Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement(1), increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively(2,3). Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement(4). Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP2,3. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Enhancing dominant modes in nonstationary time series by means of the symbolic resonance analysis

We present the symbolic resonance analysis (SRA) as a viable method for addressing the problem of enhancing a weakly dominant mode in a mixture of impulse responses obtained from a nonlinear dynamical system. We demonstrate this using results from a numerical simulation with Duffing oscillators in different domains of their parameter space, and by analyzing event-related brain potentials (ERPs) from a language processing experiment in German as a representative application. In this paradigm, the averaged ERPs exhibit an N400 followed by a sentence final negativity. Contemporary sentence processing models predict a late positivity (P600) as well. We show that the SRA is able to unveil the P600 evoked by the critical stimuli as a weakly dominant mode from the covering sentence final negativity. (c) 2007 American Institute of Physics. (c) 2007 American Institute of Physics.

Interference filters and coatings for mid-infrared astronomy (8-30µm)

The VISIR instrument for the European Southern Observatory (ESO) Very Large Telescope (VLT) is a thermal-infrared imager and spectrometer currently being developed by the French Service d'Astrophysique of CEA Saclay, and Dutch NFRA ASTRON Dwingeloo consortium. This cryogenic instrument will employ precision infrared bandpass filters in the N-( =7.5-14µm) and Q-( =16-28µm) band mid-IR atmospheric windows to study interstellar and circumstellar environments crucial for star and planetary formation theories. As the filters in these mid-IR wavelength ranges are of interest to many astronomical cryogenic instruments, a worldwide astronomical filter consortium was set up with participation from 12 differing institutes, each requiring instrument specific filter operating environments and optical metrology. This paper describes the design and fabrication methods used to manufacture these astronomical consortium filters, including the rationale for the selection of multilayer coating designs, temperature-dependant optical properties of the filter materials and FTIR spectral measurements showing the changes in passband and blocking performance on cooling to <50K. We also describe the development of a 7-14µm broadband antireflection coating deposited on Ge lenses and KRS-5 grisms for cryogenic operation at 40K

Performance evaluation of enhanced relay-enabled distributed coordination function

In this paper we evaluate the performance of our earlier proposed enhanced relay-enabled distributed coordination function (ErDCF) for wireless ad hoc networks. The idea of ErDCF is to use high data rate nodes to work as relays for the low data rate nodes. ErDCF achieves higher throughput and reduced energy consumption compared to IEEE 802.11 distributed coordination function (DCF). This is a result of. 1) using relay which helps to increase the throughput and lower overall blocking time of nodes due to faster dual-hop transmission, 2) using dynamic preamble (i.e. using short preamble for the relay transmission) which further increases the throughput and lower overall blocking time and also by 3) reducing unnecessary overhearing (by other nodes not involved in transmission). We evaluate the throughput and energy performance of the ErDCF with different rate combinations. ErDCF (11,11) (ie. R1=R2=11 Mbps) yields a throughput improvement of 92.9% (at the packet length of 1000 bytes) and an energy saving of 72.2% at 50 nodes.

An enhanced relay-enabled medium access control protocol for wireless ad hoc networks

In this paper we propose an enhanced relay-enabled distributed coordination function (rDCF) for wireless ad hoc networks. The idea of rDCF is to use high data rate nodes to work as relays for the low data rate nodes. The relay helps to increase the throughput and lower overall blocking time of nodes due to faster dual-hop transmission. rDCF achieves higher throughput over IEEE 802.11 distributed coordination function (DCF). The protocol is further enhanced for higher throughput and reduced energy. These enhancements result from the use of a dynamic preamble (i.e. using short preamble for the relay transmission) and also by reducing unnecessary overhearing (by other nodes not involved in transmission). We have modeled the energy consumption of rDCF, showing that rDCF provides an energy efficiency of 21.7% at 50 nodes over 802.11 DCF. Compared with the existing rDCF, the enhanced rDCF (ErDCF) scheme proposed in this paper yields a throughput improvement of 16.54% (at the packet length of 1000 bytes) and an energy saving of 53% at 50 nodes.

