The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria

A New Technique for Firn Grain-Size Measurement Using Sem Image Analysis

Firn microstructure is accurately characterized using images obtained from scanning electron microscopy (SEM). Visibly etched grain boundaries within images are used to create a skeleton outline of the microstructure. A pixel-counting utility is applied to the outline to determine grain area. Firn grain sizes calculated using the technique described here are compared to those calculated using the techniques of Gow (1969) and Gay and Weiss (1999) on samples of the same material, and are found to be substantially smaller. The differences in grain size between the techniques are attributed to sampling deficiencies (e.g. the inclusion of pore filler in the grain area) in earlier methods. The new technique offers the advantages of greater accuracy and the ability to determine individual components of the microstructure (grain and pore), which have important applications in ice-core analyses. The new method is validated by calculating activation energies of grain boundary diffusion using predicted values based on the ratio of grain-size measurements between the new and existing techniques. The resulting activation energy falls within the range of values previously reported for firn/ice

The Quark Propagator from the Dyson-Schwinger Equations: I. the Chiral Solution

Within the framework of the Dyson-Schwinger equations in the axial gauge, we study the effect that non-perturbative glue has on the quark propagator. We show that Ward-Takahashi identities, combined with the requirement of matching perturbative QCD at high momentum transfer, guarantee the multiplicative renormalisability of the answer. Technically, the matching with perturbation theory is accomplished by the introduction of a transverse part to the quark-gluon vertex. We show that this transverse vertex is crucial for chiral symmetry breaking, and that massless solutions exist below a critical value of the strong coupling constant. Using the gluon propagator that we previously calculated, we obtain small corrections to the quark propagator, which keeps a pole at the origin in the chiral phase.Comment: 21 pages, 6 figures; McGill/94-24, SHEP 93/94-26 We generalise our results by showing that they are not sensitive to the specific choice that we make for the transverse vertex. We illustrate that fact in two new figure

A service oriented architecture for decision making in engineering design

Decision making in engineering design can be effectively addressed by using genetic algorithms to solve multi-objective problems. These multi-objective genetic algorithms (MOGAs) are well suited to implementation in a Service Oriented Architecture. Often the evaluation process of the MOGA is compute-intensive due to the use of a complex computer model to represent the real-world system. The emerging paradigm of Grid Computing offers a potential solution to the compute-intensive nature of this objective function evaluation, by allowing access to large amounts of compute resources in a distributed manner. This paper presents a grid-enabled framework for multi-objective optimisation using genetic algorithms (MOGA-G) to aid decision making in engineering design

Dynamical Systems approach to Saffman-Taylor fingering. A Dynamical Solvability Scenario

A dynamical systems approach to competition of Saffman-Taylor fingers in a channel is developed. This is based on the global study of the phase space structure of the low-dimensional ODE's defined by the classes of exact solutions of the problem without surface tension. Some simple examples are studied in detail, and general proofs concerning properties of fixed points and existence of finite-time singularities for broad classes of solutions are given. The existence of a continuum of multifinger fixed points and its dynamical implications are discussed. The main conclusion is that exact zero-surface tension solutions taken in a global sense as families of trajectories in phase space spanning a sufficiently large set of initial conditions, are unphysical because the multifinger fixed points are nonhyperbolic, and an unfolding of them does not exist within the same class of solutions. Hyperbolicity (saddle-point structure) of the multifinger fixed points is argued to be essential to the physically correct qualitative description of finger competition. The restoring of hyperbolicity by surface tension is discussed as the key point for a generic Dynamical Solvability Scenario which is proposed for a general context of interfacial pattern selection.Comment: 3 figures added, major rewriting of some sections, submitted to Phys. Rev.

