finally, we also measured the mechanical forces generated by mast cells while antigen receptors are ligated. We showed that mast cells respond to antigen delivered by the AFM cantilever with prompt degranulation and the generation of strong pushing and pulling forces. We did not discern any relationship between applied mechanical forces and the kinetics of degranulation. These experiments present a new method for dissecting the interactions of mechanical and biochemical cues in signaling responses of immune cells. PMID:24777418

The Eyes Are the Windows to the Mind: Direct Eye Gaze Triggers the Ascription of Others' Minds.

PubMed

Khalid, Saara; Deska, Jason C; Hugenberg, Kurt

2016-12-01

Eye gaze is a potent source of social information with direct eye gaze signaling the desire to approach and averted eye gaze signaling avoidance. In the current work, we proposed that eye gaze signals whether or not to impute minds into others. Across four studies, we manipulated targets' eye gaze (i.e., direct vs. averted eye gaze) and measured explicit mind ascriptions (Study 1a, Study 1b, and Study 2) and beliefs about the likelihood of targets having mind (Study 3). In all four studies, we find novel evidence that the ascription of sophisticated humanlike minds to others is signaled by the display of direct eye gaze relative to averted eye gaze. Moreover, we provide evidence suggesting that this differential mentalization is due, at least in part, to beliefs that direct gaze targets are more likely to instigate social interaction. In short, eye contact triggers mind perception. © 2016 by the Society for Personality and Social Psychology, Inc.

Out-of-plane ultrasonic velocity measurement

DOEpatents

Hall, M.S.; Brodeur, P.H.; Jackson, T.G.

1998-07-14

A method for improving the accuracy of measuring the velocity and time of flight of ultrasonic signals through moving web-like materials such as paper, paperboard and the like, includes a pair of ultrasonic transducers disposed on opposing sides of a moving web-like material. In order to provide acoustical coupling between the transducers and the web-like material, the transducers are disposed in fluid-filled wheels. Errors due to variances in the wheel thicknesses about their circumference which can affect time of flight measurements and ultimately the mechanical property being tested are compensated by averaging the ultrasonic signals for a predetermined number of revolutions. The invention further includes a method for compensating for errors resulting from the digitization of the ultrasonic signals. More particularly, the invention includes a method for eliminating errors known as trigger jitter inherent with digitizing oscilloscopes used to digitize the signals for manipulation by a digital computer. In particular, rather than cross-correlate ultrasonic signals taken during different sample periods as is known in the art in order to determine the time of flight of the ultrasonic signal through the moving web, a pulse echo box is provided to enable cross-correlation of predetermined transmitted ultrasonic signals with predetermined reflected ultrasonic or echo signals during the sample period. By cross-correlating ultrasonic signals in the same sample period, the error associated with trigger jitter is eliminated. 20 figs.

Out-of-plane ultrasonic velocity measurement

DOEpatents

Hall, Maclin S.; Brodeur, Pierre H.; Jackson, Theodore G.

1998-01-01

A method for improving the accuracy of measuring the velocity and time of flight of ultrasonic signals through moving web-like materials such as paper, paperboard and the like, includes a pair of ultrasonic transducers disposed on opposing sides of a moving web-like material. In order to provide acoustical coupling between the transducers and the web-like material, the transducers are disposed in fluid-filled wheels. Errors due to variances in the wheel thicknesses about their circumference which can affect time of flight measurements and ultimately the mechanical property being tested are compensated by averaging the ultrasonic signals for a predetermined number of revolutions. The invention further includes a method for compensating for errors resulting from the digitization of the ultrasonic signals. More particularly, the invention includes a method for eliminating errors known as trigger jitter inherent with digitizing oscilloscopes used to digitize the signals for manipulation by a digital computer. In particular, rather than cross-correlate ultrasonic signals taken during different sample periods as is known in the art in order to determine the time of flight of the ultrasonic signal through the moving web, a pulse echo box is provided to enable cross-correlation of predetermined transmitted ultrasonic signals with predetermined reflected ultrasonic or echo signals during the sample period. By cross-correlating ultrasonic signals in the same sample period, the error associated with trigger jitter is eliminated.