A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids

Background and purpose: Molecular mechanisms underlying the links between dietary intake of flavonoids and reduced cardiovascular disease risk are only partially understood. Key events in the pathogenesis of cardiovascular disease, particularly thrombosis, are inhibited by these polyphenolic compounds via mechanisms such as inhibition of platelet activation and associated signal transduction, attenuation of generation of reactive oxygen species, enhancement of nitric oxide production and binding to thromboxane A2 receptors. In vivo, effects of flavonoids are mediated by their metabolites, but the effects and modes of action of these compounds are not well-characterized. A good understanding of flavonoid structure–activity relationships with regard to platelet function is also lacking. Experimental approach: Inhibitory potencies of structurally distinct flavonoids (quercetin, apigenin and catechin) and plasma metabolites (tamarixetin, quercetin-3′-sulphate and quercetin-3-glucuronide) for collagen-stimulated platelet aggregation and 5-hydroxytryptamine secretion were measured in human platelets. Tyrosine phosphorylation of total protein, Syk and PLCγ2 (immunoprecipitation and Western blot analyses), and Fyn kinase activity were also measured in platelets. Internalization of flavonoids and metabolites in a megakaryocytic cell line (MEG-01 cells) was studied by fluorescence confocal microscopy. Key results: The inhibitory mechanisms of these compounds included blocking Fyn kinase activity and the tyrosine phosphorylation of Syk and PLCγ2 following internalization. Principal functional groups attributed to potent inhibition were a planar, C-4 carbonyl substituted and C-3 hydroxylated C ring in addition to a B ring catechol moiety. Conclusions and implications: The structure–activity relationship for flavonoids on platelet function presented here may be exploited to design selective inhibitors of cell signalling.

On the structure of Langmuir turbulence

The Stokes drift induced by surface waves distorts turbulence in the wind-driven mixed layer of the ocean, leading to the development of streamwise vortices, or Langmuir circulations, on a wide range of scales. We investigate the structure of the resulting Langmuir turbulence, and contrast it with the structure of shear turbulence, using rapid distortion theory (RDT) and kinematic simulation of turbulence. Firstly, these linear models show clearly why elongated streamwise vortices are produced in Langmuir turbulence, when Stokes drift tilts and stretches vertical vorticity into horizontal vorticity, whereas elongated streaky structures in streamwise velocity fluctuations (u) are produced in shear turbulence, because there is a cancellation in the streamwise vorticity equation and instead it is vertical vorticity that is amplified. Secondly, we develop scaling arguments, illustrated by analysing data from LES, that indicate that Langmuir turbulence is generated when the deformation of the turbulence by mean shear is much weaker than the deformation by the Stokes drift. These scalings motivate a quantitative RDT model of Langmuir turbulence that accounts for deformation of turbulence by Stokes drift and blocking by the air–sea interface that is shown to yield profiles of the velocity variances in good agreement with LES. The physical picture that emerges, at least in the LES, is as follows. Early in the life cycle of a Langmuir eddy initial turbulent disturbances of vertical vorticity are amplified algebraically by the Stokes drift into elongated streamwise vortices, the Langmuir eddies. The turbulence is thus in a near two-component state, with suppressed and . Near the surface, over a depth of order the integral length scale of the turbulence, the vertical velocity (w) is brought to zero by blocking of the air–sea interface. Since the turbulence is nearly two-component, this vertical energy is transferred into the spanwise fluctuations, considerably enhancing at the interface. After a time of order half the eddy decorrelation time the nonlinear processes, such as distortion by the strain field of the surrounding eddies, arrest the deformation and the Langmuir eddy decays. Presumably, Langmuir turbulence then consists of a statistically steady state of such Langmuir eddies. The analysis then provides a dynamical connection between the flow structures in LES of Langmuir turbulence and the dominant balance between Stokes production and dissipation in the turbulent kinetic energy budget, found by previous authors.

Adsorption and dissociation of benzene on bimetallic surfaces - the influence of surface geometry and electronic structure

This topical review discusses the influence of the surface geometry (e.g. lattice parameters and termination) and electronic structure of well-defined bimetallic surfaces on the adsorption and dissociation of benzene. The available data can be divided into two categories with combinations of non-transition metals and transition metals on the one side and combinations of two transition metals on the other. The main effect of non-transition metals in surface alloys is site blocking which can suppress chemisorption and dissociation of the molecules completely. When two transition metals are combined, the effects are less dramatic. They mainly affect the strength of the chemisorption bond and the degree of dissociation due to electronic and template effects.

