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The transforming growth factor-beta (TGFB) plays an essential role in the pathogenesis of some ophthalmologic diseases, including neovascular age-related macular degeneration (nAMD) and proliferative vitreoretinopathy (PVR). TGFB activates the transcription factors SMAD2 and SMAD3 via the TGFB receptor, which together activate several genes, including VEGFA. TGFB treated ARPE-19 cells show an increased proliferation rate and undergo epithelial to mesenchymal transition (EMT). Since microRNAs (miRNAs) are capable of inhibiting the translation of multiple genes, we screened for miRNAs that regulate the TGFB signalling pathways at multiple levels. In this study, we focused on two miRNAs, miR-302d and miR-93, which inhibit TGFB signalling pathway and therefore TGFB-induced EMT transition as well as VEGFA secretion from ARPE-19 cells. Furthermore, we could show that both miRNAs can retransform TGFB-stimulated mesenchymal ARPE-19 cells towards the morphological epithelial-like state. Taken together, transient overexpression of these miRNAs in RPE cells might be a promising approach for further translational strategies.

Background: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness. Methods: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1

In the present study, a porous meniscal-shaped scaffold consisting of polyurethane (PU)-based 1, 4-butanediisocyanate (BDI), which provided a 3-D culture condition for human bone mesenchymal stromal cells (hBMSC) was employed. A bioreactor was utilized to produce perfusion and mechanical stimulations. The viability, proliferation and fibro-cartilaginous differentiation of the hBMSC cultured on the PU-based meniscal scaffold were investigated during the perfusion and mechanical stimulation process. In addition, the mechanical properties of the cell-laden scaffolds were examined as well. Our finding indicated that the perfusion (10 ml/min) and on-off cyclic compressions mechanical stimulation (10% strain, 0.5 Hz, 4 times/day, 2 h/time with 4 h of rest thereafter) maintained the viability and promoted the proliferation of hBMSC over 2 weeks. The on-off cyclic compression caused a 1.85 fold increase in equilibrium modulus. Meanwhile, type I procollagen produced by hBMSC was increased for 3.02-fold after 2 weeks culture. On the other hand, the irrigating medium enhanced the synthesis of type III procollagen for 2.24-fold after 2 weeks. Tensile modulus was elevated for 2.02-fold in perfusion group after 1 week, which was decreased after 2 weeks unexpectedly. Our study suggests that the perfusion and on-off compression are promising to enhance the functional properties of the hBMSC-laden PU-based meniscal scaffold.

Snow and weather observations at Weissfluhjoch were initiated in 1936, when a research team set a snow stake and started digging snow pits on a plateau located at 2,540 m asl above Davos, Switzerland. This was the beginning of what is now the longest series of daily snow depth, new snow height and bi-monthly snow water equivalent measurements from a high-altitude research station. Our investigations reveal that the snow depth at Weissfluhjoch with regard to the evolution and inter-annual variability represents a good proxy for the entire Swiss Alps. In order to set the snow and weather observations from Weissfluhjoch in a broader context, this paper also shows some comparisons with measurements from five other high-altitude observatories in the European Alps. The results show a surprisingly uniform warming of 0.8°C during the last three decades at the six investigated mountain stations. The long-term snow measurements reveal no change in mid-winter, but decreasing trends (especially since the 1980s) for the solid precipitation ratio, snow fall, snow water equivalent and snow depth during the melt season due to a strong temperature increase of 2.5°C in the spring and summer months of the last three decades.

Snow avalanche case reports have documented the survival of skiers apparently without permanent hypoxic sequelae, after prolonged complete burial despite there being only a small air pocket on extrication. We investigated the underlying pathophysiological changes in a prospective, randomised 2 x 2 crossover study in 12 volunteers (28 tests) breathing into an artificial air pocket (1- or 2-l volume) in snow. Peripheral SpO(2), ETCO(2), arterialised capillary blood variables, air pocket O(2) and CO(2), snow density, and snow conditions at the inner surface of the air pocket were determined. SpO(2) decreased from a median of 99% (93-100%) to 88% (71-94%; P

We report measurements of the anchoring energy of 5CB (4-cyano-4′-n-pentyl-biphenyl) at a commercial polyimide (AL1051) with a method using a large applied electric field on thick measurement cells. The experiments reveal a deviation from the expected behavior of the system and cannot be described by the usual Frank elastic bulk energy density plus anchoring surface energy within the thermodynamic limit. We, therefore, discuss the effect of a surface electric field coupled to director distortions by the flexoelectric effect. Numerical calculations show, indeed, that the experiments can be described reasonably by the model. Experiments for thin cells indicate that the Debye screening length does not depend on the cell thickness. We derive an easy way to get an estimate of the Debye screening length from the experiments.