MECHANISM OF THYMUS-INDEPENDENT IMMUNOCYTE TRIGGERING

PubMed Central

Coutinho, Antonio; Gronowicz, Eva; Bullock, Wesley W.; Möller, Göran

1974-01-01

The present experiments were performed in order to analyze the mechanism by which thymus-independent antigens (nonspecific B-cell mitogens) can induce specific immune responses to antigenic determinants present on the same molecule. The hapten NNP was coupled to the B-cell mitogen, lipopolysaccharide (LPS). The conjugate retained full mitogenic activity and bound specifically to NNP-reactive cells. NNP-LPS activated polyclonal as well as specific anti-NNP antibody synthesis, but the optimal concentrations for induction of specific anti-NNP cells were several orders of magnitude lower than the concentrations required for polyclonal activation. These low concentrations failed to activate nonspecific cells, but they induced specific thymus-independent responses of high-avidity NNP-specific cells with the typical kinetics of antigenic responses in vitro. Furthermore, hapten-specific cells were paralyzed by NNP-LPS concentrations that were optimal for induction of polyclonal activation. Specific activation and paralysis could be abolished by free hapten indicating that selective binding of NNP-LPS to hapten-specific cells was responsible for the specificity of the response. However, the triggering signal lacked specificity, since high-avidity specific anti-NNP cells could still be activated by stimulating concentrations of NNP-LPS in the presence of free hapten, even though the Ig receptor combining sites were presumably occupied by NNP. The findings show that B cells with specific Ig receptors for the antigenic determinants on mitogen molecules preferentially bind these molecules and become activated at concentrations still unsufficient to trigger other B cells that lack specific receptors. It is suggested that activation for primary IgM responses in B cells is the result of "one nonspecific signal." This nonspecific signal is provided by the mitogenic properties of some antigens (highly thymus independent or, alternatively, by nonspecific T-cell factors (for highly T cell-dependent antigens), or both, and the surface structures responsible for triggering are not the Ig receptors. The specific Ig receptors only act as passive focusing devices for nonspecific stimuli, entitling the cell to be selectively activated, even though both the signal and the receptors for the triggering are nonspecific. PMID:4128449

PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65

PubMed Central

Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen; Byun, Hee Sun; Jeon, Juhee; Lee, Yoonjung; Hong, Jang Hee; Kim, Jin Man; Huang, Song-Mei; Choi, Seung-Won; Kim, Sun-Hwan; Sohn, Kyung-Cheol; Ro, Hyunju; Lee, Ji Hoon; Lu, Tao; Stark, George R.; Shen, Han-Ming; Liu, Zheng-gang; Park, Jongsun; Hur, Gang Min

2014-01-01

Constitutive NF-κB activation in cancer cells is caused by defects in the signalling network responsible for terminating the NF-κB response. Here we report that plant homeodomain finger protein 20 maintains NF-κB in an active state in the nucleus by inhibiting the interaction between PP2A and p65. We show that plant homeodomain finger protein 20 induces canonical NF-κB signalling by increasing the DNA-binding activity of NF-κB subunit p65. In plant homeodomain finger protein 20-overexpressing cells, the termination of tumour necrosis factor-induced p65 phosphorylation is impaired whereas upstream signalling events triggered by tumour necrosis factor are unaffected. This effect strictly depends on the interaction between plant homeodomain finger protein 20 and methylated lysine residues of p65, which hinders recruitment of PP2A to p65, thereby maintaining p65 in a phosphorylated state. We further show that plant homeodomain finger protein 20 levels correlate with p65 phosphorylation levels in human glioma specimens. Our work identifies plant homeodomain finger protein 20 as a novel regulator of NF-κB activation and suggests that elevated expression of plant homeodomain finger protein 20 may drive constitutive NF-κB activation in some cancers. PMID:23797602

Induction of the unfolded protein response by constitutive G-protein signaling in rod photoreceptor cells.

