Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF

Background Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor is the main target of current antiangiogenic treatment strategies in AMD. However, other growth factors, such as platelet-derived growth factor (PDGF) and placenta growth factor (PlGF), have a substantial impact on development of AMD. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells. Methods Primary human RPE cells were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reactions, immunohistochemistry and enzyme-linked immunosorbent assays. Results Light exposure decreased cell viability and increased expression and secretion of VEGF-A, PDGF-BB and PlGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 mu g/ml. Conclusion The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD

Validation of a small cough detector

Research question The assessment of cough frequency in clinical practice relies predominantly on the patient's history. Currently, objective evaluation of cough is feasible with bulky equipment during a brief time (i.e., hours up to one day). Thus, monitoring of cough has been rarely performed outside clinical studies. We developed a small wearable cough detector (SIVA-P3) that uses deep neural networks for the automatic counting of coughs. This study examined the performance of the SIVA-P3 in an outpatient setting. Methods We recorded cough epochs with SIVA-P3 over eight consecutive days in patients suffering from chronic cough. During the first 24 h, the detector was validated against cough events counted by trained human listeners. The wearing comfort and the device usage were assessed by a questionnaire. Results In total, 27 participants (50±14 years) with either chronic unexplained cough (n=12), COPD (n=4), asthma (n=5) or interstitial lung disease (n=6) were studied. During the daytime, the sensitivity of SIVA-P3 cough detection was 88.5±2.49%, and the specificity was 99.97±0.01%. During the night-time, the sensitivity was 84.15±5.04% and the specificity was 99.97±0.02%. The wearing comfort and usage of the device was rated as very high by most participants. Conclusion SIVA-P3 enables automatic continuous cough monitoring in an outpatient setting for objective assessment of cough over days and weeks. It shows comparable or higher sensitivity than other devices with fully automatic cough counting. Thanks to its wearing comfort and the high performance for cough detection, it has the potential for being used in routine clinical practice

Excess-noise-enhanced parametric down conversion

We calculate the influence of excess noise on parametric down conversion in an unstable optical parametric oscillator (OPO), using a quantum quasimode description. We find a strongly enhanced pair photon generation rate below threshold as compared to a conventional stable cavity setup of comparable gain and loss. In addition, the oscillation threshold is lowered due to the influence of the excess noise and the squeezing properties of the emitted light are significantly changed. In general, the maximal quantum-noise suppression in one quadrature component is reduced, which poses strong limitations for the practical usefulness of a geometrically unstable OPO source. The analytical results from our quasimode description are in good agreement with numerical simulations using a positive-P representation of the field in mode space and in position space

Evidence for methane and ammonia in the coma of comet P/Halley

Methane and ammonia abundances in the coma of Halley are derived from Giotto IMS data using an Eulerian model of chemical and physical processes inside the contact surface to simulate Giotto HIS ion mass spectral data for mass-to-charge ratios (m/q) from 15 to 19. The ratio m/q = 19/18 as a function of distance from the nucleus is not reproduced by a model for a pure water coma. It is necessary to include the presence of NH_3 , and uniquely NH_3 , in coma gases in order to explain the data. A ratio of production rates Q(NH_3)/Q(H20) = 0.01-Q.02 results in model values approximating the Giotto data. Methane is identified as the most probable source of the distinct peak at m/q = 15. The observations are fit best with Q(CH_4)/Q(H_20) = 0.02. The chemical composition of the comet nucleus implied by these production rate ratios is unlike that of the outer planets. On the other hand, there are also significant differences from observations of gas phase interstellar material

THE ROLE OF INTERDEPENDENCE IN THE MICRO-FOUNDATIONS OF ORGANIZATION DESIGN: TASK, GOAL, AND KNOWLEDGE INTERDEPENDENCE

Interdependence is a core concept in organization design, yet one that has remained consistently understudied. Current notions of interdependence remain rooted in seminal works, produced at a time when managers’ near-perfect understanding of the task at hand drove the organization design process. In this context, task interdependence was rightly assumed to be exogenously determined by characteristics of the work and the technology. We no longer live in that world, yet our view of interdependence has remained exceedingly task-centric and our treatment of interdependence overly deterministic. As organizations face increasingly unpredictable workstreams and workers co-design the organization alongside managers, our field requires a more comprehensive toolbox that incorporates aspects of agent-based interdependence. In this paper, we synthesize research in organization design, organizational behavior, and other related literatures to examine three types of interdependence that characterize organizations’ workflows: task, goal, and knowledge interdependence. We offer clear definitions for each construct, analyze how each arises endogenously in the design process, explore their interrelations, and pose questions to guide future research

