Mutational and Biochemical Analysis of Isoprenylcysteine Carboxyl Methyltransferase

Ninety percent of pancreatic cancers are attributed to mutations in the Ras protein, making it paramount to concentrate on Ras activity. This study focuses on Ras activity by targeting a post-translational modifying enzyme of Ras called Isoprenylcysteine carboxyl methyltransferase (Icmt). Elucidation of the binding site of Icmt will allow the development of therapeutics that effectively inhibit Icmt causing the mislocalization of Ras, and in turn, aid in the treatment of Ras driven cancers. Currently, the hydrophobic substrate binding site of Icmt is unknown. In order to characterize the substrate binding site of Icmt, site-directed mutagenesis was used to design mutations in the yeast homolog of Icmt, Ste14p, and these mutants were tested on substrate specificity. Residues L33, L34, L40, L176, L190, and L195 were mutated to alanine and residue F80 was mutated to tyrosine. When tested with a methyltransferase assay, all of the mutants lost activity as compared to wild type (WT). Noticeably, L190A had only 44% WT activity. This suggests that L190A is important for either substrate binding or the overall structural integrity of Ste14p. The results from trypsin digestion show that all mutants have cleavage patterns similar to WT. This indicates that the structural integrity of Ste14p remains intact regardless of these mutations. Substrate specificity and photolabeling experiments should be conducted in the future to elucidate if these residues are vital for the substrate binding site of Icmt. These results could be utilized to design more potent and effective drug therapies to minimize Ras signaling in cancer cells

Extended Quintessence with non-minimally coupled phantom scalar field

We investigate evolutional paths of an extended quintessence with a non-minimally coupled phantom scalar field $\psi$ to the Ricci curvature. The dynamical system methods are used to investigate typical regimes of dynamics at the late time. We demonstrate that there are two generic types of evolutional scenarios which approach the attractor (a focus or a node type critical point) in the phase space: the quasi-oscillatory and monotonic trajectories approach to the attractor which represents the FRW model with the cosmological constant. We demonstrate that dynamical system admits invariant two-dimensional submanifold and discussion that which cosmological scenario is realized depends on behavior of the system on the phase plane $(\psi, \psi')$. We formulate simple conditions on the value of coupling constant $\xi$ for which trajectories tend to the focus in the phase plane and hence damping oscillations around the mysterious value $w=-1$. We describe this condition in terms of slow-roll parameters calculated at the critical point. We discover that the generic trajectories in the focus-attractor scenario come from the unstable node. It is also investigated the exact form of the parametrization of the equation of state parameter $w(z)$ (directly determined from dynamics) which assumes a different form for both scenarios.Comment: revtex4, 15 pages, 9 figures; (v2) published versio

Potential Tools for Eradicating HIV Reservoirs in the Brain: Development of Trojan Horse Prodrugs for the Inhibition of P-Glycoprotein with Anti-HIV-1 Activity

Combination antiretroviral therapy is the mainstay of HIV treatment, lowering plasma viral levels below detection. However, eradication of HIV is a major challenge due to cellular and anatomical viral reservoirs that are often protected from treatment by efflux transporters, such as P-glycoprotein (P-gp) at the blood–brain barrier (BBB). Herein we described a Trojan horse approach to therapeutic evasion of P-gp based on a reversibly linked combination of HIV reverse transcriptase and protease inhibitors. Potent inhibition of P-gp efflux in cells, including human brain endothelial cells, was observed with the linked heterodimeric compounds. In vitro regeneration of active monomeric drugs was observed in a reducing environment with these dimeric prodrugs, with the superior leaving group promoting more facile release from the tether. These release trends were mirrored in the efficacy of the in cyto anti-HIV-1 activity of the Trojan horse heterodimers

Effective dynamics of the closed loop quantum cosmology

In this paper we study dynamics of the closed FRW model with holonomy corrections coming from loop quantum cosmology. We consider models with a scalar field and cosmological constant. In case of the models with cosmological constant and free scalar field, dynamics reduce to 2D system and analysis of solutions simplify. If only free scalar field is included then universe undergoes non-singular oscillations. For the model with cosmological constant, different behaviours are obtained depending on the value of $\Lambda$. If the value of $\Lambda$ is sufficiently small, bouncing solutions with asymptotic de Sitter stages are obtained. However if the value of $\Lambda$ exceeds critical value $\Lambda_{\text{c}} =\frac{\sqrt{3}m^2_{\text{Pl}}}{2\pi\gamma^3} \simeq 21 m^2_{\text{Pl}}$ then solutions become oscillatory. Subsequently we study models with a massive scalar field. We find that this model possess generic inflationary attractors. In particular field, initially situated in the bottom of the potential, is driven up during the phase of quantum bounce. This subsequently leads to the phase of inflation. Finally we find that, comparing with the flat case, effects of curvature do not change qualitatively dynamics close to the phase of bounce. Possible effects of inverse volume corrections are also briefly discussed.Comment: 18 pages, 11 figure

Uniting cosmological epochs through the twister solution in cosmology with non-minimal coupling