PubMed

Wang, Tian; Chen, Jeannie

2014-10-17

Phototransduction is a G-protein signal transduction cascade that converts photon absorption to a change in current at the plasma membrane. Certain genetic mutations affecting the proteins in the phototransduction cascade cause blinding disorders in humans. Some of these mutations serve as a genetic source of "equivalent light" that activates the cascade, whereas other mutations lead to amplification of the light response. How constitutive phototransduction causes photoreceptor cell death is poorly understood. We showed that persistent G-protein signaling, which occurs in rod arrestin and rhodopsin kinase knock-out mice, caused a rapid and specific induction of the PERK pathway of the unfolded protein response. These changes were not observed in the cGMP-gated channel knock-out rods, an equivalent light condition that mimics light-stimulated channel closure. Thus transducin signaling, but not channel closure, triggers rapid cell death in light damage caused by constitutive phototransduction. Additionally, we show that in the albino light damage model cell death was not associated with increase in global protein ubiquitination or unfolded protein response induction. Taken together, these observations provide novel mechanistic insights into the cell death pathway caused by constitutive phototransduction and identify the unfolded protein response as a potential target for therapeutic intervention. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Contrasting roles of DAP10 and KARAP/DAP12 signaling adaptors in activation of the RBL-2H3 leukemic mast cell line.

PubMed

Anfossi, Nicolas; Lucas, Mathias; Diefenbach, Andreas; Bühring, Hans-Jörg; Raulet, David; Tomasello, Elena; Vivier, Eric

2003-12-01

A common feature of hematopoietic activating immunoreceptors resides in their association at the cell surface with transmembrane signaling adaptors. Several adaptors, such as the CD3 molecules, FcRgamma and KARAP/DAP12, harbor intracytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) that activate Syk-family protein tyrosine kinases. In contrast, another transmembrane adaptor, DAP10, bears a YxxM motif that delivers signals by activation of lipid kinase pathways. We show here that the human signal-regulatory protein SIRPbeta1 can associate with both DAP10 and KARAP/DAP12 in a model of RBL-2H3 cell transfectants. In association with KARAP/DAP12, SIRPbeta1 complexes are capable of inducing serotonin release and tumor necrosis factor (TNF) secretion. By contrast,in the absence of KARAP/DAP12, engagement of SIRPbeta1:DAP10 complexes does not lead to detectable serotonin release or TNF secretion by RBL-2H3 transfectants. However, triggering of SIRPbeta1:DAP10 complexes co-stimulates RBL-2H3 effector function induced by sub-optimal stimulation of the endogenous FcepsilonRI complex. Therefore, we report here a cellular model in which the association of a cell surface receptor with various signaling adaptors dictates the co-stimulatory or the direct stimulatory properties of the complex.

Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

PubMed Central

Stamateris, Rachel E.; Sharma, Rohit B.; Kong, Yahui; Ebrahimpour, Pantea; Panday, Deepika; Ranganath, Pavana; Zou, Baobo; Levitt, Helena; Parambil, Nisha Abraham; O’Donnell, Christopher P.; García-Ocaña, Adolfo

2016-01-01

An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID:26740601

Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer.

PubMed

Filardo, Edward J

2002-02-01

The biological and biochemical effects of estrogen have been ascribed to its known receptors, which function as ligand-inducible transcription factors. However, estrogen also triggers rapid activation of classical second messengers (cAMP, calcium, and inositol triphosphate) and stimulation of intracellular signaling cascades mitogen-activated protein kinase (MAP K), PI3K and eNOS. These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins. We have shown that estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via the G-protein-coupled receptor (GPCR), GPR30, through the release of surface-bound proHB-EGF from estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling. GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the EGF-like effects of estrogen. This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review.

Cascade Signal Amplification Based on Copper Nanoparticle-Reported Rolling Circle Amplification for Ultrasensitive Electrochemical Detection of the Prostate Cancer Biomarker.

