Effector ExoU from the type III secretion system is an important modulator of gene expression in lung epithelial cells in response to Pseudomonas aeruginosa infection

Pseudomonas aeruginosa is an important pathogen in immunocompromised patients and secretes a diverse set of virulence factors that aid colonization and influence host cell defenses. An important early step in the establishment of infection is the production of type III-secreted effectors translocated into host cells by the bacteria. We used cDNA microarrays to compare the transcriptomic response of lung epithelial cells to P. aeruginosa mutants defective in type IV pili, the type III secretion apparatus, or in the production of specific type III-secreted effectors. Of the 18,000 cDNA clones analyzed, 55 were induced or repressed after 4 It of infection and could be classified into four different expression patterns. These include (i) host genes that are induced or repressed in a type III secretion-independent manner (32 clones), (ii) host genes induced specifically by ExoU (20 clones), and (iii) host genes induced in an ExoU-independent but type III secretion dependent manner (3 clones). In particular, ExoU was essential for the expression of immediate-early response genes, including the transcription factor c-Fos. ExoU-dependent gene expression was mediated in part by early and transient activation of the AN transcription factor complex. In conclusion, the present study provides a detailed insight into the response of epithelial cells to infection and indicates the significant role played by the type III virulence mechanism in the initial host response.

T1/ST2 - an IL-1 receptor-like modulator of immune responses

Th2-associated factors such as IL-4 are involved in both the development of Th2 responses (via modulating Th2 cell differentiation) and in the effector phase of Th2 responses (via modulating macrophage activation). The IL-1 receptor-like protein ST2 (T1, Fit-1, or DER4) is expressed as a membrane-bound (ST2L) or secreted form (sST2), and has been clearly implicated as a regulator of both the development and effector phases of Th2-type responses. Here we analyze the mechanisms and therapeutic implications of the unique ability of ST2 to promote development and function of type 2 helper T cells through a positive feedback loop, as well as to act as a negative feedback modulator of macrophage pro-inflammatory function. (C) 2004 Elsevier Ltd. All rights reserved.

Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors

ATP and glutamate are fast excitatory neurotransmitters in the central nervous system acting primarily on ionotropic P2X and glutamate [N-methyl-D-aspartate (NMDA) and non-NMDA] receptors, respectively. Both neurotransmitters regulate synaptic plasticity and long-term potentiation in hippocampal neurons. NMDA receptors are responsible primarily for the modulatory action of glutamate, but the mechanism underlying the modulatory effect of ATP remains uncertain. In the present study, the effect of ATP on recombinant NR1a + 2A, NR1a + 2B, and NR1a + 2C NMDA receptors expressed in Xenopus laevis oocytes was investigated. ATP inhibited NR1a + 2A and NR1a + 2B receptor currents evoked by low concentrations of glutamate but potentiated currents evoked by saturating glutamate concentrations. In contrast, ATP potentiated NR1a + 2C receptor currents evoked by nonsaturating glutamate concentrations. ATP shifted the glutamate concentration-response curve to the right, indicating a competitive interaction at the agonist binding site. ATP inhibition and potentiation of glutamate-evoked currents was voltage-independent, indicating that ATP acts outside the membrane electric field. Other nucleotides, including ADP, GTP, CTP, and UTP, inhibited glutamate-evoked currents with different potencies, revealing that the inhibition is dependent on both the phosphate chain and nucleotide ring structure. At high concentrations, glutamate outcompetes ATP at the agonist binding site, revealing a potentiation of the current. This effect must be caused by ATP binding at a separate site, where it acts as a positive allosteric modulator of channel gating. A simple model of the NMDA receptor, with ATP acting both as a competitive antagonist at the glutamate binding site and as a positive allosteric modulator at a separate site, reproduced the main features of the data.

Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity

Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPAR gamma M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of RA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR-gamma M with promising therapeutic utility with the potential for less weight gain.

Drop and insert multiplexing with simultaneous clock recovery using an electroabsorption modulator

A three-node optical time-division multiplexing (OTDM) network is demonstrated that utilizes electroabsorption (EA) modulators as the core elements. Each node is self contained and performs its own clock recovery and synchronization. “Drop and insert” functionality is demonstrated for the first time with an EA modulator by completely removing a 10-Gb/s channel from a 40-Gb/s OTDM data stream. A different 10-Gb/s channel was subsequently inserted into the vacant time slot. Clock recovery is achieved by using an EA modulator in a novel bidirectional configuration. Bit-error-rate (BER) measurements are presented for each of the 10-Gb/s OTDM channels.

Simultaneous demultiplexing and clock recovery using a single electroabsorption modulator in a novel bi-directional configuration

A single electroabsorption modulator was used to demultiplex a 10 Gbit/s channel from a 40 Gbit/s OTDM data stream, whilst simultaneously recovering the 10 GHz electrical clock. This was achieved using a new bi-directional operation of the EA modulator, combined with a simple phase-locked loop feedback circuit. Excellent system performance was achieved, indicating that operation up to and beyond 100 Gbit/s is possible using current technology.

