Nuclear translocation and functions of growth factor receptors

Cellular signal transduction in response to environmental signals involves a relay of precisely regulated signal amplifying and damping events. A prototypical signaling relay involves ligands binding to cell surface receptors and triggering the activation of downstream enzymes to ultimately affect the subcellular distribution and activity of DNA-binding proteins that regulate gene expression. These so-called signal transduction cascades have dominated our view of signaling for decades. More recently evidence has accumulated that components of these cascades can be multifunctional, in effect playing a conventional role for example as a cell surface receptor for a ligand whilst also having alternative functions for example as transcriptional regulators in the nucleus. This raises new challenges for researchers. What are the cues/triggers that determine which role such proteins play? What are the trafficking pathways which regulate the spatial distribution of such proteins so that they can perform nuclear functions and under what circumstances are these alternative functions most relevant?

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas.

The sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit

The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways.

Exposure to children and risk of active trachoma in Tanzanian women

The authors surveyed the trachoma status of 515 women aged 18-60 years and 527 children aged 1-7 years in the trachoma hyperendemic region of Kongwa, Tanzania, in 1989 to further describe the importance of exposure to young children as a risk factor for active trachoma in women. The women were identified as caretakers, who currently cared for children aged 1-7 years; noncaretakers, who lived with, but did not care for, children aged 1-7; or those without children aged 1-7 in the household. The age-adjusted odds ratios for active trachoma seemed to rise with greater exposure to young children, from 1.00 for women without such children, to 1.63 for noncaretakers and 2.43 for caretakers (trend test, p = 0.08). Among those who lived in households with young children, the prevalence of active trachoma in women increased with the total number of young children cared for and with the number of infected children cared for. The prevalence of active trachoma was 40% (6 of 15) for caretakers of three or more infected children, compared with 0 (0 of 88) for caretakers with no infected children (p < 0.0001). Caring for infected children also appeared to be associated with signs of chronic trachoma in caretakers. Noncaretakers who lived with infected children were not at a significantly increased risk for trachoma compared with noncaretakers who were not exposed to such children (5.4% (three of 56) vs. 5.6% (one of 18); p > 0.4). None of the facial signs observed in the children (flies on the face, nasal discharge, etc.) appeared to increase the odds ratio of active trachoma in caretakers beyond the increase associated with trachoma alone in the child. These data support the hypothesis that active disease in women is associated with direct caretaking of young children with active disease. Strategies that interrupt household transmission may affect the binding sequelae of trachoma in women.

Self correction of refractive error among young people in rural China: results of cross sectional investigation.

OBJECTIVE: To compare outcomes between adjustable spectacles and conventional methods for refraction in young people. DESIGN: Cross sectional study. SETTING: Rural southern China. PARTICIPANTS: 648 young people aged 12-18 (mean 14.9 (SD 0.98)), with uncorrected visual acuity ≤ 6/12 in either eye. INTERVENTIONS: All participants underwent self refraction without cycloplegia (paralysis of near focusing ability with topical eye drops), automated refraction without cycloplegia, and subjective refraction by an ophthalmologist with cycloplegia. MAIN OUTCOME MEASURES: Uncorrected and corrected vision, improvement of vision (lines on a chart), and refractive error. RESULTS: Among the participants, 59% (384) were girls, 44% (288) wore spectacles, and 61% (393/648) had 2.00 dioptres or more of myopia in the right eye. All completed self refraction. The proportion with visual acuity ≥ 6/7.5 in the better eye was 5.2% (95% confidence interval 3.6% to 6.9%) for uncorrected vision, 30.2% (25.7% to 34.8%) for currently worn spectacles, 96.9% (95.5% to 98.3%) for self refraction, 98.4% (97.4% to 99.5%) for automated refraction, and 99.1% (98.3% to 99.9%) for subjective refraction (P = 0.033 for self refraction v automated refraction, P = 0.001 for self refraction v subjective refraction). Improvements over uncorrected vision in the better eye with self refraction and subjective refraction were within one line on the eye chart in 98% of participants. In logistic regression models, failure to achieve maximum recorded visual acuity of 6/7.5 in right eyes with self refraction was associated with greater absolute value of myopia/hyperopia (P<0.001), greater astigmatism (P = 0.001), and not having previously worn spectacles (P = 0.002), but not age or sex. Significant inaccuracies in power (≥ 1.00 dioptre) were less common in right eyes with self refraction than with automated refraction (5% v 11%, P<0.001). CONCLUSIONS: Though visual acuity was slightly worse with self refraction than automated or subjective refraction, acuity was excellent in nearly all these young people with inadequately corrected refractive error at baseline. Inaccurate power was less common with self refraction than automated refraction. Self refraction could decrease the requirement for scarce trained personnel, expensive devices, and cycloplegia in children's vision programmes in rural China.