PubMed

Zhu, Ye; Wang, Huijuan; Wang, Lin; Zhu, Jing; Jiang, Wei

2016-02-03

An ultrasensitive and highly selective electrochemical assay was first attempted by combining the rolling circle amplification (RCA) reaction with poly(thymine)-templated copper nanoparticles (CuNPs) for cascade signal amplification. As proof of concept, prostate specific antigen (PSA) was selected as a model target. Using a gold nanoparticle (AuNP) as a carrier, we synthesized the primer-AuNP-aptamer bioconjugate for signal amplification by increasing the primer/aptamer ratio. The specific construction of primer-AuNP-aptamer/PSA/anti-PSA sandwich structure triggered the effective RCA reaction, in which thousands of tandem poly(thymine) repeats were generated and directly served as the specific templates for the subsequent CuNP formation. The signal readout was easily achieved by dissolving the RCA product-templated CuNPs and detecting the released copper ions with differential pulse stripping voltammetry. Because of the designed cascade signal amplification strategy, the newly developed method achieved a linear range of 0.05-500 fg/mL, with a remarkable detection limit of 0.020 ± 0.001 fg/mL PSA. Finally, the feasibility of the developed method for practical application was investigated by analyzing PSA in the real clinical human serum samples. The ultrasensitivity, specificity, convenience, and capability for analyzing the clinical samples demonstrate that this method has great potential for practical disease diagnosis applications.

A Simulation of the Front End Signal Digitization for the ATLAS Muon Spectrometer thin RPC trigger upgrade project

NASA Astrophysics Data System (ADS)

Meng, Xiangting; Chapman, John; Levin, Daniel; Dai, Tiesheng; Zhu, Junjie; Zhou, Bing; Um Atlas Group Team

2016-03-01

The ATLAS Muon Spectrometer Phase-I (and Phase-II) upgrade includes the BIS78 muon trigger detector project: two sets of eight very thin Resistive Place Chambers (tRPCs) combined with small Monitored Drift Tube (MDT) chambers in the pseudorapidity region 1<| η|<1.3. The tRPCs will be comprised of triplet readout layer in each of the eta and azimuthal phi coordinates, with about 400 readout strips per layer. The anticipated hit rate is 100-200 kHz per strip. Digitization of the strip signals will be done by 32-channel CERN HPTDC chips. The HPTDC is a highly configurable ASIC designed by the CERN Microelectronics group. It can work in both trigger and trigger-less modes, be readout in parallel or serially. For Phase-I operation, a stringent latency requirement of 43 bunch crossings (1075 ns) is imposed. The latency budget for the front end digitization must be kept to a minimal value, ideally less than 350 ns. We conducted detailed HPTDC latency simulations using the Behavioral Verilog code from the CERN group. We will report the results of these simulations run for the anticipated detector operating environment and for various HPTDC configurations.

Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis.

PubMed

Domínguez-Andrés, Jorge; Arts, Rob J W; Ter Horst, Rob; Gresnigt, Mark S; Smeekens, Sanne P; Ratter, Jacqueline M; Lachmandas, Ekta; Boutens, Lily; van de Veerdonk, Frank L; Joosten, Leo A B; Notebaart, Richard A; Ardavín, Carlos; Netea, Mihai G

2017-09-01

Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.

A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose-tissue inflammation in obesity

PubMed Central

Hernandez, Eloy D.; Lee, Sang Jun; Kim, Ji Young; Duran, Angeles; Linares, Juan F.; Yajima, Tomoko; Müller, Timo D.; Tschöp, Matthias H.; Smith, Steven R.; Diaz-Meco, Maria T.; Moscat, Jorge

2014-01-01

SUMMARY The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity-associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adapter NBR1 correlated with the expression of pro-inflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization and chemotactic activity of macrophages, prevents inflammation of adipose tissue, and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose-tissue inflammation in obesity. PMID:25043814

Is chondroitin sulfate responsible for the biological effects attributed to the GC protein-derived Macrophage Activating Factor (GcMAF)?

PubMed

Ruggiero, Marco; Reinwald, Heinz; Pacini, Stefania

2016-09-01

We hypothesize that a plasma glycosaminoglycan, chondroitin sulfate, may be responsible for the biological and clinical effects attributed to the Gc protein-derived Macrophage Activating Factor (GcMAF), a protein that is extracted from human blood. Thus, Gc protein binds chondroitin sulfate on the cell surface and such an interaction may occur also in blood, colostrum and milk. This interpretation would solve the inconsistencies encountered in explaining the effects of GcMAF in vitro and in vivo. According to our model, the Gc protein or the GcMAF bind to chondroitin sulfate both on the cell surface and in bodily fluids, and the resulting multimolecular complexes, under the form of oligomers trigger a transmembrane signal or, alternatively, are internalized and convey the signal directly to the nucleus thus eliciting the diverse biological effects observed for both GcMAF and chondroitin sulfate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Focal adhesion kinase (FAK) perspectives in mechanobiology: implications for cell behaviour.