Molecular basis for reduced estrone sulfate transport and altered modulator sensitivity of transmembrane helix (TM) 6 and TM17 mutants of multidrug resistance protein 1 (ABCC1)

Multidrug resistance protein 1 (MRP1) confers drug resistance and also mediates cellular efflux of many organic anions. MRP1 also transports glutathione (GSH); furthermore, this tripeptide stimulates transport of several substrates, including estrone 3-sulfate. We have previously shown that mutations of Lys(332) in transmembrane helix (TM) 6 and Trp(1246) in TM17 cause different substrate-selective losses in MRP1 transport activity. Here we have extended our characterization of mutants K332L and W1246C to further define the different roles these two residues play in determining the substrate and inhibitor specificity of MRP1. Thus, we have shown that TM17-Trp(1246) is crucial for conferring drug resistance and for binding and transport of methotrexate, estradiol glucuronide, and estrone 3-sulfate, as well as for binding of the tricyclic isoxazole inhibitor N-[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo-[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide (LY465803). In contrast, TM6-Lys(332) is important for enabling GSH and GSH-containing compounds to serve as substrates (e.g., leukotriene C(4)) or modulators (e.g., S-decyl-GSH, GSH disulfide) of MRP1 and, further, for enabling GSH (or S-methyl-GSH) to enhance the transport of estrone 3-sulfate and increase the inhibitory potency of LY465803. On the other hand, both mutants are as sensitive as wild-type MRP1 to the non-GSH-containing inhibitors (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK571), 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]-ethanone (LY171883), and highly potent 6-[4'-carboxyphenylthio]-5[S]-hydroxy-7[E], 11[Z]14[Z]-eicosatetrenoic acid (BAY u9773). Finally, the differing abilities of the cysteinyl leukotriene derivatives leukotriene C(4), D(4), and F(4) to inhibit estradiol glucuronide transport by wild-type and K332L mutant MRP1 provide further evidence that TM6-Lys(332) is involved in the recognition of the gamma-Glu portion of substrates and modulators containing GSH or GSH-like moieties.

Demonstration of CoWDM using DPSK modulator array with injection-locked lasers

A practical implementation of coherent wavelength division multiplexing (CoWDM) is demonstrated for the first time using injection-locked lasers and a DPSK modulator array. For a 31.99 Gbit/s system (three subcarriers at 10.664 Gbit/s) the null-to-null spectral bandwidth was only 42.656 GHz and the average receiver sensitivity measured was -33.5 dBm when all subcarrier phases were optimised.

Evaluating the Capacity of Phase Modulator-Controlled Long-Haul Soliton Transmission

We review recent developments in the use of optical solitons for communication systems spanning transoceanic distances. The implementation of "soliton control" to alleviate the detrimental impact of effects such as amplifier noise is shown to be critical for obtaining advantages over competing technologies. The potential performance of two control strategies, namely straight line filtering and synchronous phase modulation, is examined in detail. Design diagrams are used to determine the maximum permissible amplifier spacing, which is a key determinant of system economics. To focus the enquiry, two example system spans are taken, representing transatlantic and transpacific distances. It is concluded that straight line filtering provides very little improvement over a basic design without control. However synchronous phase modulation, which may be implemented using a handful of actively driven components, provides very substantial benefits. These may be used either to extend the overall bit-rate-distance product of the system or to increase the amplifier spacing at more moderate capacities. © 1995 Academic Press. All rights reserved.

Drop and insert multiplexing with simultaneous clock recovery using an electroabsorption modulator

A three-node optical time-division multiplexing (OTDM) network is demonstrated that utilizes electroabsorption (EA) modulators as the core elements. Each node is self contained and performs its own clock recovery and synchronization. "Drop and insert" functionality is demonstrated for the first time with an EA modulator by completely removing a 10-Gb/s channel from a 40-Gb/s OTDM data stream. A different 10-Gb/s channel was subsequently inserted into the vacant time slot. Clock recovery is achieved by using an EA modulator in a novel bidirectional configuration. Bit-error-rate (BER) measurements are presented for each of the 10-Gb/s OTDM channels.

Simultaneous demultiplexing and clock recovery using a single electroabsorption modulator in a novel bi-directional configuration

A single electroabsorption modulator was used to demultiplex a 10 Gbit/s channel from a 40 Gbit/s OTDM data stream, whilst simultaneously recovering the 10 GHz electrical clock. This was achieved using a new bi-directional operation of the EA modulator, combined with a simple phase-locked loop feedback circuit. Excellent system performance was achieved, indicating that operation up to and beyond 100 Gbit/s is possible using current technology.

Active stabilisation of single drive dual-parallel Mach-Zehnder modulator for single sideband signal generation

Presented is a study on a single-drive dual-parallel Mach-Zehnder modulator implementation as a single sideband suppressed carrier generator. High values of both extinction ratio and sidemode suppression ratio were obtained at different modulation frequencies over the Cband. In addition, a stabilisation loop had been developed to preserve the single sideband generation over time. © The Institution of Engineering and Technology 2013.

Cost-effective broadband GaAs IQ modulator array for long-reach OFDM-PONs

A novel modulator array integrating eight GaAs electro-optic IQ modulators is characterized and tested over long-reach direct-detected multi-band OFDM-PONs. The GaAs IQ modulators present > 22 GHz bandwidth with 3V Vpi, being suitable for a 100-km 40-Gb/s OOFDM-PON supporting up to 1024 users.

Polyphosphate as a haemostatic modulator

Funding This work was supported by the British Heart Foundation [grant number FS/11/2/28579]. © 2016 Authors; published by Portland Press Limited.

Joint Power Amplifiers and I/Q Modulator Impairments Modelling and Compensation for LTE Transmitters Using Artificial Neural Networks

This work introduces joint power amplifier (PA) and I/Q modulator modelling and compensation for LongTerm Evolution (LTE) transmitters using artificial neural networks (ANNs). The proposed solution util-izes a powerful nonlinear autoregressive with exogenous inputs (NARX) ANN architecture, which yieldsnoticeable results for high peak to average power ratio (PAPR) LTE signals. Given the ANNs learning capa-bilities, this one-step solution, which includes the mitigation of both PA nonlinearity and I/Q modulatorimpairments, is both accurate and adaptable