The Plk1 Inhibitor BI 2536 Temporarily Arrests Primary Cardiac Fibroblasts in Mitosis and Generates Aneuploidy In Vitro

BI 2536 is a new anti-mitotic drug that targets polo-like kinase 1 (Plk1) and is currently under clinical development for cancer therapy. The effect of this drug on cancer cells has been extensively investigated, but information about the effects on primary dividing cells and differentiated non-dividing cells is scarce. We have investigated the effects of this drug on primary neonatal rat cardiac fibroblasts and on differentiated cardiomyocytes and explored the possibility to use this drug to enrich differentiated cell populations in vitro. BI 2536 had a profound effect on cardiac fibroblast proliferation in vitro and arrested these cells in mitosis with an IC50 of about 43 nM. Similar results were observed with primary human cells (HUVEC, IC50  = 30 nM), whereas the cancer cell line HeLa was more sensitive (IC50 of 9 nM). Further analysis revealed that prolonged mitotic arrest resulted in cell death for about 40% of cardiac fibroblasts. The remaining cells showed an interphase morphology with mostly multi- and micro-nucleated nuclei. This indicates that a significant number of primary fibroblasts are able to escape BI 2536 induced mitotic arrest and apparently become aneuploid. No effects were observed on cardiomyocytes and hypertrophic response (growth) upon endothelin-1 and phenylephrine stimulation was normal in the presence of BI 2536. This indicates that BI 2536 has no adverse effects on terminally differentiated cells and still allows proliferation independent growth induction in these cells. In conclusion, cardiomyocytes could be enriched using BI 2536, but the formation of aneuploidy in proliferating cells most likely limits this in vitro application and does not allow its use in putative cell based therapies

The smallest worthwhile effect of primary care physiotherapy did not differ across musculoskeletal pain sites

Objectives: To determine and compare estimates of the smallest worthwhile effect (SWE) for physiotherapy in neck, shoulder, and low-back pain patients and to investigate the influence of sociodemographic, clinical, and psychological factors on these estimates. Methods: A structured telephone interview was conducted before treatment was commenced in 160 patients referred for primary care physiotherapy. The benefit-harm trade-off method was used to estimate the SWE of physiotherapy for the following outcomes; pain, disability, and time to recovery, compared with the improvement achieved without any treatment (natural course). Regression analyses were used to assess the influence of sociodemographics, clinical variables, and intake scores on pain, disability, and psychological scales. Results: The median SWE for improvements on pain and disability was 20% (interquartile range 10%–30%), and the SWE for time to recovery was 10 days (interquartile range 7–14 days) over a period of 6 weeks. These estimates did not differ with respect to pain location (neck, shoulder, or back) and were generally unaffected by sociodemographic, clinical, and psychological factors. Conclusion: People with neck, shoulder, and low-back pain need to see at least 20% of additional improvement on pain and disability compared with natural recovery to consider that the effect of physiotherapy is worthwhile, given its costs, potential side effects, and inconveniences

5-axis double-flank CNC machining of spiral bevel gears via custom-shaped milling tools -- Part I: modeling and simulation

A new category of 5-axis flank computer numerically controlled (CNC) machining, called \emph{double-flank}, is presented. Instead of using a predefined set of milling tools, we use the shape of the milling tool as a free parameter in our optimization-based approach and, for a given input free-form (NURBS) surface, compute a custom-shaped tool that admits highly-accurate machining. Aimed at curved narrow regions where the tool may have double tangential contact with the reference surface, like spiral bevel gears, the initial trajectory of the milling tool is estimated by fitting a ruled surface to the self-bisector of the reference surface. The shape of the tool and its motion then both undergo global optimization that seeks high approximation quality between the input free-form surface and its envelope approximation, fairness of the motion and the tool, and prevents overcutting. That is, our double-flank machining is meant for the semi-finishing stage and therefore the envelope of the motion is, by construction, penetration-free with the references surface. Our algorithm is validated by a commercial path-finding software and the prototype of the tool for a specific gear model is 3D printed.RYC-2017-22649 BERC 2014-201

Molecular Dynamics Simulation Study of Nonconcatenated Ring Polymers in a Melt: I. Statics

Molecular dynamics simulations were conducted to investigate the structural properties of melts of nonconcatenated ring polymers and compared to melts of linear polymers. The longest rings were composed of N=1600 monomers per chain which corresponds to roughly 57 entanglement lengths for comparable linear polymers. For the rings, the radius of gyration squared was found to scale as N to the 4/5 power for an intermediate regime and N to the 2/3 power for the larger rings indicating an overall conformation of a crumpled globule. However, almost all beads of the rings are "surface beads" interacting with beads of other rings, a result also in agreement with a primitive path analysis performed in the following paper (DOI: 10.1063/1.3587138). Details of the internal conformational properties of the ring and linear polymers as well as their packing are analyzed and compared to current theoretical models.Comment: 15 pages, 14 figure

5-axis double-flank CNC machining of spiral bevel gears via custom-shaped tools – Part II: physical validations and experiments

