Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

Evolution of an eruptive flare loop system

<p><b>Context:</b> Flares, eruptive prominences and coronal mass ejections are phenomena where magnetic reconnection plays an important role. However, the location and the rate of the reconnection, as well as the mechanisms of particle interaction with ambient and chromospheric plasma are still unclear.</p> <p><b>Aims:</b> In order to contribute to the comprehension of the above mentioned processes we studied the evolution of the eruptive flare loop system in an active region where a flare, a prominence eruption and a CME occurred on August 24, 2002.</p> <p><b>Methods:</b> We measured the rate of expansion of the flare loop arcade using TRACE 195 Å images and determined the rising velocity and the evolution of the low and high energy hard X-ray sources using RHESSI data. We also fitted HXR spectra and considered the radio emission at 17 and 34 GHZ.</p> <p><b>Results:</b> We observed that the top of the eruptive flare loop system initially rises with a linear behavior and then, after 120 mn from the start of the event registered by GOES at 1–8 Å, it slows down. We also observed that the heating source (low energy X-ray) rises faster than the top of the loops at 195 Å and that the high energy X-ray emission (30–40 keV) changes in time, changing from footpoint emission at the very onset of the flare to being coincident during the flare peak with the whole flare loop arcade.</p> <p><b>Conclusions:</b> The evolution of the loop system and of the X-ray sources allowed us to interpret this event in the framework of the Lin & Forbes model (2000), where the absolute rate of reconnection decreases when the current sheet is located at an altitude where the Alfvén speed decreases with height. We estimated that the lower limit for the altitude of the current sheet is km. Moreover, we interpreted the unusual variation of the high energy HXR emission as a manifestation of the non thermal coronal thick-target process which appears during the flare in a manner consistent with the inferred increase in coronal column density.</p&gt

The global oscillation network group site survey. II. Results

The Global Oscillation Network Group (GONG) Project will place a network of instruments around the world to observe solar oscillations as continuously as possible for three years. The Project has now chosen the six network sites based on analysis of survey data from fifteen sites around the world. The chosen sites are: Big Bear Solar Observatory, California; Mauna Loa Solar Observatory, Hawaii; Learmonth Solar Observatory, Australia; Udaipur Solar Observatory, India; Observatorio del Teide, Tenerife; and Cerro Tololo Interamerican Observatory, Chile. Total solar intensity at each site yields information on local cloud cover, extinction coefficient, and transparency fluctuations. In addition, the performance of 192 reasonable components analysis. An accompanying paper describes the analysis methods in detail; here we present the results of both the network and individual site analyses. The selected network has a duty cycle of 93.3%, in good agreement with numerical simulations. The power spectrum of the network observing window shows a first diurnal sidelobe height of 3 × 10⁻⁴ with respect to the central component, an improvement of a factor of 1300 over a single site. The background level of the network spectrum is lower by a factor of 50 compared to a single-site spectrum

Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases

The global oscillation network group site survey. II. Results

The Global Oscillation Network Group (GONG) Project will place a network of instruments around the world to observe solar oscillations as continuously as possible for three years. The Project has now chosen the six network sites based on analysis of survey data from fifteen sites around the world. The chosen sites are: Big Bear Solar Observatory, California; Mauna Loa Solar Observatory, Hawaii; Learmonth Solar Observatory, Australia; Udaipur Solar Observatory, India; Observatorio del Teide, Tenerife; and Cerro Tololo Interamerican Observatory, Chile. Total solar intensity at each site yields information on local cloud cover, extinction coefficient, and transparency fluctuations. In addition, the performance of 192 reasonable components analysis. An accompanying paper describes the analysis methods in detail; here we present the results of both the network and individual site analyses. The selected network has a duty cycle of 93.3%, in good agreement with numerical simulations. The power spectrum of the network observing window shows a first diurnal sidelobe height of 3 × 10⁻⁴ with respect to the central component, an improvement of a factor of 1300 over a single site. The background level of the network spectrum is lower by a factor of 50 compared to a single-site spectrum

On the detection and tracking of space debris using the Murchison Widefield Array. I. Simulations and test observations demonstrate feasibility

The Murchison Widefield Array (MWA) is a new low-frequency interferometric radio telescope, operating in the benign radio frequency environment of remote Western Australia. The MWA is the low-frequency precursor to the Square Kilometre Array (SKA) and is the first of three SKA precursors to be operational, supporting a varied science mission ranging from the attempted detection of the Epoch of Reionization to the monitoring of solar flares and space weather. In this paper we explore the possibility that the MWA can be used for the purposes of Space Situational Awareness (SSA). In particular we propose that the MWA can be used as an element of a passive radar facility operating in the frequency range 87.5-108 MHz (the commercial FM broadcast band). In this scenario the MWA can be considered the receiving element in a bi-static radar configuration, with FM broadcast stations serving as non-cooperative transmitters. The FM broadcasts propagate into space, are reflected off debris in Earth orbit and are received at the MWA. The imaging capabilities of the MWA can be used to simultaneously detect multiple pieces of space debris, image their positions on the sky as a function of time and provide tracking data that can be used to determine orbital parameters. Such a capability would be a valuable addition to Australian and global SSA assets, in terms of southern and eastern hemispheric coverage. We provide a feasibility assessment of this proposal, based on simple calculations and electromagnetic simulations, that shows that the detection of sub-meter size debris should be possible (debris radius of >0.5 m to ∼1000 km altitude). We also present a proof-of-concept set of observations that demonstrate the feasibility of the proposal, based on the detection and tracking of the International Space Station via reflected FM broadcast signals originating in southwest Western Australia. These observations broadly validate our calculations and simulations. We discuss some significant challenges that need to be addressed in order to turn the feasible concept into a robust operational capability for SSA. The aggregate received power due to reflections off space debris in the FM band is equivalent to a <1 mJy increase in the background confusion noise for the long integrations needed for Epoch of Reionization experiments, which is insignificant

The development of the Australian Space Forecast Centre (ASFC)

The Ionospheric Prediction Service (IPS) was formed in 1947 to provide monthly prediction services for high frequency (HF) radio, in particular to support HF communications with the United Kingdom. It was quickly recognized that to be effective such a service also had to provide advice when ionospheric storms prevented HF communications from taking place. With the advent of the International Geophysical Year (IGY), short-term forecasts were also required for research programmes and the task of supplying the Australian input to these was given to Frank Cook, of the IPS, while Jack Turner, also of the IPS, supervised the generation of ionospheric maps to support high latitude HF communications. These two important IGY activities formed the platform on which all future IPS services would be built. This paper reviews the development of the Australian Space Forecast Centre (ASFC), which arose from these early origins