Laser-driven x-ray and neutron source development for industrial applications of plasma accelerators

Pulsed beams of energetic x-rays and neutrons from intense laser interactions with solid foils are promising for applications where bright, small emission area sources, capable of multi-modal delivery are ideal. Possible end users of laser-driven multi-modal sources are those requiring advanced non-destructive inspection techniques in industry sectors of high value commerce such as aerospace, nuclear and advanced manufacturing. We report on experimental work that demonstrates multi-modal operation of high power laser-solid interactions for neutron and x-ray beam generation. Measurements and Monte Carlo radiation transport simulations show that neutron yield is increased by a factor ∼2 when a 1 mm copper foil is placed behind a 2 mm lithium foil, compared to using a 2 cm block of lithium only. We explore x-ray generation with a 10 picosecond drive pulse in order to tailor the spectral content for radiography with medium density alloy metals. The impact of using >1 ps pulse duration on laser-accelerated electron beam generation and transport is discussed alongside the optimisation of subsequent bremsstrahlung emission in thin, high atomic number target foils. X-ray spectra are deconvolved from spectrometer measurements and simulation data generated using the GEANT4 Monte Carlo code. We also demonstrate the unique capability of laser-driven x-rays in being able to deliver single pulse high spatial resolution projection imaging of thick metallic objects. Active detector radiographic imaging of industrially relevant sample objects with a 10 ps drive pulse is presented for the first time, demonstrating that features of 200 μm size are resolved when projected at high magnification.

Inexact-aware architecture design for ultra-low power bio-signal analysis

This study introduces an inexact, but ultra-low power, computing architecture devoted to the embedded analysis of bio-signals. The platform operates at extremely low voltage supply levels to minimise energy consumption. In this scenario, the reliability of static RAM (SRAM) memories cannot be guaranteed when using conventional 6-transistor implementations. While error correction codes and dedicated SRAM implementations can ensure correct operations in this near-threshold regime, they incur in significant area and energy overheads, and should therefore be employed judiciously. Herein, the authors propose a novel scheme to design inexact computing architectures that selectively protects memory regions based on their significance, i.e. their impact on the end-to-end quality of service, as dictated by the bio-signal application characteristics. The authors illustrate their scheme on an industrial benchmark application performing the power spectrum analysis of electrocardiograms. Experimental evidence showcases that a significance-based memory protection approach leads to a small degradation in the output quality with respect to an exact implementation, while resulting in substantial energy gains, both in the memory and the processing subsystem.

