Natural selection and genetic variation in a promising Chagas disease drug target: Trypanosoma cruzi trans-sialidase

Rational drug design is a powerful method in which new and innovative therapeutics can be designed based on knowledge of the biological target aiming to provide more efficacious and responsible therapeutics. Understanding aspects of the targeted biological agent is important to optimize drug design and preemptively design to slow or avoid drug resistance. Chagas disease, an endemic disease for South and Central America and Mexico is caused by Trypanosoma cruzi, a protozoan parasite known to consist of six separate genetic clusters or DTUs (discrete typing units). Chagas disease therapeutics are problematic and a call for new therapeutics is widespread. Many researchers are working to use rational drug design for developing Chagas drugs and one potential target that receives a lot of attention is the T. cruzi trans-sialidase protein. Trans-sialidase is a nuclear gene that has been shown to be associated with virulence. In T. cruzi, trans-sialidase (TcTS) codes for a protein that catalyzes the transfer of sialic acid from a mammalian host coating the parasitic surface membrane to avoid immuno-detection. Variance in disease pathology depends somewhat on T. cruzi DTU, as well, there is considerable genetic variation within DTUs. However, the role of TcTS in pathology variance among and within DTU’s is not well understood despite numerous studies of TcTS. These previous studies include determining the crystalline structure of TcTS as well as the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. In order to understand the role of natural selection in TcTS DNA sequence and protein variation, we sequenced 540 bp of the TcTS gene from 48 insect vectors. Because all 48 sequences had multiple polymorphic bases, we examined cloned sequences from two of the insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target

Particle Acceleration at Relativistic Shocks

I review the current status of Fermi acceleration theory at relativistic shocks. I first discuss the relativistic shock jump conditions, then describe the non-relativistic Fermi mechanism and the differences introduced by relativistic flows. I present numerical calculations of the accelerated particle spectrum, and examine the maximum energy attainable by this process. I briefly consider the minimum energy for Fermi acceleration, and a possible electron pre-acceleration mechanism.Comment: 17 pages, 4 figures. To appear in "Relativistic Flows in Astrophysics", A.W. Guthmann, M. Georganopoulos, A. Marcowith and K. Manolokou, eds., Lecture Notes in Pysics, Springer Verla

Highly charged ions in Penning traps, a new tool for resolving low lying isomeric states

The use of highly charged ions increases the precision and resolving power, in particular for short-lived species produced at on-line radio-isotope beam facilities, achievable with Penning trap mass spectrometers. This increase in resolving power provides a new and unique access to resolving low-lying long-lived ($T_{1/2} > 50$ ms) nuclear isomers. Recently, the $111.19(22)$ keV (determined from $\gamma$-ray spectroscopy) isomeric state in $^{78}$Rb has been resolved from the ground state, in a charge state of $q=8+$ with the TITAN Penning trap at the TRIUMF-ISAC facility. The excitation energy of the isomer was measured to be $108.7(6.4)$ keV above the ground state. The extracted masses for both the ground and isomeric states, and their difference, agree with the AME2003 and Nuclear Data Sheet values. This proof of principle measurement demonstrates the feasibility of using Penning trap mass spectrometers coupled to charge breeders to study nuclear isomers and opens a new route for isomer searches.Comment: 8 pages, 6 figure

X-Ray Observations of the supernova remnant G21.5-0.9

We present the analysis of archival X-ray observations of the supernova remnant (SNR) G21.5-0.9. Based on its morphology and spectral properties, G21.5-0.9 has been classified as a Crab-like SNR. In their early analysis of the CHANDRA calibration data, Slane et al. (2000) discovered a low-surface-brightness, extended emission. They interpreted this component as the blast wave formed in the supernova (SN) explosion. In this paper, we present the CHANDRA analysis using a total exposure of ~150 ksec. We also include ROSAT and ASCA observations. Our analysis indicates that the extended emission is non-thermal -- a result in agreement with XMM observations. The entire remnant of radius ~ 2'.5 is best fitted with a power law model with a photon index steepening away from the center. The total unabsorbed flux in the 0.5-10 keV is 1.1E-10 erg/cm2/s with an 85% contribution from the 40" radius inner core. Timing analysis of the High-Resolution Camera (HRC) data failed to detect any pulsations. We put a 16% upper limit on the pulsed fraction. We derive the physical parameters of the putative pulsar and compare them with those of other plerions (such as the Crab and 3C 58). G21.5-0.9 remains the only plerion whose size in X-rays is bigger than in the radio. Deep radio observations will address this puzzle.Comment: 23 pages including 11 figures and 3 tables; accepted by ApJ June 22, 2001; to appear in Oct 20, 2001 issue of Ap

