4,539 research outputs found
The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni
Natural selection acts on all organisms, including parasites, to maximize reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian state-space models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma mansoni may be limited by life-history costs not present in susceptible counterparts. S. mansoni parasites from a praziquantel-susceptible (S), a praziquantel-resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life-history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond
Harnessing autophagy to overcome mitogenâactivated protein kinase kinase inhibitorâinduced resistance in metastatic melanoma
Background
Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogenâactivated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance.
Objectives
To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy.
Methods
Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinibâinduced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinibâresistant melanoma cell survival and invasion, respectively.
Results
CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAFâmutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271âexpressing subpopulations. Trametinibâinduced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271âexpressing melanoma subpopulations with RNA interference and smallâmolecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents â including Î9âtetrahydrocannabinol and Vps34 â reduced survival of MEKiâresistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKiâresistant cells in an in vivo zebrafish xenograft.
Conclusions
These results highlight a novel mechanism of MEKiâinduced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drugâresistant melanoma cells to the cytotoxic effects of MEKi
Germination responses of a dry sclerophyll forest soil-stored seedbank to fire related cues
Fire is an integral component of many ecosystems worldwide. Many plant species require fire-related cues, primarily heat and smoke, to trigger germination. Despite the importance of this process, the responses of many Australian species to these cues are unknown. Without this knowledge fire management strategies may be developed that are inappropriate for individual species and vegetation communities. In this study we examined the responses of a dry sclerophyll forest seed bank to heat and smoke germination cues. Analysis was possible for 48 taxa within the soil seedbank with 34 of these showing a response to one or both of the germination cues. 10 species responded to the heat treatment, 11 species responded to the smoke treatment and 13 species responded to both the heat and smoke treatments. Germination cues acted independently for all species considered. Results in this study were consistent with published reports for most species, although some differences were seen at the species and genus level. The study highlights the importance of fire-related cues in enhancing germination of a large proportion of the species occurring in dry sclerophyll forests
Direct Dark Matter Detection with Velocity Distribution in the Eddington approach
Exotic dark matter together with the vacuum energy (associated with the
cosmological constant) seem to dominate the Universe. Thus its direct detection
is central to particle physics and cosmology. Supersymmetry provides a natural
dark matter candidate, the lightest supersymmetric particle (LSP). One
essential ingredient in obtaining the direct detection rates is the density and
the velocity distribution of the LSP in our vicinity. In the present paper we
study simultaneously density profiles and velocity distributions in the context
of the Eddington approach. In such an approach, unlike the commonly assumed
Maxwell-Boltzmann (M-B) distribution, the upper bound of the velocity arises
naturally from the potential.Comment: 21 LaTex pages, 27 figure
Layer dependent band dispersion and correlations using tunable Soft X-ray ARPES
Soft X-ray Angle-Resolved Photoemission Spectroscopy is applied to study
in-plane band dispersions of Nickel as a function of probing depth. Photon
energies between 190 and 780 eV were used to effectively probe up to 3-7
layers. The results show layer dependent band dispersion of the Delta_2
minority-spin band which crosses the Fermi level in 3 or more layers, in
contrast to known top 1-2 layers dispersion obtained using ultra-violet rays.
The layer dependence corresponds to an increased value of exchange splitting
and suggests reduced correlation effects in the bulk compared to the surface.Comment: 7 pages, 3 figures Revised text and figur
The three-body problem and the Hannay angle
The Hannay angle has been previously studied for a celestial circular
restricted three-body system by means of an adiabatic approach. In the present
work, three main results are obtained. Firstly, a formal connection between
perturbation theory and the Hamiltonian adiabatic approach shows that both lead
to the Hannay angle; it is thus emphasised that this effect is already
contained in classical celestial mechanics, although not yet defined nor
evaluated separately. Secondly, a more general expression of the Hannay angle,
valid for an action-dependent potential is given; such a generalised expression
takes into account that the restricted three-body problem is a time-dependent,
two degrees of freedom problem even when restricted to the circular motion of
the test body. Consequently, (some of) the eccentricity terms cannot be
neglected {\it a priori}. Thirdly, we present a new numerical estimate for the
Earth adiabatically driven by Jupiter. We also point out errors in a previous
derivation of the Hannay angle for the circular restricted three-body problem,
with an action-independent potential.Comment: 11 pages. Accepted by Nonlinearit
Capturing Hiproofs in HOL Light
Hierarchical proof trees (hiproofs for short) add structure to ordinary proof
trees, by allowing portions of trees to be hierarchically nested. The
additional structure can be used to abstract away from details, or to label
particular portions to explain their purpose. In this paper we present two
complementary methods for capturing hiproofs in HOL Light, along with a tool to
produce web-based visualisations. The first method uses tactic recording, by
modifying tactics to record their arguments and construct a hierarchical tree;
this allows a tactic proof script to be modified. The second method uses proof
recording, which extends the HOL Light kernel to record hierachical proof trees
alongside theorems. This method is less invasive, but requires care to manage
the size of the recorded objects. We have implemented both methods, resulting
in two systems: Tactician and HipCam
Electron-phonon interaction at the Be(0001) surface
We present a first principle study of the electron-phonon (e-p) interaction
at the Be(0001) surface. The real and imaginary part of the e-p self energy are
calculated for the surface state in the binding energy range from the
point to the Fermi level. Our calculation shows an overall good
agreement with several photoemission data measured at high and low
temperatures. Additionally, we show that the energy derivative of real part of
the self-energy presents a strong temperature and energy variation close to
, making it difficult to measure its value just at .Comment: Accepted in Phys. Rev. Lett., 5 figure
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