Heterogeneous error-resilient scheme for spectral analysis in ultra-low power wearable electrocardiogram devices

Wearable devices performing advanced bio-signal analysis algorithms are aimed to foster a revolution in healthcare provision of chronic cardiac diseases. In this context, energy efficiency is of paramount importance, as long-term monitoring must be ensured while relying on a tiny power source. Operating at a scaled supply voltage, just above the threshold voltage, effectively helps in saving substantial energy, but it makes circuits, and especially memories, more prone to errors, threatening the correct execution of algorithms. The use of error detection and correction codes may help to protect the entire memory content, however it incurs in large area and energy overheads which may not be compatible with the tight energy budgets of wearable systems. To cope with this challenge, in this paper we propose to limit the overhead of traditional schemes by selectively detecting and correcting errors only in data highly impacting the end-to-end quality of service of ultra-low power wearable electrocardiogram (ECG) devices. This partition adopts the protection of either significant words or significant bits of each data element, according to the application characteristics (statistical properties of the data in the application buffers), and its impact in determining the output. The proposed heterogeneous error protection scheme in real ECG signals allows substantial energy savings (11% in wearable devices) compared to state-of-the-art approaches, like ECC, in which the whole memory is protected against errors. At the same time, it also results in negligible output quality degradation in the evaluated power spectrum analysis application of ECG signals.

Evaluation of the human factor in the scheduling of smart appliances in smart grids

Recently there has been an increase of interest in implementing a new set of home appliances, known as Smart Appliances that integrate Information Technologies, the Internet of Things and the ability of communicating with other devices. While Smart Appliances are characterized as an important milestone on the path to the Smart Grid, by being able to automatically schedule their loads according to a tariff or reflecting the power that is generated using renewable sources, there is not a clear understanding on the impact that the behavior of such devices will have in the comfort levels of users, when they shift their working periods to earlier, or later than, a preset time. Given these considerations, in this work we analyse the results of an assessment survey carried out to a group of Home Appliance users regarding their habits when dealing with these machines and the subjective impact in quality caused by either finishing its programs before or after the time limit set by the user. The results of this work are expected to be used as input for the evaluation of load scheduling algorithms running in energy management systems. © 2014 Springer International Publishing.

Understanding the Patient Experience Through the Power of Film: a Mixed Method Qualitative Research Project

Film is a highly attractive teaching instrument for the study of different terminal diseases, exploring bioethics (Beauchamp and Childress, 2009) and is a preferred medium over traditional lectures (Edmunds, 2013) to provide realistic examples for adult learners. It can tap into ethical issues; facilitate decision-making; and examine underlying issues such as euthanasia; assisted suicide; and professional responsibility. Contrast this with standard means of teaching, such as scenarios- although a useful pedagogic tool, these are limited because students must imagine the clinical scenario. Film can fill that imaginative gap (Volandes, 2007). It can be utilised as an active teaching strategy for a variety of topics in nursing (Edmunds, 2013) providing a unique way to promote active learning in nursing education (Herrman, 2006). The objectives of the study, aim to help pre registration student nurses from each year of study to engage with their role as health care professionals; provide open discussion and debate on how they view the personal experience of illness/disease/disability/death and to reflect on their role and provision of patient care. It is delivered in 3 tiers to provide a range of data for thematic analysis; 1) Film screening followed by a ‘5 minute reaction’ discussion and post screening questionnaire; 2) Pre screening guided activities for reflection and discussion; 3) Focus groups. This project meets identified aims from the UK Professional Standards Framework (UKPSF) by fostering creative and innovative approaches to teaching and learning; facilitating and supporting the design and delivery of continuing education development programmes and activities; and demonstrates professionalism that staff and institutions bring to teaching. Preliminary feedback and themes will be presented.

Perceived Social Pressures and the Internalization of the Mesomorphic Ideal: the Role of Drive for Muscularity and Autonomy in Physically Active Men