We investigate dynamics of a flat FRW cosmological model with a barotropic matter and a non-minimally coupled scalar field (both canonical and phantom). In our approach we do not assume any specific form of a potential function for the scalar field and we are looking for generic scenarios of evolution. We show that dynamics of universe can be reduced to a 3-dimensional dynamical system. We have found the set of fixed points and established their character. These critical points represent all important epochs in evolution of the universe : (a) a finite scale factor singularity, (b) an inflation (rapid-roll and slow-roll), (c) a radiation domination, (d) a matter domination and (e) a quintessence era. We have shown that the inflation, the radiation and matter domination epochs are transient ones and last for a finite amount of time. The existence of the radiation domination epoch is purely the effect of a non-minimal coupling constant. We show the existence of a twister type solution wandering between all these critical points.Comment: 22 pages, 5 figs; (v2.) 27 pages, 12 figs, JCAP in pres

Phantom cosmology as a scattering process

We study the general chaotic features of dynamics of the phantom field modelled in terms of a single scalar field conformally coupled to gravity. We demonstrate that the dynamics of the FRW model with dark energy in the form of phantom field can be regarded as a scattering process of two types: multiple chaotic and classical non-chaotic. It depends whether the spontaneously symmetry breaking takes place. In the first class of models with the spontaneously symmetry breaking the dynamics is similar to the Yang-Mills theory. We find the evidence of a fractal structure in the phase space of initial conditions. We observe similarities to the phenomenon of a multiple scattering process around the origin. In turn the class of models without the spontaneously symmetry breaking can be described as the classical non-chaotic scattering process and the methods of symbolic dynamic are also used in this case. We show that the phantom cosmology can be treated as a simple model with scattering of trajectories which character depends crucially on a sign of a square of mass. We demonstrate that there is a possibility of chaotic behavior in the flat Universe with a conformally coupled phantom field in the system considered on non-zero energy level. We obtain that the acceleration is a generic feature in the considered model without the spontaneously symmetry breaking. We observe that the effective EOS coefficient oscillates and then approach to $w=-1$.Comment: RevTeX4, 19 pages, 17 figures; v2 - added a comment on the Yang-Mills cosmological models and bibliography; v3 - added a section on acceleration, 2 figures, some references

Universe from vacuum in loop-string cosmology

In this paper we study the description of the Universe based on the low energy superstring theory modified by the Loop Quantum Gravity effects.This approach was proposed by De Risi et al. in the Phys. Rev. D {\bf 76} (2007) 103531. We show that in the contrast with the string motivated pre-Big Bang scenario, the cosmological realisation of the $t$-duality transformation is not necessary to avoid an initial singularity. In the model considered the universe starts its evolution in the vacuum phase at time $t\to - \infty$. In this phase the scale factor $a\to 0$, energy density $\rho \to 0$ and coupling of the interactions $g^2_s \to 0$. After this stage the universe evolves to the non-singular hot Big Bang phase $\rho \to \rho_{\text{max}} < \infty$. Then the standard classical universe emerges. During the whole evolution the scale factor increases monotonically. We solve this model analytically. We also propose and solve numerically the model with an additional dilaton potential in which the universe starts the evolution from the asymptotically free vacuum phase $g^2_s \to 0$ and then evolves non-singularly to the emerging dark energy dominated phase with the saturated coupling constant $g^2_s \to \text{const}$.Comment: JHEP3 LaTeX class, 19 pages, 9 figures, v2: added some comments and references, v3: new numerical result added, new figure

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.

Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity

Effects of the quantisation ambiguities on the Big Bounce dynamics

In this paper we investigate dynamics of the modified loop quantum cosmology models using dynamical systems methods. Modifications considered come from the choice of the different field strength operator $\hat{F}$ and result in different forms of the effective Hamiltonian. Such an ambiguity of the choice of this expression from some class of functions is allowed in the framework of loop quantisation. Our main goal is to show how such modifications can influence the bouncing universe scenario in the loop quantum cosmology. In effective models considered we classify all evolutional paths for all admissible initial conditions. The dynamics is reduced to the form of a dynamical system of the Newtonian type on a 2-dimensional phase plane. These models are equivalent dynamically to the FRW models with the decaying effective cosmological term parametrised by the canonical variable $p$ (or by the scale factor $a$). We find that for the positive cosmological constant there is a class of oscillating models without the initial and final singularities. The new phenomenon is the appearance of curvature singularities for the finite values of the scale factor, but we find that for the positive cosmological constant these singularities can be avoided. For the positive cosmological constant the evolution begins at the asymptotic state in the past represented by the deSitter contracting (deS$_{-}$) spacetime or the static Einstein universe H=0 or $H=-\infty$ state and reaches the deSitter expanding state (deS$_{+}$), the state H=0 or $H=+\infty$ state. In the case of the negative cosmological constant we obtain the past and future asymptotic states as the Einstein static universes.Comment: RevTeX4, 28 pages, 11 figs; rev.2 new section on exact solutions; (v3) published versio

De Sitter ground state of scalar-tensor gravity and its primordial perturbation

Scalar-tensor gravity is one of the most competitive gravity theory to Einstein's relativity. We reconstruct the exact de Sitter solution in scalar-tensor gravity, in which the non-minimal coupling scalar is rolling along the potential. This solution may have some relation to the early inflation and present acceleration of the universe. We investigated its primordial quantum perturbation around the adiabatic vacuum. We put forward for the first time that exact de Sitter generates non-exactly scale invariant perturbations. In the conformal coupling case, this model predicts that the tensor mode of the perturbation (gravity wave) is strongly depressed.Comment: 9 page