Recently, a new methodology for 5-axis flank computer numerically controlled (CNC) machining, called double-flank machining, has been introduced (see “5-axis double-flank CNC machining of spiral bevel gears via custom-shaped milling tools–Part I: Modeling and simulation”). Certain geometries, such as curved teeth of spiral bevel gear, admit this approach where the machining tool has tangential contact with the material block on two sides, yielding a more efficient variant of flank machining. To achieve high machining accuracy, the path-planning algorithm, however, does not look only for the path of the tool, but also for the shape of the tool itself. The proposed approach is validated by series of physical experiments using an abrasive custom-shaped tool specifically designed for a particular type of a spiral bevel gear. The potential of this new methodology is shown in the semifinishing stage of gear manufacturing, where it outperforms traditional ball end milling by an order of magnitude in terms of machining time, while keeping, or even improving, the machining error.RYC-2017-22649 KK-2020/0010

Mapping of agricultural subsurface drainage systems using a frequency-domain ground penetrating radar and evaluating its performance using a single-frequency multi-receiver electromagnetic induction instrument

Subsurface drainage systems are commonly used to remove surplus water from the soil profile of a poorly drained farmland. Traditional methods for drainage mapping involve the use of tile probes and trenching equipment that are time-consuming, labor-intensive, and invasive, thereby entailing an inherent risk of damaging the drainpipes. Effective and efficient methods are needed in order to map the buried drain lines: (1) to comprehend the processes of leaching and offsite release of nutrients and pesticides and (2) for the installation of a new set of drain lines between the old ones to enhance the soil water removal. Non-invasive geophysical soil sensors provide a potential alternative solution. Previous research has mainly showcased the use of time-domain ground penetrating radar, with variable success, depending on local soil and hydrological conditions and the central frequency of the specific equipment used. The objectives of this study were: (1) to test the use of a stepped-frequency continuous wave three-dimensional ground penetrating radar (3D-GPR) with a wide antenna array for subsurface drainage mapping and (2) to evaluate its performance with the use of a single-frequency multi-receiver electromagnetic induction (EMI) sensor in-combination. This sensor combination was evaluated on twelve different study sites with various soil types with textures ranging from sand to clay till. While the 3D-GPR showed a high success rate in finding the drainpipes at five sites (sandy, sandy loam, loamy sand, and organic topsoils), the results at the other seven sites were less successful due to the limited penetration depth of the 3D-GPR signal. The results suggest that the electrical conductivity estimates produced by the inversion of apparent electrical conductivity data measured by the EMI sensor could be a useful proxy for explaining the success achieved by the 3D-GPR in finding the drain lines

Mapping subsurface drainage in agricultural areas using a frequency-domain ground penetrating radar

Artificial subsurface drainage systems are installed in agricultural areas to remove excess water and convert poorly naturally drained soils into productive cropland. Some of the most productive agricultural regions in the world are a result of subsurface drainage practices. Drain lines provide a shortened pathway for the release of nutrients and pesticides into the environment, which presents a potentially increased risk for eutrophication and contamination of surface water bodies. Knowledge of drain line locations is often lacking. This complicates the understanding of the local hydrology and solute dynamics and the consequent planning of mitigation strategies such as constructed wetlands, saturated buffers, bioreactors, and nitrate and phosphate filters. In addition, accurate knowledge of the existing subsurface drainage system is required in designing the installation of a new set of drain lines to enhance soil water removal efficiency. The traditional methods of drainage mapping involve the use of tile probes and trenching equipment which are time-consuming, tiresome, and invasive, thereby carrying an inherent risk of damaging the drain pipes. Non-invasive geophysical sensors provide a potential alternative solution to the problem. Previous research has focused on the use of time-domain ground penetrating radar (GPR) with variable success depending on local soil and hydrological conditions and the center frequency of the specific equipment used. For example, 250 MHz antennas proved to be more suitable for drain line mapping. Recent technological advancements enabled the collection of high-resolution spatially exhaustive data. In this study, we present the use of a stepped-frequency continuous wave (SFCW) 3D-GPR (GeoScope Mk IV 3D-Radar with DXG1820 antenna array) mounted in a motorized survey configuration with real-time georeferencing for subsurface drainage mapping. The 3D-GPR system offers more flexibility for application to different (sub)surface conditions due to the coverage of wide frequency bandwidth (60-3000 MHz). In addition, the wide array swathe of the antenna array (1.5 m covered by 20 measurement channels) enables effective coverage of three-dimensional (3D) space. The surveys were performed on twelve different study sites with various soil types with textures ranging from sand to clay till. While we achieved good success in finding the drainage pipes at five sites with sandy, sandy loam, loamy sand and organic topsoils, the results at the other seven sites with more clay-rich soils were less successful. The high attenuation of electromagnetic waves in highly conductive clay-rich soils, which limits the penetration depth of the 3D-GPR system, can explain our findings obtained in this research

A Stochastic Broadcast Pi-Calculus

In this paper we propose a stochastic broadcast PI-calculus which can be used to model server-client based systems where synchronization is always governed by only one participant. Therefore, there is no need to determine the joint synchronization rates. We also take immediate transitions into account which is useful to model behaviors with no impact on the temporal properties of a system. Since immediate transitions may introduce non-determinism, we will show how these non-determinism can be resolved, and as result a valid CTMC will be obtained finally. Also some practical examples are given to show the application of this calculus.Comment: In Proceedings QAPL 2011, arXiv:1107.074