Altered sterol metabolism in budding yeast affects mitochondrial iron–sulfur (Fe-S) cluster synthesis

Ergosterol synthesis is essential for cellular growth and viability of the budding yeast Saccharomyces cerevisiae, and intracellular sterol distribution and homeostasis are therefore highly regulated in this species. Erg25 is an iron-containing C4-methyl sterol oxidase that contributes to the conversion of 4,4-dimethylzymosterol to zymosterol, a precursor of ergosterol. The ERG29 gene encodes an endoplasmic reticulum (ER)-associated protein, and here we identified a role for Erg29 in the methyl sterol oxidase step of ergosterol synthesis. ERG29 deletion resulted in lethality in respiring cells, but respiration-incompetent (Rho- or Rho0) cells survived, suggesting that Erg29 loss leads to accumulation of oxidized sterol metabolites that affect cell viability. Down-regulation of ERG29 expression in Δerg29 cells indeed led to accumulation of methyl sterol metabolites, resulting in increased mitochondrial oxidants and a decreased ability of mitochondria to synthesize iron-sulfur (Fe-S) clusters due to reduced levels of Yfh1, the mammalian frataxin homolog, which is involved in mitochondrial iron metabolism. Using a high-copy genomic library, we identified suppressor genes that permitted growth of Δerg29 cells on respiratory substrates, and these included genes encoding the mitochondrial proteins Yfh1, Mmt1, Mmt2, and Pet20, which reversed all phenotypes associated with loss of ERG29 Of note, loss of Erg25 also resulted in accumulation of methyl sterol metabolites and also increased mitochondrial oxidants and degradation of Yfh1. We propose that accumulation of toxic intermediates of the methyl sterol oxidase reaction increases mitochondrial oxidants, which affect Yfh1 protein stability. These results indicate an interaction between sterols generated by ER proteins and mitochondrial iron metabolism

Charm Cross Sections for the Tevatron Run II

We present a calculation of the D^{*+}, D^+ and D^0 meson single inclusive production cross section for the Tevatron Run II. We use the FONLL approach in perturbative QCD, which, besides including the known next-to-leading order corrections, also provides for the resummation at the next-to-leading logarithmic level of terms enhanced at large p_T by powers of log(p_T/m), where m is the charm mass and p_T is its transverse momentum. Non-perturbative effects in charm hadronization are extracted, in moment space, from recent ALEPH data for D^* fragmentation in e^+e^- collisions.Comment: 11 pages, 5 figures, LaTe

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells

Endosomal sorting complexes required for transport III (ESCRT-III) proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Here, we report that Lem2p (LEM2), a member of the LEM (Lap2-Emerin-Man1) family of inner nuclear membrane proteins, and the ESCRT-II/ESCRT-III hybrid protein Cmp7p (CHMP7), work together to recruit additional ESCRT-III proteins to holes in the nuclear membrane. In Schizosaccharomyces pombe, deletion of the ATPase vps4 leads to severe defects in nuclear morphology and integrity. These phenotypes are suppressed by loss-of-function mutations that arise spontaneously in lem2 or cmp7, implying that these proteins may function upstream in the same pathway. Building on these genetic interactions, we explored the role of LEM2 during nuclear envelope reformation in human cells. We found that CHMP7 and LEM2 enrich at the same region of the chromatin disk periphery during this window of cell division and that CHMP7 can bind directly to the C-terminal domain of LEM2 in vitro. We further found that, during nuclear envelope formation, recruitment of the ESCRT factors CHMP7, CHMP2A, and IST1/CHMP8 all depend on LEM2 in human cells. We conclude that Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope

Hadronic Cross-sections in two photon Processes at a Future Linear Collider

In this note we address the issue of measurability of the hadronic cross-sections at a future photon collider as well as for the two-photon processes at a future high energy linear $e^+e^-$ collider. We extend, to higher energy, our previous estimates of the accuracy with which the \gamgam\ cross-section needs to be measured, in order to distinguish between different theoretical models of energy dependence of the total cross-sections. We show that the necessary precision to discriminate among these models is indeed possible at future linear colliders in the Photon Collider option. Further we note that even in the $e^+e^-$ option a measurement of the hadron production cross-section via \gamgam processes, with an accuracy necessary to allow discrimination between different theoretical models, should be possible. We also comment briefly on the implications of these predictions for hadronic backgrounds at the future TeV energy $e^+e^-$ collider CLIC.Comment: 20 pages, 5 figures, LaTeX. Added an acknowledgemen

