12 research outputs found
Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads
In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification
Exact S-matrices for supersymmetric sigma models and the Potts model
We study the algebraic formulation of exact factorizable S-matrices for
integrable two-dimensional field theories. We show that different formulations
of the S-matrices for the Potts field theory are essentially equivalent, in the
sense that they can be expressed in the same way as elements of the
Temperley-Lieb algebra, in various representations. This enables us to
construct the S-matrices for certain nonlinear sigma models that are invariant
under the Lie ``supersymmetry'' algebras sl(m+n|n) (m=1,2; n>0), both for the
bulk and for the boundary, simply by using another representation of the same
algebra. These S-matrices represent the perturbation of the conformal theory at
theta=pi by a small change in the topological angle theta. The m=1, n=1 theory
has applications to the spin quantum Hall transition in disordered fermion
systems. We also find S-matrices describing the flow from weak to strong
coupling, both for theta=0 and theta=pi, in certain other supersymmetric sigma
models.Comment: 32 pages, 8 figure
Statistical mechanics of Roskilde liquids: Configurational adiabats, specific heat contours, and density dependence of the scaling exponent
We derive exact results for the rate of change of thermodynamic quantities,
in particular the configurational specific heat at constant volume, ,
along configurational adiabats (curves of constant excess entropy
). Such curves are designated isomorphs for so-called Roskilde
liquids, in view of the invariance of various structural and dynamical
quantities along them. Their slope in a double logarithmic representation of
the density-temperature phase diagram, can be interpreted as one third
of an effective inverse power-law potential exponent. We show that in liquids
where increases (decreases) with density, the contours of have
smaller (larger) slope than configurational adiabats. We clarify also the
connection between and the pair potential. A fluctuation formula for
the slope of the -contours is derived. The theoretical results are
supported with data from computer simulations of two systems, the Lennard-Jones
fluid and the Girifalco fluid. The sign of is thus a third key
parameter in characterizing Roskilde liquids, after and the
virial-potential energy correlation coefficient . To go beyond isomorph
theory we compare invariance of a dynamical quantity, the self-diffusion
coefficient along adiabats and -contours, finding it more invariant along
adiabats
Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution
<p>Abstract</p> <p>Background</p> <p>The Toll-like receptors represent a large superfamily of type I transmembrane glycoproteins, some common to a wide range of species and others are more restricted in their distribution. Most members of the Toll-like receptor superfamily have few paralogues; the exception is the TLR1 gene family with four closely related genes in mammals TLR1, TLR2, TLR6 and TLR10, and four in birds TLR1A, TLR1B, TLR2A and TLR2B. These genes were previously thought to have arisen by a series of independent gene duplications. To understand the evolutionary pattern of the TLR1 gene family in vertebrates further, we cloned the sequences of TLR1A, TLR1B, TLR2A and TLR2B in duck and turkey, constructed phylogenetic trees, predicted codons under positive selection and identified co-evolutionary amino acid pairs within the TLR1 gene family using sequences from 4 birds, 28 mammals, an amphibian and a fish.</p> <p>Results</p> <p>This detailed phylogenetic analysis not only clarifies the gene gains and losses within the TLR1 gene family of birds and mammals, but also defines orthologues between these vertebrates. In mammals, we predict amino acid sites under positive selection in TLR1, TLR2 and TLR6 but not TLR10. We detect co-evolution between amino acid residues in TLR2 and the other members of this gene family predicted to maintain their ability to form functional heterodimers. In birds, we predict positive selection in the TLR2A and TLR2B genes at functionally significant amino acid residues. We demonstrate that the TLR1 gene family has mostly been subject to purifying selection but has also responded to directional selection at a few sites, possibly in response to pathogen challenge.</p> <p>Conclusions</p> <p>Our phylogenetic and structural analyses of the vertebrate TLR1 family have clarified their evolutionary origins and predict amino acid residues likely to be important in the host's defense against invading pathogens.</p
Small molecule screening in zebrafish: an <it>in vivo </it>approach to identifying new chemical tools and drug leads
Abstract In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification.</p
ALDH2 mediates 5-nitrofuran activity in multiple species
Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of pro-drugs widely used to treat bacterial and trypanosome infections, but despite relative specificity 5-nitrofurans often cause serious toxic side-effects in people. Here, we use yeast, zebrafish and human in vitro systems to assess the biological activity of 5-nitrofurans, and identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome pro-drug, is dependent on zebrafish Aldh2 and that nifurtimox is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5nitrofuran treatment.PostprintPeer reviewe