Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

Evidential Fusion for Gender Profiling

Gender profiling is a fundamental task that helps CCTV systems to
provide better service for intelligent surveillance. Since subjects being detected
by CCTVs are not always cooperative, a few profiling algorithms are proposed
to deal with situations when faces of subjects are not available, among which
the most common approach is to analyze subjects’ body shape information. In
addition, there are some drawbacks for normal profiling algorithms considered
in real applications. First, the profiling result is always uncertain. Second, for a
time-lasting gender profiling algorithm, the result is not stable. The degree of
certainty usually varies, sometimes even to the extent that a male is classified
as a female, and vice versa. These facets are studied in a recent paper [16] using
Dempster-Shafer theory. In particular, Denoeux’s cautious rule is applied for
fusion mass functions through time lines. However, this paper points out that if
severe mis-classification is happened at the beginning of the time line, the result
of applying Denoeux’s rule could be disastrous. To remedy this weakness,
in this paper, we propose two generalizations to the DS approach proposed in
[16] that incorporates time-window and time-attenuation, respectively, in applying
Denoeux’s rule along with time lines, for which the DS approach is a special
case. Experiments show that these two generalizations do provide better results
than their predecessor when mis-classifications happen.

Comet C/2012 S1 (ISON): Observations of the Dust Grains from SOFIA and of the Atomic Gas from NSO Dunn and McMath-Pierce Solar Telescopes (Invited)

Comet C/2012 S1 (ISON) is unique in that it is a dynamically new comet derived from the Oort cloud reservoir of comets with a sun-grazing orbit. Infrared (IR) and visible wavelength observing campaigns were planned on NASA's Stratospheric Observatory For Infrared Astronomy (SOFIA) and on National Solar Observatory Dunn (DST) and McMath-Pierce Solar Telescopes, respectively. We highlight our early results. SOFIA (+FORCAST [1]) mid- to far-IR images and spectroscopy (~5-35 μm) of the dust in the coma of ISON are to be obtained by the ISON-SOFIA Team during a flight window 2013 Oct 21-23 UT (r_h≈1.18 AU). Dust characteristics, identified through the 10 μm silicate emission feature and its strength [2], as well as spectral features from cometary crystalline silicates (Forsterite) at 11.05-11.2 μm, and near 16, 19, 23.5, 27.5, and 33 μm are compared with other Oort cloud comets that span the range of small and/or highly porous grains (e.g., C/1995 O1 (Hale-Bopp) [3,4,5] and C/2001 Q4 (NEAT) [6]) to large and/or compact grains (e.g., C/2007 N4 (Lulin) [7] and C/2006 P1 (McNaught) [8]). Measurement of the crystalline peaks in contrast to the broad 10 and 20 μm amorphous silicate features yields the cometary silicate crystalline mass fraction [9], which is a benchmark for radial transport in our protoplanetary disk [10]. The central wavelength positions, relative intensities, and feature asymmetries for the crystalline peaks may constrain the shapes of the crystals [11]. Only SOFIA can look for cometary organics in the 5-8 μm region. Spatially resolved measurements of atoms and simple molecules from when comet ISON is near the Sun (r_h<0.4 AU, near Nov-20--Dec-03 UT) were proposed for by the ISON-DST Team. Comet ISON is the first comet since comet Ikeya-Seki (1965f) [12,13] suitable for studying the alkalai metals Na and K and the atoms specifically attributed to dust grains including Mg, Si, Fe, as well as Ca. DST's Horizontal Grating Spectrometer (HGS) measures 4 settings: Na I, K, C2 to sample cometary organics (along with Mg I), and [O I] as a proxy for activity from water [14] (along with Si I and Fe I). State-of-the-art instruments that will also be employed include IBIS [15], which is a Fabry-Perot spectral imaging system that concurrently measures lines of Na, K, Ca II, or Fe, and ROSA (CSUN/QUB) [16], which is a rapid imager that simultaneously monitors Ca II or CN. From McMath-Pierce, the Solar-Stellar Spectrograph also will target ISON (320-900 nm, R~21,000, r_h

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase).

