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

The Margaret Chase Smith Library

Description of the contents and organization of the Margaret Chase Smith Library in Skowhegan, Maine

Maine Code of Election Ethics

In the Margaret Chase Smith Essay, Gregory Gallant discusses the voluntary Maine Code of Election Ethics, sponsored and organized by the University of Maine’s Margaret Chase Smith Policy Center and the Margaret Chase Smith Library in Skowhegan. The code is a voluntary effort designed to elevate political discourse in Maine’s federal and gubernatorial elections. Gallant reflects on the ways in which this code reinforces Margaret Chase Smith’s recognition of the critical role played by civic engagement in American society

Lateral Spreading and Stability of Embankments Supported on Fractured Unreinforced High-Modulus Columns

Construction of column-supported embankments (CSEs) with unreinforced high-modulus elements is now common practice to accelerate fill placement. These brittle columns are susceptible to column fracturing and CSE designs often limit the degree of lateral spreading such that tensile rupture will not occur, which stems from salient concerns that fracturing may trigger uncontrolled lateral spreading and/or the cessation of intended vertical load transfer. However, tensile rupture is unlikely to coincide with full mobilization of available passive resistance at the toe. Thus, it is disputed in industry whether some degree of column fracturing is tolerable. The objective of this study is to elucidate the influence of column fracturing on lateral spreading and stability of CSEs

Control of transcription by Pontin and Reptin

Pontin and Reptin are two closely related members of the AAA+ family of DNA helicases. They have roles in diverse cellular processes, including the response to DNA double-strand breaks and the control of gene expression. The two proteins share residence in different multiprotein complexes, such as the Tip60, Ino80, SRCAP and Uri1 complexes in animals, which are involved (directly or indirectly) in transcriptional regulation, but they also function independently from each other. Both Reptin and Pontin repress certain transcriptional targets of Myc, but only Reptin is required for the repression of specific ?-catenin and nuclear factor-?B targets. Here, I review recent studies that have addressed the mechanisms of transcriptional control by Pontin and Reptin

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

Finding discrete logarithms with a set orbit distinguisher

We consider finding discrete logarithms in a group \GG when the help of an algorithm $D$ that distinguishes certain subsets of \GG from each other is available. For a group \GG of prime order $p$, if algorithm $D$ is polynomial-time with complexity c(\log(p))$, we can find discrete logarithms faster than square-root algorithms. We consider two variations on this idea and give algorithms solving the discrete logarithm problem in$\GG$with complexity${\cal O}(p^{\frac{1}{3}}\log(p)^3 + p^{\frac{1}{3}}c(\log(p) )$and${\cal O}(p^{\frac{1}{4}}\log(p)^3 + p^{\frac{1}{4}}c( \log(p) )$in the best cases. When multiple distinguishers are available logarithms can be found in polynomial time. We discuss natural classes of algorithms$D$ that distinguish the required subsets, and prove that for {\em some} of these classes no algorithm for distinguishing can be efficient. The subsets distinguished are also relevant in the study of error correcting codes, and we give an application of our work to bounds for error-correcting codes