Developing combinatorial multi-component therapies (CMCT) of drugs that are more specific and have fewer side effects than traditional one drug therapies

Drugs designed for a specific target are always found to have multiple effects. Rather than hope that one bullet can be designed to hit only one target, nonlinear interactions across genomic and proteomic networks could be used to design Combinatorial Multi-Component Therapies (CMCT) that are more targeted with fewer side effects. We show here how computational approaches can be used to predict which combinations of drugs would produce the best effects. Using a nonlinear model of how the output effect depends on multiple input drugs, we show that an artificial neural network can accurately predict the effect of all 215 = 32,768 combinations of drug inputs using only the limited data of the output effect of the drugs presented one-at-a-time and pairs-at-a-time

Screening of diverse phytochemicals with Aurora Kinase C protein: An In Silico approach

Aurora Kinase C, a vital serine-threonine protein Kinase, is an important member of the Aurora Kinase protein family which plays an important role in mitosis is a part of Chromosomal Passenger Complex (CPC).  Aurora Kinase C over expression is found to be linked with several cancer cell lines which demonstrate its oncogenic involvement and activity. Aurora C over expression in certain cancer types makes it an important target to be considered for cancer therapeutics. The present research work focuses on the Aurora Kinase C as an important target for computational studies. The protein model of  Aurora Kinase C, as a proten target on docking with 1500 natural compounds (phytochemicals) reveals  the binding of the natural  ligand 3-beta,23,28-trihydroxy-12-oleanene 23-caffeate belonging to the terpenoid class with highest docking score. This best bound ligand with the protein Aurora Kinase C was chosen for further understanding their protein-ligand interactions at the the molecular level using the molecular dynamic simulation approach. Stability of the protein-ligand complex and its conformation helps in disclosing the potentiality of the best bound ligand to be further chosen as an important small molecule inhibitor that would help playing a lead role in further drug discovery process Keywords: Aurora Kinase C, Cancer, Phytochemicals, Docking, Molecular Dynamic

Radio Emission Reveals Inner Meter-Scale Structure of Negative Lightning Leader Steps

We use the Low Frequency Array (LOFAR) to probe the dynamics of the stepping process of negatively charged plasma channels (negative leaders) in a lightning discharge. We observe that at each step of a leader, multiple pulses of vhf (30-80 MHz) radiation are emitted in short-duration bursts (&lt;10 mu s). This is evidence for streamer formation during corona flashes that occur with each leader step, which has not been observed before in natural lightning and it could help explain x-ray emission from lightning leaders, as x rays from laboratory leaders tend to be associated with corona flashes. Surprisingly, we find that the stepping length is very similar to what was observed near the ground, however with a stepping time that is considerably larger, which as yet is not understood. These results will help to improve lightning propagation models, and eventually lightning protection models.</p

Determining Electric Fields in Thunderclouds With the Radiotelescope LOFAR

An analysis is presented of electric fields in thunderclouds using a recently proposed method based on measuring radio emission from extensive air shower events during thunderstorm conditions. This method can be regarded as a tomography of thunderclouds using cosmic rays as probes. The data cover the period from December 2011 till August 2014. We have developed an improved fitting procedure to be able to analyze the data. Our measurements show evidence for the main negative-charge layer near the −10° isotherm. This we have seen for a winter as well as for a summer cloud where multiple events pass through the same cloud and also the vertical component of the electric field could be reconstructed. On the day of measurement of some cosmic-ray events showing evidence for strong fields, no lightning activity was detected within 100 km distance. For the winter events, the top heights were between 5 and 6 km, while in the summer, typical top heights of 9 km were seen. Large horizontal components in excess of 70 kV/m of the electric fields are observed in the middle and top layers

Determining electric fields in thunderclouds with the radiotelescope LOFAR

An analysis is presented of electric fields in thunderclouds using a recently proposed method based on measuring radio emission from extensive air shower events during thunderstorm conditions. This method can be regarded as a tomography of thunderclouds using cosmic rays as probes. The data cover the period from December 2011 till August 2014. We have developed an improved fitting procedure to be able to analyze the data. Our measurements show evidence for the main negative-charge layer near the −10° isotherm. This we have seen for a winter as well as for a summer cloud where multiple events pass through the same cloud and also the vertical component of the electric field could be reconstructed. On the day of measurement of some cosmic-ray events showing evidence for strong fields, no lightning activity was detected within 100 km distance. For the winter events, the top heights were between 5 and 6 km, while in the summer, typical top heights of 9 km were seen. Large horizontal components in excess of 70 kV/m of the electric fields are observed in the middle and top layers

All-sky search for time-integrated neutrino emission from astrophysical sources with 7 years of IceCube data

Since the recent detection of an astrophysical flux of high energy neutrinos, the question of its origin has not yet fully been answered. Much of what is known about this flux comes from a small event sample of high neutrino purity, good energy resolution, but large angular uncertainties. In searches for point-like sources, on the other hand, the best performance is given by using large statistics and good angular reconstructions. Track-like muon events produced in neutrino interactions satisfy these requirements. We present here the results of searches for point-like sources with neutrinos using data acquired by the IceCube detector over seven years from 2008--2015. The discovery potential of the analysis in the northern sky is now significantly below $E_\nu^2d\phi/dE_\nu=10^{-12}\:\mathrm{TeV\,cm^{-2}\,s^{-1}}$, on average $38\%$ lower than the sensitivity of the previously published analysis of four years exposure. No significant clustering of neutrinos above background expectation was observed, and implications for prominent neutrino source candidates are discussed.Comment: 19 pages, 17 figures, 3 tables; ; submitted to The Astrophysical Journa

Neutrinos and Cosmic Rays Observed by IceCube

The core mission of the IceCube Neutrino observatory is to study the origin and propagation of cosmic rays. IceCube, with its surface component IceTop, observes multiple signatures to accomplish this mission. Most important are the astrophysical neutrinos that are produced in interactions of cosmic rays, close to their sources and in interstellar space. IceCube is the first instrument that measures the properties of this astrophysical neutrino flux, and constrains its origin. In addition, the spectrum, composition and anisotropy of the local cosmic-ray flux are obtained from measurements of atmospheric muons and showers. Here we provide an overview of recent findings from the analysis of IceCube data, and their implications on our understanding of cosmic rays.Comment: Review article, to appear in Advances in Space Research, special issue "Origins of Cosmic Rays

Lowering IceCube’s energy threshold for point source searches in the southern sky

Observation of a point source of astrophysical neutrinos would be a "smoking gun" signature of a cosmic-ray accelerator. While IceCube has recently discovered a diffuse flux of astrophysical neutrinos, no localized point source has been observed. Previous IceCube searches for point sources in the southern sky were restricted by either an energy threshold above a few hundred TeV or poor neutrino angular resolution. Here we present a search for southern sky point sources with greatly improved sensitivities to neutrinos with energies below 100 TeV. By selecting charged-current nu(mu) interacting inside the detector, we reduce the atmospheric background while retaining efficiency for astrophysical neutrino-induced events reconstructed with sub-degree angular resolution. The new event sample covers three years of detector data and leads to a factor of 10 improvement in sensitivity to point sources emitting below 100 TeV in the southern sky. No statistically significant evidence of point sources was found, and upper limits are set on neutrino emission from individual sources. A posteriori analysis of the highest-energy (similar to 100 TeV) starting event in the sample found that this event alone represents a 2.8 sigma deviation from the hypothesis that the data consists only of atmospheric background