High throughput screening for discovery of materials that control stem cell fate

Insights into the complex stem cell niche have identified the cell–material interface to be a potent regulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this, materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicit specific cellular responses. To accelerate materials discovery, high throughput screening platforms have been designed which can rapidly evaluate combinatorial material libraries in two and three-dimensional environments. In this review, we present screening platforms for the discovery of material properties that influence stem cell behavior

Factors contributing to the quality of the junior-to-senior transition in Greek athletes

The aim of this study was to investigate which factors contribute to the quality of the junior-to-senior transition (JST) which includes adjustment to senior level, sport and life satisfaction in Greek athletes. The sample consisted of 177 aspiring young Greek athletes who were in the process of JST. Participants completed a Greek version of the Transition Monitoring Survey (TMS) developed by Stambulova et al. (Stambulova, N., Franck, A., & Weibull, F. (2012). Assessment of the transition from junior-to-senior sports in Swedish athletes. International Journal of Sport and Exercise Psychology, 10(2), 79–95). Multiple regressions were used to assess how key factors related to the JST contribute to the adjustment of athletes to senior level in sport, to their sport and life satisfaction. Results showed that personal resources (p

The effect of mechanical loading on osteogenesis of human dental pulp stromal cells in a novel in vitro model

Tooth loss often results in alveolar bone resorption because of lack of mechanical stimulation. Thus, the mechanism of mechanical loading on stem cell osteogenesis is crucial for alveolar bone regeneration. We have investigated the effect of mechanical loading on osteogenesis in human dental pulp stromal cells (hDPSCs) in a novel in vitro model. Briefly, 1 × 107 hDPSCs were seeded into 1 ml 3 % agarose gel in a 48-well-plate. A loading tube was then placed in the middle of the gel to mimic tooth-chewing movement (1 Hz, 3 × 30 min per day, n = 3). A non-loading group was used as a control. At various time points, the distribution of live/dead cells within the gel was confirmed by fluorescence markers and confocal microscopy. The correlation and interaction between the factors (e.g. force, time, depth and distance) were statistically analysed. The samples were processed for histology and immunohistochemistry. After 1-3 weeks of culture in the in-house-designed in vitro bioreactor, fluorescence imaging confirmed that additional mechanical loading increased the viable cell numbers over time as compared with the control. Cells of various phenotypes formed different patterns away from the reaction tube. The cells in the middle part of the gel showed enhanced alkaline phosphatase staining at week 1 but reduced staining at weeks 2 and 3. Additional loading enhanced Sirius Red and type I collagen staining compared with the control. We have thus successfully developed a novel in-house-designed in vitro bioreactor mimicking the biting force to enhance hDPSC osteogenesis in an agarose scaffold and to promote bone formation and/or prevent bone resorption

Real-time quantitative monitoring of hiPSC-based model of macular degeneration on Electric Cell-substrate Impedance Sensing microelectrodes

AbstractAge-related macular degeneration (AMD) is the leading cause of blindness in the developed world. Humanized disease models are required to develop new therapies for currently incurable forms of AMD.In this work, a tissue-on-a-chip approach was developed through combining human induced pluripotent stem cells, Electric Cell–substrate Impedance Sensing (ECIS) and reproducible electrical wounding assays to model and quantitatively study AMD. Retinal Pigment Epithelium (RPE) cells generated from a patient with an inherited macular degeneration and from an unaffected sibling were used to test the model platform on which a reproducible electrical wounding assay was conducted to model RPE damage. First, a robust and reproducible real-time quantitative monitoring over a 25-day period demonstrated the establishment and maturation of RPE layers on the microelectrode arrays. A spatially controlled RPE layer damage that mimicked cell loss in AMD disease was then initiated. Post recovery, significant differences (P<0.01) in migration rates were found between case (8.6±0.46μm/h) and control cell lines (10.69±0.21μm/h). Quantitative data analysis suggested this was achieved due to lower cell–substrate adhesion in the control cell line. The ECIS cell–substrate adhesion parameter (α) was found to be 7.8±0.28Ω1/2cm for the case cell line and 6.5±0.15Ω1/2cm for the control. These findings were confirmed using cell adhesion biochemical assays. The developed disease model-on-a-chip is a powerful platform for translational studies with considerable potential to investigate novel therapies by enabling real-time, quantitative and reproducible patient-specific RPE cell repair studies