High-performance infrared filters for the HIRDLS 21-channel focal plane detector array

The High Resolution Dynamics Limb Sounder is described, with particular reference to the atmospheric measurements to be made and the rationale behind the measurement strategy. The demands this strategy places on the filters to be used in the instrument and the designs to which this leads to are described. A second set of filters at an intermediate image plane to reduce "Ghost Imaging" is discussed together with their required spectral properties. A method of combining the spectral characteristics of the primary and secondary filters in each channel are combined together with the spectral response of the detectors and other optical elements to obtain the system spectral response weighted appropriately for the Planck function and atmospheric limb absorption. This method is used to demonstrate whether the out-of-band spectral blocking requirement for a channel is being met and an example calculation is demonstrated showing how the blocking is built up for a representative channel. Finally, the techniques used to produce filters of the necessary sub-millimetre sizes together with the testing methods and procedures used to assess the environmental durability and establish space flight quality are discussed.

Spectral design and verification of HIRDLS filters and antireflection coatings using an integrated system performance approach

The HIRDLS instrument contains 21 spectral channels spanning a wavelength range from 6 to 18mm. For each of these channels the spectral bandwidth and position are isolated by an interference bandpass filter at 301K placed at an intermediate focal plane of the instrument. A second filter cooled to 65K positioned at the same wavelength but designed with a wider bandwidth is placed directly in front of each cooled detector element to reduce stray radiation from internally reflected in-band signals, and to improve the out-of-band blocking. This paper describes the process of determining the spectral requirements for the two bandpass filters and the antireflection coatings used on the lenses and dewar window of the instrument. This process uses a system throughput performance approach taking the instrument spectral specification as a target. It takes into account the spectral characteristics of the transmissive optical materials, the relative spectral response of the detectors, thermal emission from the instrument, and the predicted atmospheric signal to determine the radiance profile for each channel. Using this design approach an optimal design for the filters can be achieved, minimising the number of layers to improve the in-band transmission and to aid manufacture. The use of this design method also permits the instrument spectral performance to be verified using the measured response from manufactured components. The spectral calculations for an example channel are discussed, together with the spreadsheet calculation method. All the contributions made by the spectrally active components to the resulting instrument channel throughput are identified and presented.

Sleeping with half open eyes: dreams and realities in The Cry of the Owl

This article is a close analysis of The Cry of the Owl (Thraves, 2009). It is also part of larger project to bring together traditions of detailed criticism with those of production history, which culminates in second article on the film due to be published in 2011. The detail of the argument concerns analysing a range of the film’s key signifying systems, with a particular interest in the way the film explores the gap between images / impressions and characters’ realities; engages in a complex way with generic traditions and modes of address; establishes complex patterns of connection and contrast through blocking, camera strategies and narrative structure.

The influence of ultraviolet radiation on growth, photosynthesis and phenolic levels of green and red lettuce: potential for exploiting effects of ultraviolet radiation in a production system

Studies have shown that natural ultraviolet (UV) radiation increases secondary products such as phenolics but can significantly inhibit biomass accumulation in lettuce plants. In the work presented here, the effect of UV radiation on phenolic concentration and biomass accumulation was assessed in relation to photosynthetic performance in red and green lettuce types. Lettuce plants in polythene clad tunnels were exposed to either ambient (UV transparent film) or UV-free conditions (UV blocking film). The study tested whether growth reduction in lettuce plants exposed to natural UV radiation is because of inhibition of photosynthesis by direct damage to the photosynthetic apparatus or by internal shading by anthocyanins. Ambient levels of UV radiation did not limit the efficiency of photosynthesis suggesting that phenolic compounds may effectively protect the photosynthetic apparatus. Growth inhibition does, however, occur in red lettuce and could be explained by the high metabolic cost of phenolic compounds for UV protection. From a commercial perspective, UV transparent and UV blocking films offer opportunities because, in combination, they could increase plant quality as well as productivity. Growing plants continuously under a UV blocking film, and then 6 days before the final harvest transferring them to a UV transparent film, showed that high yields and high phytochemical content can be achieved complementarily.