Inhaled antibiotics, such as tobramycin, for the treatment of Pseudomonas aeruginosa pulmonary infections are associated with the increase in life expectancy seen in cystic fibrosis (CF) patients over recent years. However, the effectiveness of this aminoglycoside is still limited by its inability to penetrate the thick DNA-rich mucus in the lungs of these patients, leading to low antibiotic exposure to resident bacteria. In this study, we created novel polymeric nanoparticle (NP) delivery vehicles for tobramycin. Using isothermal titration calorimetry, we showed that tobramycin binds with alginate polymer and, by exploiting this interaction, optimised the production of tobramycin alginate/chitosan NPs. It was established that NP antimicrobial activity against P. aeruginosa PA01 was equivalent to unencapsulated tobramycin (minimum inhibitory concentration 0.625 mg/L). Galleria mellonella was employed as an in vivo model for P. aeruginosa infection. Survival rates of 90% were observed following injection of NPs, inferring low NP toxicity. After infection with P. aeruginosa, we showed that a lethal inoculum was effectively cleared by tobramycin NPs in a dose dependent manner. Crucially, a treatment with NPs prior to infection provided a longer window of antibiotic protection, doubling survival rates from 40% with free tobramycin to 80% with NP treatment. Tobramycin NPs were then functionalised with dornase alfa (recombinant human deoxyribonuclease I, DNase), demonstrating DNA degradation and improved NP penetration of CF sputum. Following incubation with CF sputum, tobramycin NPs both with and without DNase functionalisation, exhibited anti-pseudomonal effects. Overall, this work demonstrates the production of effective antimicrobial NPs, which may have clinical utility as mucus-penetrating tobramycin delivery vehicles, combining two widely used CF therapeutics into a single NP formulation. This nano-antibiotic represents a strategy to overcome the mucus barrier, increase local drug concentrations, avoid systemic adverse effects and improve outcomes for pulmonary infections in CF.

Hybrid probabilistic wind power forecasting using temporally local Gaussian process

The demand for sustainable development has resulted in a rapid growth in wind power worldwide. Despite various approaches have been proposed to improve the accuracy and to overcome the uncertainties associated with traditional methods, the stochastic and variable nature of wind still remains the most challenging issue in accurately forecasting wind power. This paper presents a hybrid deterministic-probabilistic method where a temporally local ‘moving window’ technique is used in Gaussian Process to examine estimated forecasting errors. This temporally local Gaussian Process employs less measurement data while faster and better predicts wind power at two wind farms, one in the USA and the other in Ireland. Statistical analysis on the results shows that the method can substantially reduce the forecasting error while more likely generate Gaussian-distributed residuals, particularly for short-term forecast horizons due to its capability to handle the time-varying characteristics of wind power.

System flexibility provision using short term grid scale storage

This paper presents a novel analysis of the utilisation of small grid scale energy storage to mitigate negative system operational impacts due to high penetrations of wind power. This was investigated by artificially lowering the minimum stable generation level of a gas thermal generating unit coupled to a storage device over a five hour storage charging window using a unit commitment and economic dispatch model. The key findings of the analysis were a 0.18% reduction in wind curtailment, a 2.35 MW/min reduction in the ramping rate required to be met by all generators in the test system during a representative period and a total generation cost reduction of €6.5 million.

Overview of laser-driven generation of electron–positron beams

Electron–positron (e–p) plasmas are widely thought to be emitted, in the form of ultra-relativistic winds or collimated jets, by some of the most energetic or powerful objects in the Universe, such as black-holes, pulsars, and quasars. These phenomena represent an unmatched astrophysical laboratory to test physics at its limit and, given their immense distance from Earth (some even farther than several billion light years), they also provide a unique window on the very early stages of our Universe. However, due to such gigantic distances, their properties are only inferred from the indirect interpretation of their radiative signatures and from matching numerical models: their generation mechanism and dynamics still pose complicated enigmas to the scientific community. Small-scale reproductions in the laboratory would represent a fundamental step towards a deeper understanding of this exotic state of matter. Here we present recent experimental results concerning the laser-driven production of ultra-relativistic e–p beams. In particular, we focus on the possibility of generating beams that present charge neutrality and that allow for collective effects in their dynamics, necessary ingredients for the testing pair-plasma physics in the laboratory. A brief discussion of the analytical and numerical modelling of the dynamics of these plasmas is also presented in order to provide a summary of the novel plasma physics that can be accessed with these objects. Finally, general considerations on the scalability of laboratory plasmas up to astrophysical scenarios are given.

Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents

Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70

The Wilms tumor suppressor WT1 encodes a zinc finger transcription factor that is expressed in glomerular podocytes during a narrow window in kidney development. By immunoprecipitation and protein microsequencing analysis, we have identified a major cellular protein associated with endogenous WT1 to be the inducible chaperone Hsp70. WT1 and Hsp70 are physically associated in embryonic rat kidney cells, in primary Wilms tumor specimens and in cultured cells with inducible expression of WT1. Colocalization of WT1 and Hsp70 is evident within podocytes of the developing kidney, and Hsp70 is recruited to the characteristic subnuclear clusters that contain WT1. The amino-terminal transactivation domain of WT1 is required for binding to Hsp70, and expression of that domain itself is sufficient to induce expression of Hsp70 through the heat shock element (HSE). Substitution of a heterologous Hsp70-binding domain derived from human DNAJ is sufficient to restore the functional properties of a WT1 protein with an amino-terminal deletion, an effect that is abrogated by a point mutation in DNAJ that reduces binding to Hsp70. These observations indicate that Hsp70 is an important cofactor for the function of WT1, and suggest a potential role for this chaperone during kidney differentiation.

