Differential effects of the phosphatidylinositol 4-kinases, PI4KII alpha and PI4KIII beta, on Akt activation and apoptosis

In this study, we investigated the role of PI4P synthesis by the phosphatidylinositol 4-kinases, PI4KII alpha and PI4KIII beta, in epidermal growth factor (EGF)-stimulated phosphoinositide signaling and cell survival. In COS-7 cells, knockdown of either isozyme by RNA interference reduced basal levels of PI4P and PI(4,5)P-2, without affecting receptor activation. Only knockdown of PI4KII alpha inhibited EGF-stimulated Akt phosphorylation, indicating that decreased PI(4,5)P-2 synthesis observed by loss of either isoform could not account for this PI4KII alpha-specific effect. Phospholipase Cc activation was also differentially affected by knockdown of either PI4K isozyme. Overexpression of kinase-inactive PI4KII alpha, which induces defective endosomal trafficking without reducing PI(4,5)P-2 levels, also reduced Akt activation. Furthermore, PI4KII alpha knockdown profoundly inhibited cell proliferation and induced apoptosis as evidenced by the cleavage of caspase-3 and its substrate poly(ADP-ribose) polymerase. However, in MDA-MB-231 breast cancer cells, apoptosis was observed subsequent to knockdown of either PI4KII alpha or PI4KIII beta and this correlated with enhanced proapoptotic Akt phosphorylation. The differential effects of phosphatidylinositol 4-kinase knockdown in the two cell lines lead to the conclusion that phosphoinositide turnover is inhibited through PI4P substrate depletion, whereas impaired antiapoptotic Akt signaling is an indirect consequence of dysfunctional endosomal trafficking

Sign-reversal of the in-plane resistivity anisotropy in hole-doped iron pnictides

The in-plane anisotropy of the electrical resistivity across the coupled orthorhombic and magnetic transitions of the iron pnictides has been extensively studied in the parent and electron-doped compounds. All these studies universally show that the resistivity $\rho_{a}$ across the long orthorhombic axis $a_{O}$ - along which the spins couple antiferromagnetically below the magnetic transition temperature - is smaller than the resistivity $\rho_{b}$ of the short orthorhombic axis $b_{O}$, i. e. $\rho_{a}<\rho_{b}$. Here we report that in the hole-doped compounds Ba$_{1-x}$K$_{x}$Fe$_{2}$As$_{2}$, as the doping level increases, the resistivity anisotropy initially becomes vanishingly small, and eventually changes sign for sufficiently large doping, i. e. $\rho_{b}<\rho_{a}$. This observation is in agreement with a recent theoretical prediction that considers the anisotropic scattering of electrons by spin-fluctuations in the orthorhombic/nematic state.Comment: This paper has been replaced by the new version offering new explanation of the experimental results first reported her

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Post-Lie Algebras, Factorization Theorems and Isospectral-Flows

In these notes we review and further explore the Lie enveloping algebra of a post-Lie algebra. From a Hopf algebra point of view, one of the central results, which will be recalled in detail, is the existence of a second Hopf algebra structure. By comparing group-like elements in suitable completions of these two Hopf algebras, we derive a particular map which we dub post-Lie Magnus expansion. These results are then considered in the case of Semenov-Tian-Shansky's double Lie algebra, where a post-Lie algebra is defined in terms of solutions of modified classical Yang-Baxter equation. In this context, we prove a factorization theorem for group-like elements. An explicit exponential solution of the corresponding Lie bracket flow is presented, which is based on the aforementioned post-Lie Magnus expansion.Comment: 49 pages, no-figures, review articl

Anisotropic Impurity-States, Quasiparticle Scattering and Nematic Transport in Underdoped Ca(Fe1-xCox)2As2

Iron-based high temperature superconductivity develops when the `parent' antiferromagnetic/orthorhombic phase is suppressed, typically by introduction of dopant atoms. But their impact on atomic-scale electronic structure, while in theory quite complex, is unknown experimentally. What is known is that a strong transport anisotropy with its resistivity maximum along the crystal b-axis, develops with increasing concentration of dopant atoms; this `nematicity' vanishes when the `parent' phase disappears near the maximum superconducting Tc. The interplay between the electronic structure surrounding each dopant atom, quasiparticle scattering therefrom, and the transport nematicity has therefore become a pivotal focus of research into these materials. Here, by directly visualizing the atomic-scale electronic structure, we show that substituting Co for Fe atoms in underdoped Ca(Fe1-xCox)2As2 generates a dense population of identical anisotropic impurity states. Each is ~8 Fe-Fe unit cells in length, and all are distributed randomly but aligned with the antiferromagnetic a-axis. By imaging their surrounding interference patterns, we further demonstrate that these impurity states scatter quasiparticles in a highly anisotropic manner, with the maximum scattering rate concentrated along the b-axis. These data provide direct support for the recent proposals that it is primarily anisotropic scattering by dopant-induced impurity states that generates the transport nematicity; they also yield simple explanations for the enhancement of the nematicity proportional to the dopant density and for the occurrence of the highest resistivity along the b-axis

Flux Discharge Cascades in Various Dimensions

We study the dynamics of electric flux discharge by charged particle pair or spherical string or membrane production in various dimensions. When electric flux wraps at least one compact cycle, we find that a single "pair" production event can initiate a cascading decay in real time that "shorts out" the flux and discharges many units of it. This process arises from local dynamics in the compact space, and so is invisible in the dimensionally-reduced truncation. It occurs in theories as simple as the Schwinger model on a circle, and has implications for any theory with compact dimensions and electric flux, including string theories and the string landscape.Comment: 19+8 pages, 3 figures, 3 appendice

Morphological adaptations linked to flight efficiency and aerial lifestyle determine natal dispersal distance in birds

Natal dispersal—the movement from birthplace to breeding location—is often considered the most significant dispersal event in an animal's lifetime. Natal dispersal distances may be shaped by a variety of intrinsic and extrinsic factors, and remain poorly quantified in most groups, highlighting the need for indices that capture variation in dispersal among species. In birds, it is hypothesized that dispersal distance can be predicted by flight efficiency, which can be estimated using wing morphology. However, the use of morphological indices to predict dispersal remains contentious and the mechanistic links between flight efficiency and natal dispersal are unclear. Here, we use phylogenetic comparative models to test whether hand-wing index (HWI, a morphological proxy for wing aspect ratio) predicts natal dispersal distance across a global sample of 114 bird species. In addition, we assess whether HWI is correlated with flight usage in foraging and daily routines. We find that HWI is a strong predictor of both natal dispersal distance and a more aerial lifestyle. Our results support the use of HWI as a valid proxy for relative natal dispersal distance, and also suggest that evolutionary adaptation to aerial lifestyles is a major factor connecting flight efficiency with patterns of natal dispersal

A single residue substitution in the receptor-binding domain of H5N1 hemagglutinin is critical for packaging into pseudotyped lentiviral particles

© 2012 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Serological studies for influenza infection and vaccine response often involve microneutralization and hemagglutination inhibition assays to evaluate neutralizing antibodies against human and avian influenza viruses, including H5N1. We have previously characterized lentiviral particles pseudotyped with H5-HA (H5pp) and validated an H5pp-based assay as a safe alternative for high-throughput serological studies in BSL-2 facilities. Here we show that H5-HAs from different clades do not always give rise to efficient production of H5pp and the underlying mechanisms are addressed. Methodology/Findings: We have carried out mutational analysis to delineate the molecular determinants responsible for efficient packaging of HA from A/Cambodia/40808/2005 (H5Cam) and A/Anhui/1/2005 (H5Anh) into H5pp. Our results demonstrate that a single A134V mutation in the 130-loop of the receptor binding domain is sufficient to render H5Anh the ability to generate H5Anh-pp efficiently, whereas the reverse V134A mutation greatly hampers production of H5Cam-pp. Although protein expression in total cell lysates is similar for H5Anh and H5Cam, cell surface expression of H5Cam is detected at a significantly higher level than that of H5Anh. We further demonstrate by several independent lines of evidence that the behaviour of H5Anh can be explained by a stronger binding to sialic acid receptors implicating residue 134. Conclusions: We have identified a single A134V mutation as the molecular determinant in H5-HA for efficient incorporation into H5pp envelope and delineated the underlying mechanism. The reduced binding to sialic acid receptors as a result of the A134V mutation not only exerts a critical influence in pseudotyping efficiency of H5-HA, but has also an impact at the whole virus level. Because A134V substitution has been reported as a naturally occurring mutation in human host, our results may have implications for the understanding of human host adaptation of avian influenza H5N1 virusesThis work was supported by grants from the Research Fund for the Control of Infectious Diseases of Hong Kong (RFCID#08070972), the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China), the French Ministry of Health, and the RESPARI project of the Institut Pasteur International Network