The connection between radio and high energy emission in black hole powered systems in the SKA era

Strong evidence exists for a highly significant correlation between the radio flux density and gamma-ray energy flux in blazars revealed by Fermi. However, there are central issues that need to be clarified in this field: what are the counterparts of the about 30% of gamma-ray sources that are as yet unidentified? Are they just blazars in disguise or they are something more exotic, possibly associated with dark matter? How would they fit in the radio-gamma ray connection studied so far? With their superb sensitivity, SKA1-MID and SKA1-SUR will help to resolve all of these questions. Even more, while the radio-MeV/GeV connection has been firmly established, a radio-VHE connection has been entirely elusive so far. The advent of CTA in the next few years and the expected CTA-SKA1 synergy will offer the chance to explore this connection, even more intriguing as it involves the opposite ends of the electromagnetic spectrum and the acceleration of particles up to the highest energies. We are already preparing to address these questions by exploiting data from the various SKA pathfinders and precursors. We have obtained 18 cm European VLBI Network observations of E>10 GeV sources, with a detection rate of 83%. Moreover, we are cross correlating the Fermi catalogs with the MWA commissioning survey: when faint gamma-ray sources are considered, pure positional coincidence is not significant enough for selecting counterparts and we need an additional physical criterion to pinpoint the right object. It can be radio spectral index, variability, polarization, or compactness, needing high angular resolution in SKA1-MID; timing studies can also reveal pulsars, which are often found from dedicated searches of unidentified gamma-ray sources. SKA will be the ideal instrument for investigating these characteristics in conjunction with CTA. (abridged)Comment: 12 pages, to be published in the proceedings of "Advancing Astrophysics with the Square Kilometre Array", PoS(AASKA14)15

A Fundamental Study of Spark Ignition for a Large-Bore Single Cylinder Natural Gas Engine

The natural gas industry has entered a substantial boom recently as the world seeks out more forms of inexpensive, reliable, and more environmentally friendly energy. Moving this natural gas requires a complex network of pipelines and compressors, including reciprocating engines, to keep the gas moving. These engines are of older design and must be retrofit with modern technologies to improve their performance as well as reduce the emissions that they produce. In this study a directed energy ignition system is tested on a two-stroke, single cylinder engine. Stability and emissions will be observed throughout a range of spark durations and currents for a single speed and load that allows for the most fuel-lean operation of the engine. The results from this study will be analyzed and discussed with Altronic LLC., so as to improve their directed energy ignition technologies. Many of the pipeline engines in use today lack many of the features found on more modern engines, being as many of the engines are between forty and seventy years old. A challenge under active research by those associated with these engines is in meeting emissions. One means of doing so is by running the engine with less fuel. To accomplish this an ignition system that can send more energy to the spark plug in a controlled manner is of great interest in optimizing for use on these engines. This research investigates a single operating speed and load for 9 different spark energy configurations. Engine operation at these test conditions will allow data of the emissions and engine performance to be assessed in contrast to standard ignition performance

Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents

DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 – DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 – DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents

Stationary Properties of a Randomly Driven Ising Ferromagnet

We consider the behavior of an Ising ferromagnet obeying the Glauber dynamics under the influence of a fast switching, random external field. Analytic results for the stationary state are presented in mean-field approximation, exhibiting a novel type of first order phase transition related to dynamic freezing. Monte Carlo simulations performed on a quadratic lattice indicate that many features of the mean field theory may survive the presence of fluctuations.Comment: 5 pages in RevTex format, 7 eps/ps figures, send comments to "mailto:[email protected]", submitted to PR

X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket

AbstractThe serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC50 values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding

Prikazi: Propovijedi sv. Antuna; Lendićevi "Božji kotači" u Zagrebu

Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect