889 research outputs found
Identification of T. gondii myosin light chain-1 as a direct target of TachypleginA-2, a small-molecule inhibitor of parasite motility and invasion
This work was supported by US Public Health Service grant AI054961 (GEW/NJW), a University Research Fellowship from the Royal Society (NJW) and funding for the mass spectrometry analysis was provided by the Vermont Genetics Network/NIH Grant 8P20GM103449 from the INBRE program of the NIGMS.Motility of the protozoan parasite Toxoplasma gondii plays an important role in the parasite's life cycle and virulence within animal and human hosts. Motility is driven by a myosin motor complex that is highly conserved across the Phylum Apicomplexa. Two key components of this complex are the class XIV unconventional myosin, TgMyoA, and its associated light chain, TgMLC1. We previously showed that treatment of parasites with a small-molecule inhibitor of T. gondii invasion and motility, tachypleginA, induces an electrophoretic mobility shift of TgMLC1 that is associated with decreased myosin motor activity. However, the direct target(s) of tachypleginA and the molecular basis of the compound-induced TgMLC1 modification were unknown. We show here by ''click'' chemistry labelling that TgMLC1 is a direct and covalent target of an alkyne-derivatized analogue of tachypleginA. We also show that this analogue can covalently bind to model thiol substrates. The electrophoretic mobility shift induced by another structural analogue, tachypleginA-2, was associated with the formation of a 225.118 Da adduct on S57 and/or C58, and treatment with deuterated tachypleginA-2 confirmed that the adduct was derived from the compound itself. Recombinant TgMLC1 containing a C58S mutation (but not S57A) was refractory to click labelling and no longer exhibited a mobility shift in response to compound treatment, identifying C58 as the site of compound binding on TgMLC1. Finally, a knock-in parasite line expressing the C58S mutation showed decreased sensitivity to compound treatment in a quantitative 3D motility assay. These data strongly support a model in which tachypleginA and its analogues inhibit the motility of T. gondii by binding directly and covalently to C58 of TgMLC1, thereby causing a decrease in the activity of the parasite's myosin motor. Publisher PDFPeer reviewe
How to find discrete contact symmetries
This paper describes a new algorithm for determining all discrete contact
symmetries of any differential equation whose Lie contact symmetries are known.
The method is constructive and is easy to use. It is based upon the observation
that the adjoint action of any contact symmetry is an automorphism of the Lie
algebra of generators of Lie contact symmetries. Consequently, all contact
symmetries satisfy various compatibility conditions. These conditions enable
the discrete symmetries to be found systematically, with little effort
On-Mass-Shell Renormalization of Fermion Mixing Matrices
We consider favourable extensions of the standard model (SM) where the lepton
sector contains Majorana neutrinos with vanishing left-handed mass terms, thus
allowing for the see-saw mechanism to operate, and propose physical
on-mass-shell (OS) renormalization conditions for the lepton mixing matrices
that comply with ultraviolet finiteness, gauge-parameter independence, and
(pseudo)unitarity. A crucial feature is that the texture zero in the neutrino
mass matrix is preserved by renormalization, which is not automatically the
case for possible generalizations of existing renormalization prescriptions for
the Cabibbo-Kobayashi-Maskawa (CKM) quark mixing matrix in the SM. Our
renormalization prescription also applies to the special case of the SM and
leads to a physical OS definition of the renormalized CKM matrix.Comment: 18 pages (Latex), to appear in Nucl. Phys.