The effect of probe interval estimation on attack detection performance of a WLAN independent intrusion detection system

A new niche of densely populated, unprotected networks is becoming more prevalent in public areas such as Shopping Malls, defined here as independent open-access networks, which have attributes that make attack detection more challenging than in typical enterprise networks. To address these challenges, new detection systems which do not rely on knowledge of internal device state are investigated here. This paper shows that this lack of state information requires an additional metric (The exchange timeout window) for detection of WLAN Denial of Service Probe Flood attacks. Variability in this metric has a significant influence on the ability of a detection system to reliably detect the presence of attacks. A parameter selection method is proposed which is shown to provide reliability and repeatability in attack detection in WLANs. Results obtained from ongoing live trials are presented that demonstrate the importance of accurately estimating probe request and probe response timeouts in future Independent Intrusion Detection Systems.

Direct Visual Indication of pH Windows: 'Off-On-Off' Fluorescent PET (Photoinduced Electron Transfer) Sensors/Switches

1–3, which contain a fluorophore and two proton receptors with opposite PET (photoinduced electron transfer) characteristics, only display strong fluorescence within a pH window whose position and width are tunable.

Hardware Software Interface: a Strategy for the implementation of Urban Agriculture

This paper describes how urban agriculture differs from conventional agriculture not only in the way it engages with the technologies of growing, but also in the choice of crop and the way these are brought to market. The authors propose a new model for understanding these new relationships, which is analogous to a systems view of information technology, namely Hardware-Software- Interface.
The first component of the system is hardware. This is the technological component of the agricultural system. Technology is often thought of as equipment, but its linguistic roots are in ‘technis’ which means ‘know how’. Urban agriculture has to engage new technologies, ones that deal with the scale of operation and its context which is different than rural agriculture. Often the scale is very small, and soils are polluted. There this technology in agriculture could be technical such as aquaponic systems, or could be soil-based agriculture such as allotments, window-boxes, or permaculture. The choice of method does not necessarily determine the crop produced or its efficiency. This is linked to the biotic that is added to the hardware, which is seen as the ‘software’.
The software of the system are the ecological parts of the system. These produce the crop which may or may not be determined by the technology used. For example, a hydroponic system could produce a range of crops, or even fish or edible flowers. Software choice can be driven by ideological preferences such as permaculture, where companion planting is used to reduce disease and pests, or by economic factors such as the local market at a particular time of the year. The monetary value of the ‘software’ is determined by the market. Obviously small, locally produced crops are unlikely to compete against intensive products produced globally, however the value locally might be measured in different ways, and might be sold on a different market. This leads to the final part of the analogy - interface.
The interface is the link between the system and the consumer. In traditional agriculture, there is a tenuous link between the producer of asparagus in Peru and the consumer in Europe. In fact very little of the money spent by the consumer ever reaches the grower. Most of the money is spent on refrigeration, transport and profit for agents and supermarket chains. Local or hyper-local agriculture needs to bypass or circumvent these systems, and be connected more directly to the consumer. This is the interface. In hyper-localised systems effectiveness is often more important than efficiency, and direct links between producer and consumer create new economies.

Effect of ultraviolet-B light on lymphocyte activity at doses at which normal bone marrow stem cells are preserved

Ultraviolet B (UVB) light is known to be immunosuppressive, but, probably because of a small UVC component in the emission spectra of some of the UVB lamps used, reports vary on effective dose levels. To prevent potentially lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, alloreactive donor T-cell activity must be suppressed. In this study, a narrow wavelength UVB lamp (TL01, 312 nm peak emission) was used to determine what doses of UVB were required to abolish rat lymphocyte proliferation while simultaneously preserving rat bone marrow progenitor cell and primitive hematopoietic stem cell viability. Lymphocyte proliferation, as measured by 3H-Thymidine incorporation, in response to lectin stimulation was abolished below detection at doses greater than 3,500 J/m2. When T-cell clonogenicity was measured in a limiting dilution assay, a small fraction (0.6%) was maintained at doses up to 4,000 J/m2. Cytotoxic T-lymphocyte (CTL) activity was reduced after treatment with 4,000 J/m2, but a significant level of cytotoxicity was still maintained. Natural killer cell cytolytic activity was not affected by doses up to 4,000 J/m2. At 4,000 J+m2 there was a 10% survival of colony-forming units-granulocyte-macrophage; a 1% and 4% survival of day-8 and day-12 colony-forming units-spleen, respectively; and 11% survival of marrow repopulating ability cells. Up to 25% of late cobblestone area forming cells (4 to 5 weeks), reflecting the more immature hematopoietic stem cells, were preserved in bone marrow treated with 4,000 J/m2, indicating that early stem cells are less sensitive to UVB damage than are more committed progenitor cells. Thus, a potential therapeutic window was established at approximately 4,000 J/m2 using this light source, whereby the potentially GVHD-inducing T cells were suppressed, but a sufficient proportion of the cells responsible for engraftment was maintained.