Measurement of two-halo neutron transfer reaction p(11^{11}Li,9^{9}Li)t at 3AA MeV

The p(\nuc{11}{Li},\nuc{9}{Li})t reaction has been studied for the first time at an incident energy of 3$A$ MeV delivered by the new ISAC-2 facility at TRIUMF. An active target detector MAYA, build at GANIL, was used for the measurement. The differential cross sectionshave been determined for transitions to the \nuc{9}{Li} ground andthe first excited states in a wide range of scattering angles. Multistep transfer calculations using different \nuc{11}{Li} model wave functions, shows that wave functions with strong correlations between the halo neutrons are the most successful in reproducing the observation.Comment: 6 pages, 3 figures, submitted to Physical Review Letter

Trapped-ion decay spectroscopy towards the determination of ground-state components of double-beta decay matrix elements

A new technique has been developed at TRIUMF's TITAN facility to perform in-trap decay spectroscopy. The aim of this technique is to eventually measure weak electron capture branching ratios (ECBRs) and by this to consequently determine GT matrix elements of $\beta\beta$ decaying nuclei. These branching ratios provide important input to the theoretical description of these decays. The feasibility and power of the technique is demonstrated by measuring the ECBR of $^{124}$Cs.Comment: 9 pages, 9 figure

Implications of electron acceleration for high-energy radiation from gamma-ray bursts

In recent work we suggested that photons of energy >100 MeV detected from GRBs by the Fermi Satellite are produced via synchrotron emission in the external forward shock with a weak magnetic field - consistent with shock compressed upstream magnetic field of a few tens of micro-Gauss. Here we investigate whether electrons can be accelerated to energies such that they radiate synchrotron photons with energy up to about 10 GeV in this particular scenario. We do this using two methods: (i) we check if these electrons can be confined to the shock front; and (ii) we calculate radiative losses while they are being accelerated. We find that these electrons remain confined to the shock front, as long as the upstream magnetic field is >~ 10 micro-Gauss, and don't suffer substantial radiative losses, the only condition required is that the external reverse shock emission be not too bright: peak flux less than 1 Jy in order to produce photons of 100 MeV, and less than ~100 mJy for producing 1-GeV photons. We also find that the acceleration time for electrons radiating at 100 MeV is a few seconds (in observer frame), and the acceleration time is somewhat longer for electrons radiating at a few GeV. This could explain the lack of >100 MeV photons for the first few seconds after the trigger time for long GRBs reported by the Fermi Satellite, and also the slight lag between photons of GeV and 100 MeV energies. We model the onset of the external forward shock light curve in this scenario and find it consistent with the sharp rise observed in the 100-MeV light curve of GRB080916C and similar bursts.Comment: 7 pages, 1 figure. Minor changes; Accepted for publication in MNRA

Swift observations of the very intense flaring activity of Mrk 421 during 2006: I. Phenomenological picture of electron acceleration and predictions for the MeV/GeV emission

We present results from a deep spectral analysis of all the Swift observations of Mrk 421 from April 2006 to July 2006, when it reached its largest X-ray flux recorded until 2006. The peak flux was about 85 milli-Crab in the 2.0-10.0 keV band, with the peak energy (Ep) of the spectral energy distribution (SED) laying often at energies larger than 10 keV. We performed spectral analysis of the Swift observations investigating the trends of the spectral parameters in terms of acceleration and energetic features phenomenologically linked to the SSC model parameters, predicting their effects in the gamma-ray band, in particular the spectral shape expected in the Fermi Gamma-ray Space Telescope-LAT band. We confirm that the X-ray spectrum is well described by a log-parabolic distribution close to Ep, with the peak flux of the SED (Sp) being correlated with Ep, and Ep anti-correlated with the curvature parameter (b). During the most energetic flares the UV-to-soft-X-ray spectral shape requires an electron distribution spectral index s about 2.3. Present analysis shows that the UV-to-X-ray emission from Mrk 421 is likely to be originated by a population of electrons that is actually curved, with a low energy power-law tail. The observed spectral curvature is consistent both with stochastic acceleration or energy dependent acceleration probability mechanisms, whereas the power-law slope form XRT-UVOT data is very close to that inferred from the GRBs X-ray afterglow and in agreement with the universal first-order relativistic shock acceleration models. This scenario hints that the magnetic turbulence may play a twofold role: spatial diffusion relevant to the first order process and momentum diffusion relevant to the second order process.Comment: Accepted, Astronomy and Astrophysic