Fat Fisher Zeroes

We show that it is possible to determine the locus of Fisher zeroes in the thermodynamic limit for the Ising model on planar (``fat'') phi4 random graphs and their dual quadrangulations by matching up the real part of the high and low temperature branches of the expression for the free energy. The form of this expression for the free energy also means that series expansion results for the zeroes may be obtained with rather less effort than might appear necessary at first sight by simply reverting the series expansion of a function g(z) which appears in the solution and taking a logarithm. Unlike regular 2D lattices where numerous unphysical critical points exist with non-standard exponents, the Ising model on planar phi4 graphs displays only the physical transition at c = exp (- 2 beta) = 1/4 and a mirror transition at c=-1/4 both with KPZ/DDK exponents (alpha = -1, beta = 1/2, gamma = 2). The relation between the phi4 locus and that of the dual quadrangulations is akin to that between the (regular) triangular and honeycomb lattices since there is no self-duality.Comment: 12 pages + 6 eps figure

Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes

COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported menstrual cycle irregularity after receiving COVID-19 vaccines, and this led to renewed fears concerning COVID-19 vaccines and their effects on fertility. Herein we devised an informatics workflow to explore the causal drivers of menstrual cycle irregularity in response to vaccination with mRNA COVID-19 vaccine BNT162b2. Our methods relied on gene expression analysis in response to vaccination, followed by network biology analysis to derive testable hypotheses regarding the causal links between BNT162b2 and menstrual cycle irregularity. Five high-confidence transcription factors were identified as causal drivers of BNT162b2-induced menstrual irregularity, namely: IRF1, STAT1, RelA (p65 NF-kB subunit), STAT2 and IRF3. Furthermore, some biomarkers of menstrual irregularity, including TNF, IL6R, IL6ST, LIF, BIRC3, FGF2, ARHGDIB, RPS3, RHOU, MIF, were identified as topological genes and predicted as causal drivers of menstrual irregularity. Our network-based mechanism reconstruction results indicated that BNT162b2 exerted biological effects similar to those resulting from prolactin signaling. However, these effects were short-lived and didn’t raise concerns about long-term infertility issues. This approach can be applied to interrogate the functional links between drugs/vaccines and other side effects

Banner News

https://openspace.dmacc.edu/banner_news/1421/thumbnail.jp

Effects of small surface tension in Hele-Shaw multifinger dynamics: an analytical and numerical study

We study the singular effects of vanishingly small surface tension on the dynamics of finger competition in the Saffman-Taylor problem, using the asymptotic techniques described in [S. Tanveer, Phil. Trans. R. Soc. Lond. A 343, 155 (1993)]and [M. Siegel, and S. Tanveer, Phys. Rev. Lett. 76, 419 (1996)] as well as direct numerical computation, following the numerical scheme of [T. Hou, J. Lowengrub, and M. Shelley,J. Comp. Phys. 114, 312 (1994)]. We demonstrate the dramatic effects of small surface tension on the late time evolution of two-finger configurations with respect to exact (non-singular) zero surface tension solutions. The effect is present even when the relevant zero surface tension solution has asymptotic behavior consistent with selection theory.Such singular effects therefore cannot be traced back to steady state selection theory, and imply a drastic global change in the structure of phase-space flow. They can be interpreted in the framework of a recently introduced dynamical solvability scenario according to which surface tension unfolds the structually unstable flow, restoring the hyperbolicity of multifinger fixed points.Comment: 16 pages, 15 figures, submitted to Phys. Rev

Muon studies of Li+ diffusion in LiFePO4 nanoparticles of different polymorphs

The lithium diffusion in nanostructured olivine LiFePO4 has been investigated for the first time using muon spectroscopy (μSR). A microwave-assisted approach has been employed for nanoparticle preparation, where the choice of solvent is shown to play an important role in determining particle morphology and crystal chemistry. Two phases have been obtained: Pnma LiFePO4 and the high pressure Cmcm phase. The Li+ diffusion behaviour is strikingly different in both phases, with DLi of 6.25 × 10−10 cm2 s−1 obtained for Pnma LiFePO4 in good agreement with measurements of bulk materials. In contrast, Li+ diffusion is impeded with the addition of the high pressure Cmcm phase, with a lower DLi of 3.96 × 10−10 cm2 s−1 noted. We have demonstrated an efficient microwave route to nanoparticle synthesis of positive electrode materials and we have also shown μSR measurements to be a powerful probe of Li+ diffusion behaviour in nanoparticles