BACKGROUND: Researchers have tested the beliefs of sportspeople and sports medicine specialists that cognitive strategies influence strength performance. Few investigators have synthesised the literature. OBJECTIVES: The specific objectives were to review evidence regarding (a) the cognitive strategy-strength performance relationship; (b) participant skill level as a moderator; and (c) cognitive, motivational, biomechanical/physiological, and emotional mediators. METHOD: Studies were sourced via electronic databases, reference lists of retrieved articles, and manual searches of relevant journals. Studies had to be randomised or counterbalanced experiments with a control group or condition, repeated measures, and a quality control score above 0.5 (out of 1). Cognitive strategies included goal setting, imagery, self-talk, preparatory arousal, and free choice. Dependent variables included maximal strength, local muscular endurance, or muscular power. RESULTS: Globally, cognitive strategies were reliability associated with increased strength performance (results ranged from 61 to 65 %). Results were mixed when examining the effects of specific strategies on particular dependent variables, although no intervention had an overall negative influence. Indeterminate relationships emerged regarding hypothesised mediators (except cognitive variables) and participant skill level as a moderator. CONCLUSIONS: Although cognitive strategies influence strength performance, there are knowledge gaps regarding specific types of strength, especially muscular power. Cognitive variables, such as concentration, show promise as possible mediators.

Virtual power players demand response programs management based on locational marginal prices

Power systems have been suffering huge changes mainly due to the substantial increase of distributed generation and to the operation in competitive environments. Virtual power players can aggregate a diversity of players, namely generators and consumers, and a diversity of energy resources, including electricity generation based on several technologies, storage and demand response. Resource management gains an increasing relevance in this competitive context, while demand side active role provides managers with increased demand elasticity. This makes demand response use more interesting and flexible, giving rise to a wide range of new opportunities.This paper proposes a methodology for managing demand response programs in the scope of virtual power players. The proposed method is based on the calculation of locational marginal prices (LMP). The evaluation of the impact of using demand response specific programs on the LMP value supports the manager decision concerning demand response use. The proposed method has been computationally implemented and its application is illustrated in this paper using a 32 bus network with intensive use of distributed generation.

Energy resource scheduling in a real distribution network managed by several virtual power players

Smart Grids (SGs) appeared as the new paradigm for power system management and operation, being designed to integrate large amounts of distributed energy resources. This new paradigm requires a more efficient Energy Resource Management (ERM) and, simultaneously, makes this a more complex problem, due to the intensive use of distributed energy resources (DER), such as distributed generation, active consumers with demand response contracts, and storage units. This paper presents a methodology to address the energy resource scheduling, considering an intensive use of distributed generation and demand response contracts. A case study of a 30 kV real distribution network, including a substation with 6 feeders and 937 buses, is used to demonstrate the effectiveness of the proposed methodology. This network is managed by six virtual power players (VPP) with capability to manage the DER and the distribution network.

Combined heat and power and consumption optimization in a SCADA-based system

The operation of power systems in a Smart Grid (SG) context brings new opportunities to consumers as active players, in order to fully reach the SG advantages. In this context, concepts as smart homes or smart buildings are promising approaches to perform the optimization of the consumption, while reducing the electricity costs. This paper proposes an intelligent methodology to support the consumption optimization of an industrial consumer, which has a Combined Heat and Power (CHP) facility. A SCADA (Supervisory Control and Data Acquisition) system developed by the authors is used to support the implementation of the proposed methodology. An optimization algorithm implemented in the system in order to perform the determination of the optimal consumption and CHP levels in each instant, according to the Demand Response (DR) opportunities. The paper includes a case study with several scenarios of consumption and heat demand in the context of a DR event which specifies a maximum demand level for the consumer.

Multi-agent electricity market simulation with dynamic strategies & virtual power producers

Distributed energy resources will provide a significant amount of the electricity generation and will be a normal profitable business. In the new decentralized grid, customers will be among the many decentralized players and may even help to co-produce the required energy services such as demand-side management and load shedding. So, they will gain the opportunity to be more active market players. The aggregation of DG plants gives place to a new concept: the Virtual Power Producer (VPP). VPPs can reinforce the importance of these generation technologies making them valuable in electricity markets. In this paper we propose the improvement of MASCEM, a multi-agent simulation tool to study negotiations in electricity spot markets based on different market mechanisms and behavior strategies, in order to take account of decentralized players such as VPP.