Acceleration of radio network optimisation algorithms

The increasing demand for cheaper-faster-better services anytime and anywhere has made radio network optimisation much more complex than ever before. In order to dynamically optimise the serving network, Dynamic Network Optimisation (DNO), is proposed as the ultimate solution and future trend. The realization of DNO, however, has been hindered by a significant bottleneck of the optimisation speed as the network complexity grows. This paper presents a multi-threaded parallel solution to accelerate complicated proprietary network optimisation algorithms, under a rigid condition of numerical consistency. ariesoACP product from Arieso Ltd serves as the platform for parallelisation. This parallel solution has been benchmarked and results exhibit a high scalability and a run-time reduction by 11% to 42% based on the technology, subscriber density and blocking rate of a given network in comparison with the original version. Further, it is highly essential that the parallel version produces equivalent optimisation quality in terms of identical optimisation outputs.

Evaluation of two "integrated" polarimetric Quantitative Precipitation Estimation (QPE) algorithms at C-band

Two so-called “integrated” polarimetric rate estimation techniques, ZPHI (Testud et al., 2000) and ZZDR (Illingworth and Thompson, 2005), are evaluated using 12 episodes of the year 2005 observed by the French C-band operational Trappes radar, located near Paris. The term “integrated” means that the concentration parameter of the drop size distribution is assumed to be constant over some area and the algorithms retrieve it using the polarimetric variables in that area. The evaluation is carried out in ideal conditions (no partial beam blocking, no ground-clutter contamination, no bright band contamination, a posteriori calibration of the radar variables ZH and ZDR) using hourly rain gauges located at distances less than 60 km from the radar. Also included in the comparison, for the sake of benchmarking, is a conventional Z = 282R1.66 estimator, with and without attenuation correction and with and without adjustment by rain gauges as currently done operationally at Météo France. Under those ideal conditions, the two polarimetric algorithms, which rely solely on radar data, appear to perform as well if not better, pending on the measurements conditions (attenuation, rain rates, …), than the conventional algorithms, even when the latter take into account rain gauges through the adjustment scheme. ZZDR with attenuation correction is the best estimator for hourly rain gauge accumulations lower than 5 mm h−1 and ZPHI is the best one above that threshold. A perturbation analysis has been conducted to assess the sensitivity of the various estimators with respect to biases on ZH and ZDR, taking into account the typical accuracy and stability that can be reasonably achieved with modern operational radars these days (1 dB on ZH and 0.2 dB on ZDR). A +1 dB positive bias on ZH (radar too hot) results in a +14% overestimation of the rain rate with the conventional estimator used in this study (Z = 282R^1.66), a -19% underestimation with ZPHI and a +23% overestimation with ZZDR. Additionally, a +0.2 dB positive bias on ZDR results in a typical rain rate under- estimation of 15% by ZZDR.

Effect of phonetic complexity on word reading and repetition in deep dyslexia

This investigation moves beyond the traditional studies of word reading to identify how the production complexity of words affects reading accuracy in an individual with deep dyslexia (JO). We examined JO’s ability to read words aloud while manipulating both the production complexity of the words and the semantic context. The classification of words as either phonetically simple or complex was based on the Index of Phonetic Complexity. The semantic context was varied using a semantic blocking paradigm (i.e., semantically blocked and unblocked conditions). In the semantically blocked condition words were grouped by semantic categories (e.g., table, sit, seat, couch,), whereas in the unblocked condition the same words were presented in a random order. JO’s performance on reading aloud was also compared to her performance on a repetition task using the same items. Results revealed a strong interaction between word complexity and semantic blocking for reading aloud but not for repetition. JO produced the greatest number of errors for phonetically complex words in semantically blocked condition. This interaction suggests that semantic processes are constrained by output production processes which are exaggerated when derived from visual rather than auditory targets. This complex relationship between orthographic, semantic, and phonetic processes highlights the need for word recognition models to explicitly account for production processes.