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

Implementing a tenofovir-based first-line regimen in rural Lesotho: clinical outcomes and toxicities after two years.

The latest World Health Organization guidelines recommend replacing stavudine with tenofovir or zidovudine in first-line antiretroviral therapy in resource-limited settings. We report on outcomes and toxicities among patients on these different regimens in a routine treatment cohort in Lesotho

Human elements and the pragmatic approach in the Australian, Scottish and Swedish standards for newly qualified teachers

Peer reviewedPublisher PD

Does Fund Size Matter: An Analysis of Small and Large

Mutual funds have become a staple for retirement savings and have received much research attention. Bond funds, though, have received little attention to date, and the effects of fund size on performance are still in dispute. Using cross sectional and time series regression analysis, the performance of high yield and corporate bond funds are contrasted, with potential causes for the differences identified. A few fundamental economic variables are found to explain a large portion of fund returns. Bond index returns are found to have the greatest impact of any variable on fund returns, with the most pronounced effect on large corporate bond funds. The impact of fund size on performance is also examined, with evidence suggesting that after a point fund returns are negatively impacted as net assets grow. This poses a key microeconomic question regarding the benefits and costs of fund scale

Ultra-high-energy cosmic ray acceleration by relativistic blast waves

We consider the acceleration of charged particles at the ultra-relativistic shocks, with Lorentz factors \Gamma_s >> 1 relative to the upstream medium, arising in relativistic fireball models of gamma-ray bursts (GRBs). We show that for Fermi-type shock acceleration, particles initially isotropic in the upstream medium can gain a factor of order \Gamma_s^2 in energy in the first shock crossing cycle, but that the energy gain factor for subsequent shock crossing cycles is only of order 2, because for realistic deflection processes particles do not have time to re-isotropise upstream before recrossing the shock. We evaluate the maximum energy attainable and the efficiency of this process, and show that for a GRB fireball expanding into a typical interstellar medium, these exclude the production of ultra-high-energy cosmic rays (UHECRs), with energies in the range 10^{18.5} - 10^{20.5} eV, by the blast wave. We propose, however, that in the context of neutron star binaries as the progenitors of GRBs, relativistic ions from the pulsar wind bubbles produced by these systems could be accelerated by the blast wave. We show that if the known binary pulsars are typical, the maximum energy, efficiency, and spectrum in this case can account for the observed population of UHECRs.Comment: Accepted for MNRAS (Letters), with minor revisions. LaTeX, 5 pages, uses mn.st

A wind model for high energy pulses

A solution to the sigma problem - that of finding a mechanism capable of converting Poynting energy flux to particle-borne energy flux in a pulsar wind - was proposed several years ago by Coroniti and Michel who considered a particular prescription for magnetic reconnection in a striped wind. This prescription was later shown to be ineffective. In this paper, we discuss the basic microphysics of the reconnection process and conclude that a more rapid prescription is permissible. Assuming dissipation to set in at some distance outside the light-cylinder, we compute the resulting radiation signature and find that the synchrotron emission of heated particles appears periodic, in general showing both a pulse and an interpulse. The predicted spacing of these agrees well with observation in the case of the Crab and Vela pulsars. Using parameters appropriate for the Crab pulsar - magnetization parameter at the light cylinder sigma_L = 6 x 10^4, Lorentz factor Gamma=250 - reasonable agreement is found with the observed total pulsed luminosity. This suggest that the high-energy pulses from young pulsars originate not in the co-rotating magnetosphere within the light cylinder (as in all other models) but from the radially directed wind well outside it.Comment: 6 pages, 2 figures. To appear in the Proceedings of the 270. WE-Heraeus Seminar on Neutron Stars, Pulsars and Supernova Remnants, Jan. 21-25, 2002, Physikzentrum Bad Honnef, eds W. Becker, H. Lesch & J. Truemper. Proceedings are available as MPE-Report 27