EGF receptor trafficking: consequences for signaling and cancer

The ligand-stimulated epidermal growth factor receptor (EGFR) has been extensively studied in the analysis of molecular mechanisms regulating endocytic traffic and the role of that traffic in signal transduction. Although such studies have largely focused on mitogenic signaling and dysregulated traffic in tumorigenesis, there is growing interest in the potential role of EGFR traffic in cell survival and the consequent response to cancer therapy. Here we review recent advances in our understanding of molecular mechanisms regulating ligand-stimulated EGFR activation, internalization, and post-endocytic sorting. The role of EGFR overexpression/mutation and new modulators of EGFR traffic in cancer and the response to cancer therapeutics are also discussed. Finally, we speculate on the relationship between EGFR traffic and cell survival

Barriers & facilitators to extended working life : a focus on a predominately female ageing workforce

Many countries are reforming their pension systems so people stay in work for longer to improve the long-term sustainability of public finances to support an increasing older population. This research aimed to explore the factors that enable or inhibit people to extend working life (EWL) in a large UK based retail organisation. Semi-structured interviews were carried out with a purposive sample (n=30): 15 employees aged ≥ 60 and 15 supervisors supporting these employees. Older workers were predominately female, reflecting the gender profile of the older workers in the organisation. Older workers and supervisors reported that key facilitators to EWL were: good health, the perception that older workers are of value; flexibility and choice; the need for an ongoing conversation across the life-course; the social and community aspect of work as a facilitator to EWL; and, the financial necessity to EWL. Perceived barriers to EWL included poor health, negative impacts of work on health, and a lack of respect and support

Peak shifts due to B(∗)−Bˉ(∗)B^{(*)}-\bar{B}^{(*)} rescattering in Υ(5S)\Upsilon(5S) dipion transitions

We study the energy distributions of dipion transitions $\Upsilon(5S)$ to $\Upsilon(1S,2S,3S)\pi^+\pi^-$ in the final state rescattering model. Since the $\Upsilon(5S)$ is well above the open bottom thresholds, the dipion transitions are expected to mainly proceed through the real processes $\Upsilon(5S)\to B^{(*)}\bar{B}^{(*)}$ and $B^{(*)}\bar{B}^{(*)}\to \Upsilon(1S,2S,3S)\pi^+\pi^-$. We find that the energy distributions of $\Upsilon(1S,2S,3S)\pi^+\pi^-$ markedly differ from that of $\Upsilon(5S)\to B^{(*)}\bar{B}^{(*)}$. In particular, the resonance peak will be pushed up by about 7-20 MeV for these dipion transitions relative to the main hadronic decay modes. These predictions can be used to test the final state rescattering mechanism in hadronic transitions for heavy quarkonia above the open flavor thresholds.Comment: Version published in PRD, energy dependence of the total width in Eq.(12) restored and corresponding figure changed, more discussion and clarification adde

Gaussian process model based predictive control

Gaussian process models provide a probabilistic non-parametric modelling approach for black-box identification of non-linear dynamic systems. The Gaussian processes can highlight areas of the input space where prediction quality is poor, due to the lack of data or its complexity, by indicating the higher variance around the predicted mean. Gaussian process models contain noticeably less coefficients to be optimized. This paper illustrates possible application of Gaussian process models within model-based predictive control. The extra information provided within Gaussian process model is used in predictive control, where optimization of control signal takes the variance information into account. The predictive control principle is demonstrated on control of pH process benchmark

Gaussian Process priors with uncertain inputs? Application to multiple-step ahead time series forecasting

We consider the problem of multi-step ahead prediction in time series analysis using the non-parametric Gaussian process model. k-step ahead forecasting of a discrete-time non-linear dynamic system can be performed by doing repeated one-step ahead predictions. For a state-space model of the form y t = f(Yt-1 ,..., Yt-L ), the prediction of y at time t + k is based on the point estimates of the previous outputs. In this paper, we show how, using an analytical Gaussian approximation, we can formally incorporate the uncertainty about intermediate regressor values, thus updating the uncertainty on the current prediction

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway

Stress exposure triggers ligand-independent EGF receptor (EGFR) endocytosis, but its post-endocytic fate and role in regulating signalling are unclear. We show that the p38 MAP kinase-dependent, EGFR tyrosine kinase (TK)-independent EGFR internalization induced by ultraviolet light C (UVC) or the cancer therapeutic cisplatin, is followed by diversion from the canonical endocytic pathway. Instead of lysosomal degradation or plasma membrane recycling, EGFR accumulates in a subset of LBPA-rich perinuclear multivesicular bodies (MVBs) distinct from those carrying EGF-stimulated EGFR. Stress-internalized EGFR co-segregates with exogenously expressed pre-melanosomal markers OA1 and fibrillar PMEL, following early endosomal sorting by the actin polymerization-promoting WASH complex. Stress-internalized EGFR is retained intracellularly by continued p38 activity in a mechanism involving ubiquitin-independent, ESCRT/ALIX-dependent incorporation onto intraluminal vesicles (ILVs) of MVBs. In contrast to the internalization-independent EGF-stimulated activation, UVC/cisplatin-triggered EGFR activation depends on EGFR internalization and intracellular retention. EGFR signalling from this MVB subpopulation delays apoptosis and might contribute to chemoresistance

Cerebral and Peripheral Tissue Oxygenation in Children Supported on ECMO for Cardio-Respiratory Failure

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with cardio-respiratory failure. Establishing, maintaining and weaning from ECMO may increase the risk for intracranial injury. We used a dual channel near infrared system to monitor cerebral and peripheral tissue oxygenation in 3 venoarterial (VA) and 1 venovenous (VV) ECMO patients undergoing manipulations in the ECMO circuit flows. Spectral analysis was performed on the oxyhaemoglobin data collected from these patients with the aim of comparing oscillations at range of frequencies appearing in the two measurement sites