We report second harmonic generation (SHG) measurements of rubbed and unrubbed surfaces of the fluorinated main-chain polyimide PMDA/BDAF made from pyromellitic dianhydride (PMDA) and 2,2-bis[4-(4-aminophenoxy)phenyl]hexafluoropropane (BDAF). Such rubbed polymers are commonly used as alignment materials for the nematic phases of liquid crystal display cells (LCD), although the rubbing process itself is not yet well understood. The SHG results are used to construct the full orientational distribution function of the noncentrosymmetric part of the polymer. This allows us to determine the preferred conformations of the polyimide at the surface and gives insight into the conformational changes of the polymer during rubbing.

Adataset of daily avalanche activity observed consistently for 14 years in the surroundings of Zuoz in the Engadine valley (eastern Swiss Alps) is analyzed. All medium-sized and larger avalanches had been mapped by the local snow and avalanche observer. They were digitized into a geographic information system (GIS) and linked to the daily snow and avalanche observations. Thus the avalanche activity and its spatial distribution could be analyzed and visualized. A classification for avalanche size and avalanche activity is proposed. In 52% of the potential starting zones an avalanche is released at least once in 14 years. The avalanche area decreases strongly with the frequency of avalanche occurrence. Preliminary analysis of the relation of daily avalanche activity to weather, snow and snow cover revealed a wide variety of contributory factors. Even for large amounts of new snow, snow-cover conditions prior to snowfall or temperature evolution might decide the extent of the avalanche activity. For six examples, the avalanche hazard (five degree European scale) is visualized by means of avalanche activity. The GIS approach will be followed to build a tool for local avalanche forecasting in Zuoz.

Articular cartilage is a relatively simple tissue, but has a limited capacity of restoration. Tissue engineering is a promising field that seeks to accomplish the in vitro generation of complex, functional, 3-dimensional tissues. Various cell types and scaffolds have been tested for these purposes. The results of tissue engineered cartilage and bone are as yet inferior to native tissue. Strain and perfusion have been shown to stimulate cell proliferation and differentiation of various cell phenotypes. The perfect protocol to produce articular cartilage has not been defined yet. Bioreactors could provide the environment to engineer osteochondral constructs in vitro and to provide a stress protocol. The bioreactor has to provide an economically viable approach to automated manufacture of functional grafts under clinical aspects. Composite engineered tissues, like an engineered joint, represent a future goal. Cross-disciplinary approaches are necessary in order to succeed in engineering osteochondral grafts that provide adequate primary biomechanical stability and incorporate rapidly in vivo with histological appearance close to healthy osteochondral tissue. This review surveys current clinical and experimental concepts and discusses challenges and future expectations in this advancing field of regenerative medicine focusing human osteochondral constructs in bioreactors.

The Vibrio cholerae transcriptional regulator ToxR is anchored in the cytoplasmic membrane by a single transmembrane segment, its C-terminal domain facing the periplasm. Most of its N-terminal cytoplasmic domain shares sequence similarity with the winged helix-turn-helix (wHTH) motif of OmpR-like transcriptional regulators. In the heterologous host Escherichia coli ToxR activates transcription at the V.cholerae ctx promoter in a dimerization-dependent manner, which has led to its employment as a genetic indicator for protein-protein interactions. However, although offering a broader potential application range than other prokaryotic two-hybrid systems described to date, ToxR has so far only been used to study interactions between heterologous transmembrane segments or to monitor homodimerization of C-terminal fusion partners in the periplasm and the cytoplasm of E.coli. Here we show that the ToxR-system also allows the detection of heterodimerization in both cellular compartments of E.coli. In addition, to better understand ToxR's mode of action at ctx in E.coli, we have investigated the minimal requirements for its function as a transcriptional activator. We show that the wHTH motif of ToxR's N-terminal domain constitutes the minimal structural element required to activate transcription at ctx in E.coli when fused to a dimerizing protein module.

