Rapamycin induces transactivation of the EGFR and increases cell survival.

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway

Measuring brand image: Shopping centre case studies

'Branding' is well known for consumer products but power has shifted from manufacturers' brands towards retailers'. The term 'image' is more common than 'brand' in the context of shopping centres, but 'branding' may become more important. In this study, the authors first investigated qualitatively, asking shoppers to describe centres in 'personality' terms and eliciting clear descriptive differences between centres. For example, one in-town centre was 'dull, boring and old-fashioned . . . not exciting, just OK'; a larger regional centre was 'trendy, prestigious . . . strong, vibrant, big and colourful'. Second, the authors evaluated six UK shopping centres quantitatively using a questionnaire survey (n = 287). The 'strong and vibrant' centre scored significantly higher than the 'dull and boring' one. Despite 'branding' being little used by shopping centres, those with the better 'brand images' tended to have larger catchment areas, sales and rental incomes. The authors contend that brand management could pay rewards in terms of customer numbers, sales turnover and rental income

Singularity Free Inhomogeneous Models with Heat Flow

We present a class of singularity free exact cosmological solutions of Einstein's equations describing a perfect fluid with heat flow. It is obtained as generalization of the Senovilla class [1] corresponding to incoherent radiation field. The spacetime is cylindrically symmetric and globally regular.Comment: 6 pages, TeX, to appear in Class.Quant.Gra

Analysis and testing of stability augmentation systems

Testing and evaluation of stability augmentation systems for aircraft flight control were conducted. The flutter suppression system analysis of a scale supersonic transport wing model is described. Mechanization of the flutter suppression system is reported. The ride control synthesis for the B-52 aeroelastic model is discussed. Model analyses were conducted using equations of motion generated from generalized mass and stiffness data

The H1 Forward Track Detector at HERA II

In order to maintain efficient tracking in the forward region of H1 after the luminosity upgrade of the HERA machine, the H1 Forward Track Detector was also upgraded. While much of the original software and techniques used for the HERA I phase could be reused, the software for pattern recognition was completely rewritten. This, along with several other improvements in hit finding and high-level track reconstruction, are described in detail together with a summary of the performance of the detector.Comment: Minor revision requested by journal (JINST) edito

The “broken escalator” phenomenon: Vestibular dizziness interferes with locomotor adaptation

BACKGROUND: Although vestibular lesions degrade postural control we do not know the relative contributions of the magnitude of the vestibular loss and subjective vestibular symptoms to locomotor adaptation. OBJECTIVE: To study how dizzy symptoms interfere with adaptive locomotor learning. METHODS: We examined patients with contrasting peripheral vestibular deficits, vestibular neuritis in the chronic stable phase (n = 20) and strongly symptomatic unilateral Meniere’s disease (n = 15), compared to age-matched healthy controls (n = 15). We measured locomotor adaptive learning using the “broken escalator” aftereffect, simulated on a motorised moving sled. RESULTS: Patients with Meniere’s disease had an enhanced “broken escalator” postural aftereffect. More generally, the size of the locomotor aftereffect was related to how symptomatic patients were across both groups. Contrastingly, the degree of peripheral vestibular loss was not correlated with symptom load or locomotor aftereffect size. During the MOVING trials, both patient groups had larger levels of instability (trunk sway) and reduced adaptation than normal controls. CONCLUSION: Dizziness symptoms influence locomotor adaptation and its subsequent expression through motor aftereffects. Given that the unsteadiness experienced during the “broken escalator” paradigm is internally driven, the enhanced aftereffect found represents a new type of self-generated postural challenge for vestibular/unsteady patients

Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y2 receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y2 receptor knockout (P2Y2R−/−) mouse model to investigate the role of this receptor in bone. MicroCT analysis of P2Y2R−/− mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%). In vitro P2Y2R−/− osteoblasts displayed a 3-fold increase in bone formation and alkaline phosphatase activity, whilst P2Y2R−/− osteoclasts exhibited a 65% reduction in resorptive activity. Serum cross-linked C-telopeptide levels (CTX, resorption marker) were also decreased (≤35%). The resorption defect in P2Y2R−/− osteoclasts was rescued by the addition of exogenous ATP, suggesting that an ATP deficit could be a key factor in the reduced function of these cells. In agreement, we found that basal ATP release was reduced up to 53% in P2Y2R−/− osteoclasts. The P2Y2 receptor agonists, UTP and 2-thioUTP, increased osteoclast activity and ATP release in wild-type but not in P2Y2R−/− cells. This indicates that the P2Y2 receptor may regulate osteoclast function indirectly by promoting ATP release. UTP and 2-thioUTP also stimulate ATP release from osteoblasts suggesting that the P2Y2 receptor exerts a similar function in these cells. Taken together, our findings are consistent with the notion that the primary action of P2Y2 receptor signalling in bone is to regulate extracellular ATP levels

Radiative transfer modelling for the NOMAD-UVIS instrument on the ExoMars Trace Gas Orbiter mission

The NOMAD (Nadir and Occultation for MArs Discovery) instrument is a 3-channel (2 IR, 1 UV/Vis) spectrometer due to fly on the 2016 ExoMars Trace Gas Orbiter mission. A radiative transfer model for Mars has been developed providing synthetic spectra to simulate observations of the UVIS channel in both solar occultation and nadir viewing geometries. This will allow for the characterization and mitigation of the influence of dust on retrievals of ozone abundance