Leptons in Holographic Composite Higgs Models with Non-Abelian Discrete Symmetries

We study leptons in holographic composite Higgs models, namely in models possibly admitting a weakly coupled description in terms of five-dimensional (5D) theories. We introduce two scenarios leading to Majorana or Dirac neutrinos, based on the non-abelian discrete group $S_4\times \Z_3$ which is responsible for nearly tri-bimaximal lepton mixing. The smallness of neutrino masses is naturally explained and normal/inverted mass ordering can be accommodated. We analyze two specific 5D gauge-Higgs unification models in warped space as concrete examples of our framework. Both models pass the current bounds on Lepton Flavour Violation (LFV) processes. We pay special attention to the effect of so called boundary kinetic terms that are the dominant source of LFV. The model with Majorana neutrinos is compatible with a Kaluza-Klein vector mass scale $m_{KK}\gtrsim 3.5$ TeV, which is roughly the lowest scale allowed by electroweak considerations. The model with Dirac neutrinos, although not considerably constrained by LFV processes and data on lepton mixing, suffers from a too large deviation of the neutrino coupling to the $Z$ boson from its Standard Model value, pushing $m_{KK}\gtrsim 10$ TeV.Comment: 37 pages, 4 figures; v2: Note added in light of recent T2K and MINOS results, figures updated with new limit from MEG, references added, various minor improvements, matches JHEP published versio

Colliders and Cosmology

Dark matter in variations of constrained minimal supersymmetric standard models will be discussed. Particular attention will be given to the comparison between accelerator and direct detection constraints.Comment: Submitted for the SUSY07 proceedings, 15 pages, LaTex, 26 eps figure

Resolved Photon Processes

We review the present level of knowledge of the hadronic structure of the photon, as revealed in interactions involving quarks and gluons ``in" the photon. The concept of photon structure functions is introduced in the description of deep--inelastic $e \gamma$ scattering, and existing parametrizations of the parton densities in the photon are reviewed. We then turn to hard \gamp\ and \gaga\ collisions, where we treat the production of jets, heavy quarks, hard (direct) photons, \jpsi\ mesons, and lepton pairs. We also comment on issues that go beyond perturbation theory, including recent attempts at a comprehensive description of both hard and soft \gamp\ and \gaga\ interactions. We conclude with a list of open problems.Comment: LaTeX with equation.sty, 85 pages, 29 figures (not included). A complete PS file of the paper, including figures, can be obtained via anonymous ftp from ftp://phenom.physics.wisc.edu/pub/preprints/1995/madph-95-898.ps.

Inhibition of Lipoprotein-Associated Phospholipase A2 Ameliorates Inflammation and Decreases Atherosclerotic Plaque Formation in ApoE-Deficient Mice

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group. inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis

Pathogen Entrapment by Transglutaminase—A Conserved Early Innate Immune Mechanism

Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or—as previously shown—the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions

An agent-based model of the response to angioplasty and bare-metal stent deployment in an atherosclerotic blood vessel

Purpose: While animal models are widely used to investigate the development of restenosis in blood vessels following an intervention, computational models offer another means for investigating this phenomenon. A computational model of the response of a treated vessel would allow investigators to assess the effects of altering certain vessel- and stent-related variables. The authors aimed to develop a novel computational model of restenosis development following an angioplasty and bare-metal stent implantation in an atherosclerotic vessel using agent-based modeling techniques. The presented model is intended to demonstrate the body's response to the intervention and to explore how different vessel geometries or stent arrangements may affect restenosis development. Methods: The model was created on a two-dimensional grid space. It utilizes the post-procedural vessel lumen diameter and stent information as its input parameters. The simulation starting point of the model is an atherosclerotic vessel after an angioplasty and stent implantation procedure. The model subsequently generates the final lumen diameter, percent change in lumen cross-sectional area, time to lumen diameter stabilization, and local concentrations of inflammatory cytokines upon simulation completion. Simulation results were directly compared with the results from serial imaging studies and cytokine levels studies in atherosclerotic patients from the relevant literature. Results: The final lumen diameter results were all within one standard deviation of the mean lumen diameters reported in the comparison studies. The overlapping-stent simulations yielded results that matched published trends. The cytokine levels remained within the range of physiological levels throughout the simulations. Conclusion: We developed a novel computational model that successfully simulated the development of restenosis in a blood vessel following an angioplasty and bare-metal stent deployment based on the characteristics of the vessel crosssection and stent. A further development of this model could ultimately be used as a predictive tool to depict patient outcomes and inform treatment options. © 2014 Curtin, Zhou