PubMed

Tomakidi, Pascal; Schulz, Simon; Proksch, Susanne; Weber, Wilfried; Steinberg, Thorsten

2014-09-01

Mechanobiology is a scientific interface discipline emerging from engineering and biology. With regard to tissue-regenerative cell-based strategies, mechanobiological concepts, including biomechanics as a target for cell and human mesenchymal stem cell behaviour, are on the march. Based on the periodontium as a paradigm, this mini-review discusses the key role of focal-adhesion kinase (FAK) in mechanobiology, since it is involved in mediating the transformation of environmental biomechanical signals into cell behavioural responses via mechanotransducing signalling cascades. These processes enable cells to adjust quickly to environmental cues, whereas adjustment itself relies on the specific intramolecular phosphorylation of FAK tyrosine residues and the multiple interactions of FAK with distinct partners. Furthermore, interaction-triggered mechanotransducing pathways govern the dynamics of focal adhesion sites and cell behaviour. Facets of behaviour not only include cell spreading and motility, but also proliferation, differentiation and apoptosis. In translational terms, identified and characterized biomechanical parameters can be incorporated into innovative concepts of cell- and tissue-tailored clinically applied biomaterials controlling cell behaviour as desired.

Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis

PubMed Central

Smeekens, Sanne P.; Lachmandas, Ekta; Boutens, Lily; van de Veerdonk, Frank L.; Joosten, Leo A. B.; Ardavín, Carlos; Netea, Mihai G.

2017-01-01

Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases. PMID:28922415

HTLV-1 Tax protein cooperates with Ras in protecting cells from apoptosis.

PubMed

Vajente, Nicola; Trevisan, Roberta; Saggioro, Daniela

2009-02-01

Tax protein of the human T-cell leukemia virus type 1 (HTLV-1) plays a critical role in HTLV-I-correlated diseases through its ability to deregulate the expression of a vast array of cellular genes. We have previously shown that Tax counteracts apoptosis induced by stimuli triggering mitochondria apoptotic pathway, most likely by activating CREB-mediated transcription and affecting the phosphorylation levels of CREB at Ser-133. Here, we report data that indicate the oncoprotein Ras as a possible mediator of Tax-induced apoptosis protection and suggest a possible role of Tax in Ras activation. In addition, using inhibitors of down stream effectors of Ras, we found that ERK signaling is the most relevant for Tax-mediated apoptosis protection. As a whole, our findings provide intriguing evidence of a possible link between Ras signaling and Tax capability to counteract apoptosis and to enhance P-CREB levels, and implicates a potential role for Ras in HTLV-1-induced diseases.

Mitochondria released by cells undergoing TNF-α-induced necroptosis act as danger signals.

PubMed

Maeda, A; Fadeel, B

2014-07-03

Necrosis leads to the release of so-called damage-associated molecular patterns (DAMPs), which may provoke inflammatory responses. However, the release of organelles from dying cells, and the consequences thereof have not been documented before. We demonstrate here that mitochondria are released from cells undergoing tumor necrosis factor-α (TNF-α)-induced, receptor-interacting protein (RIP)1-dependent necroptosis, a form of programmed necrosis. The released, purified mitochondria were determined to be intact as they did not emit appreciable amounts of mitochondrial DNA (mtDNA). Pharmacological inhibition of dynamin-related protein 1 (Drp1) prevented mitochondrial fission in TNF-α-triggered cells, but this did not block necroptosis nor the concomitant release of mitochondria. Importantly, primary human macrophages and dendritic cells engulfed mitochondria from necroptotic cells leading to modulation of macrophage secretion of cytokines and induction of dendritic cell maturation. Our results show that intact mitochondria are released from necroptotic cells and suggest that these organelles act as bona fide danger signals.