Objectives: The aim of the present study was to generate a tissue engineered type of mechanically stable graft suitable for surgical replacement of the tunica albuginea penis. Methods: Porcine fibroblasts isolated from open fascia biopsies were seeded on decellularized collagen matrices and then cultivated in a bioreactor under continuous multiaxial stress for up to 21 days ( n =12). Static cultures without mechanical stress served as controls. Cell proliferation, cell alignment, and de novo synthesis of extracellular matrix proteins (proteoglycans, procollagen I, elastin) in these grafts was evaluated by hematoxylin-eosin, pentachrome, and immuno-staining. Additionally, the enzymatic isolation of porcine fibroblasts from O4 mm skin punch biopsies ( n =8) was evaluated. Results: Mechanically strained cultures of fibroblasts showed a homogeneous multilayer matrix infiltration and a regular cell alignment in the direction of strain axis after 7 days, as well as a de novo production of extracellular matrix proteins compared to the static control. A large amount of viable fibroblasts was easily obtained from small skin punch biopsies. Conclusion: This study shows that continuous multiaxial stimuli improve proliferation and extracellular matrix synthesis of mature fibroblasts reseeded on a biological matrix making this a feasible autologous tissue engineered graft for penile surgery. For the clinical setting fibroblasts harvested from small skin biopsies can be a comfortable cell source.

Avalanche Warning has been a key task of the Swiss Federal Institute for Snow and Avalanche Research in Davos (SLF) since it was established over half a century ago. In the past, the predominant methods used for avalanche forecasting at SLF have been conventional, i.e., snow stability and avalanche hazards were predicted without analytical techniques such as formal numerical and symbolic algorithms. A paradigm shift is currently taking place. Information systems and computer programmes are becoming more and more important, assisting the forecaster in collecting and analysing large amounts of field data. Furthermore, computer models are available which simulate processes in the snow cover and calculate local and regional avalanche hazards, thereby supporting forecasters and decision makers. However, the forecaster with his intuition, experience and local knowledge still plays a decisive role in the forecasting process. While the computer helps to assimilate information, to assess the hazard risks, to support the forecaster in his decision and to distribute forecasts via modern communication channels, it is still the forecasters ultimate responsibility to check and modify the computer’s prediction. This new way of avalanche forecasting, which we call ‘computer-aided avalanche forecasting’, is currently being implemented in Switzerland.

Experiments at Weissfluhjoch, Davos, Switzerland, compared mass flux measured by rocket-shaped snowdrift gages (modified Mellor traps), with gages made of porous filter fabric, and with several electronic systems. A new method of electronic analysis gave results similar to the mass flux measured by mechanical traps. The experiments also reexamined the vertical profile of drift flux in the vicinity of the ridge crest, confirming the flux maximum at about 1 m height above the ridge crest, and adding details near the surface. Profiles measured at a secondary change in the windward ridge face, within a few meters of the crest, showed only a slight maximum, supporting the view that the drift flux maximum develops near the crest.

During several winters the positions and magnitudes of excess snow deposits or denudation zones caused by wind have been evaluated on the flanks of regular, elongated mountain ridges. The surveys were carried out by conventional measurements of mass balance. According to angle of slope (10 to 35°), shape of crest (hump- or wedge-shaped) and orientation to the wind, various patterns of snow deposition may be found. It is shown that, on ridges oriented perpendicularly to the main wind direction (north-west) during snow storms, near-periodic snow deposits may be expected on the lee slope. On the windward side, there is a denudation zone near the crest. The measurements indicate that lee slopes, of mean slope angle, are buried in mid-winter under twice as much snow as the adjacent windward slopes. However, the ridge system as a whole accumulates the same amounts of snow as do areas of flat terrain. Theoretical approximations based on theories of potential flow and semi-empi rical plume models are used to simulate the presumed dispersion of snow. The model calculations, intended as diagnostic tools, suggest that snow may be diffused and deposited on lee slopes in a plume-like manner similar to other particulate matter. Snowfall, together with low-level blowing snow as an additional source of suspended particles, appears to increase the snow deposits, mainly on the foot of steeper ridges.