Knot soliton in Weinberg-Salam model
We study numerically the topological knot solution suggested recently in the
Weinberg-Salam model. Applying the SU(2) gauge invariant Abelian projection we
demonstrate that the restricted part of the Weinberg-Salam Lagrangian
containing the interaction of the neutral boson with the Higgs scalar can be
reduced to the Ginzburg-Landau model with the hidden SU(2) symmetry. The energy
of the knot composed from the neutral boson and Higgs field has been evaluated
by using the variational method with a modified Ward ansatz. The obtained
numerical value is 39 Tev which provides the upper bound on the electroweak
knot energy.Comment: 6 pages, 3 figures, analysis of stability adde
Transmogrifying Fuzzy Vortices
We show that the construction of vortex solitons of the noncommutative
Abelian-Higgs model can be extended to a critically coupled gauged linear sigma
model with Fayet-Illiopolous D-terms. Like its commutative counterpart, this
fuzzy linear sigma model has a rich spectrum of BPS solutions. We offer an
explicit construction of the degree static semilocal vortex and study in
some detail the infinite coupling limit in which it descends to a degree
\C\Pk^{N} instanton. This relation between the fuzzy vortex and
noncommutative lump is used to suggest an interpretation of the noncommutative
sigma model soliton as tilted D-strings stretched between an NS5-brane and a
stack of D3-branes in type IIB superstring theory.Comment: 21 pages, 4 figures, LaTeX(JHEP3
Application of Pulsed Field Gel Electrophoresis to Determine γ-ray-induced Double-strand Breaks in Yeast Chromosomal Molecules
The frequency of DNA double-strand breaks (dsb) was determined in yeast cells exposed to γ-rays under anoxic conditions. Genomic DNA of treated cells was separated by pulsed field gel electrophoresis, and two different approaches for the evaluation of the gels were employed: (1) The DNA mass distribution profile obtained by electrophoresis was compared to computed profiles, and the number of DSB per unit length was then derived in terms of a fitting procedure; (2) hybridization of selected chromosomes was performed, and a comparison of the hybridization signals in treated and untreated samples was then used to derive the frequency of dsb
Monte Carlo Methods for Estimating Interfacial Free Energies and Line Tensions
Excess contributions to the free energy due to interfaces occur for many
problems encountered in the statistical physics of condensed matter when
coexistence between different phases is possible (e.g. wetting phenomena,
nucleation, crystal growth, etc.). This article reviews two methods to estimate
both interfacial free energies and line tensions by Monte Carlo simulations of
simple models, (e.g. the Ising model, a symmetrical binary Lennard-Jones fluid
exhibiting a miscibility gap, and a simple Lennard-Jones fluid). One method is
based on thermodynamic integration. This method is useful to study flat and
inclined interfaces for Ising lattices, allowing also the estimation of line
tensions of three-phase contact lines, when the interfaces meet walls (where
"surface fields" may act). A generalization to off-lattice systems is described
as well.
The second method is based on the sampling of the order parameter
distribution of the system throughout the two-phase coexistence region of the
model. Both the interface free energies of flat interfaces and of (spherical or
cylindrical) droplets (or bubbles) can be estimated, including also systems
with walls, where sphere-cap shaped wall-attached droplets occur. The
curvature-dependence of the interfacial free energy is discussed, and estimates
for the line tensions are compared to results from the thermodynamic
integration method. Basic limitations of all these methods are critically
discussed, and an outlook on other approaches is given
Recent developments in planet migration theory
Planetary migration is the process by which a forming planet undergoes a
drift of its semi-major axis caused by the tidal interaction with its parent
protoplanetary disc. One of the key quantities to assess the migration of
embedded planets is the tidal torque between the disc and planet, which has two
components: the Lindblad torque and the corotation torque. We review the latest
results on both torque components for planets on circular orbits, with a
special emphasis on the various processes that give rise to additional, large
components of the corotation torque, and those contributing to the saturation
of this torque. These additional components of the corotation torque could help
address the shortcomings that have recently been exposed by models of planet
population syntheses. We also review recent results concerning the migration of
giant planets that carve gaps in the disc (type II migration) and the migration
of sub-giant planets that open partial gaps in massive discs (type III
migration).Comment: 52 pages, 18 figures. Review article to be published in "Tidal
effects in Astronomy and Astrophysics", Lecture Notes in Physic
Non-Invasive Mouse Models of Post-Traumatic Osteoarthritis
SummaryAnimal models of osteoarthritis (OA) are essential tools for investigating the development of the disease on a more rapid timeline than human OA. Mice are particularly useful due to the plethora of genetically modified or inbred mouse strains available. The majority of available mouse models of OA use a joint injury or other acute insult to initiate joint degeneration, representing post-traumatic osteoarthritis (PTOA). However, no consensus exists on which injury methods are most translatable to human OA. Currently, surgical injury methods are most commonly used for studies of OA in mice; however, these methods may have confounding effects due to the surgical/invasive injury procedure itself, rather than the targeted joint injury. Non-invasive injury methods avoid this complication by mechanically inducing a joint injury externally, without breaking the skin or disrupting the joint. In this regard, non-invasive injury models may be crucial for investigating early adaptive processes initiated at the time of injury, and may be more representative of human OA in which injury is induced mechanically. A small number of non-invasive mouse models of PTOA have been described within the last few years, including intra-articular fracture of tibial subchondral bone, cyclic tibial compression loading of articular cartilage, and anterior cruciate ligament (ACL) rupture via tibial compression overload. This review describes the methods used to induce joint injury in each of these non-invasive models, and presents the findings of studies utilizing these models. Altogether, these non-invasive mouse models represent a unique and important spectrum of animal models for studying different aspects of PTOA
- …