A heritable switch in carbon source utilization driven by an unusual yeast prion

Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is self-propagating. Through such self-propagating changes in function, yeast prions act as protein-based elements of phenotypic inheritance. We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR[superscript +]] (for “resistant to glucose-associated repression,” with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR[superscript +]] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. The Pma1 proteins from closely related Saccharomyces species are also associated with the appearance of [GAR[superscript +]]. This allowed us to confirm the relationship between Pma1, Std1, and [GAR[superscript +]] by establishing that these proteins can create a transmission barrier for prion propagation and induction in Saccharomyces cerevisiae. The fact that yeast cells employ a prion-based mechanism for heritably switching between distinct carbon source utilization strategies, and employ the plasma membrane proton pump to do so, expands the biological framework in which self-propagating protein-based elements of inheritance operate.United States. National Institutes of Health (grant GM25874

Reconstruction of Causal Networks by Set Covering

We present a method for the reconstruction of networks, based on the order of nodes visited by a stochastic branching process. Our algorithm reconstructs a network of minimal size that ensures consistency with the data. Crucially, we show that global consistency with the data can be achieved through purely local considerations, inferring the neighbourhood of each node in turn. The optimisation problem solved for each individual node can be reduced to a Set Covering Problem, which is known to be NP-hard but can be approximated well in practice. We then extend our approach to account for noisy data, based on the Minimum Description Length principle. We demonstrate our algorithms on synthetic data, generated by an SIR-like epidemiological model.Comment: Under consideration for the ECML PKDD 2010 conferenc

Parity Violation in Astrophysics

Core collapse supernovae are gigantic explosions of massive stars that radiate 99% of their energy in neutrinos. This provides a unique opportunity for large scale parity or charge conjugation violation. Parity violation in a strong magnetic field could lead to an asymmetry in the neutrino radiation and recoil of the newly formed neutron star. Charge conjugation violation in the neutrino-nucleon interaction reduces the ratio of neutrons to protons in the neutrino driven wind above the neutron star. This is a problem for r-process nucleosynthesis in this wind. On earth, parity violation is an excellent probe of neutrons because the weak charge of a neutron is much larger than that of a proton. The Parity Radius Experiment (PREX) at Jefferson Laboratory aims to precisely measure the neutron radius of $^{208}$Pb with parity violating elastic electron scattering. This has many implications for astrophysics, including the structure of neutron stars, and for atomic parity nonconservation experiments.}Comment: 4 pages, 2 figures, proceedings of PAVI04 conference in Grenoble, Franc

Infrared Exponents and Running Coupling of SU(N) Yang-Mills Theories

We present approximate solutions for the gluon and ghost propagators as well as the running coupling in Landau gauge Yang-Mills theories. We solve the corresponding Dyson-Schwinger equations in flat Euclidean space-time without any angular approximation. This supplements recently obtained results employing a four-torus, i.e. a compact space-time manifold, as infrared regulator. We confirm previous findings deduced from an extrapolation with tori of different volumes: the gluon propagator is weakly vanishing in the infrared and the ghost propagator is highly singular. For non-vanishing momenta our propagators are in remarkable agreement with recent lattice calculations.Comment: 11 pages, 4 figure

Ultra-fast Rotors for Molecular Machines and Functional Materials via Halogen Bonding: Crystals of 1,4-Bis(iodoethynyl)bicyclo 2.2.2 octane with Distinct Gigahertz Rotation at Two Sites

As a point of entry to investigate the potential of halogen-bonding interactions in the construction of functional materials and crystalline molecular machines, samples of 1,4-bis(iodoethynyl)bicyclo[2.2.2] octane (BIBCO) were synthesized and crystallized. Knowing that halogen-bonding interactions are common between electron-rich acetylenic carbons and electron-deficient iodines, it was expected that the BIBCO rotors would be an ideal platform to investigate the formation of a crystalline array of molecular rotors. Variable temperature single crystal X-ray crystallography established the presence of a halogen-bonded network, characterized by lamellarly ordered layers of crystallographically unique BIBCO rotors, which undergo a reversible monoclinic-to-triclinic phase transition at 110 K. In order to elucidate the rotational frequencies and the activation parameters of the BIBCO molecular rotors, variable-temperature H-1 wide-line and C-13 cross-polarization/magic-angle spinning solid-state NMR experiments were performed at temperatures between 27 and 290 K. Analysis of the H-1 spin-lattice relaxation and second moment as a function of temperature revealed two dynamic processes simultaneously present over the entire temperature range studied, with temperature-dependent rotational rates of k(rot) = 5.21 x 10(10) s(-1).exp(-1.48 kcal.mol(-1)/RT) and k(rot) = 8.00 x 10(10) s(-1).exp(-2.75 kcal.mol(-1)/RT). Impressively, these correspond to room temperature rotational rates of 4.3 and 0.8 GHz, respectively. Notably, the high-temperature plastic crystalline phase I of bicyclo[2.2.2]octane has a reported activation energy of 1.84 kcal.mol(-1) for rotation about the 1,4 axis, which is 24% larger than E-a = 1.48 kcal.mol(-1) for the same rotational motion of the fastest BIBCO rotor; yet, the BIBCO rotor has three fewer degrees of translational freedom and two fewer degrees of rotational freedom! Even more so, these rates represent some of the fastest engineered molecular machines, to date. The results of this study highlight the potential of halogen bonding as a valuable construction tool for the design and the synthesis of amphidynamic artificial molecular machines and suggest the potential of modulating properties that depend on the dielectric behavior of crystalline media

The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo

Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg-1; -2 h, 1 mg kg-1 i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg-1 fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10-5M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg-1 i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg-1 UFP-101 (i.v., jugular vein). Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation

CHO genome mining for synthetic promoter design

Synthetic promoters are an attractive alternative for use in mammalian hosts such as CHO cells as they can be designed de novo with user-defined functionalities. In this study, we describe and validate a method for bioprocess-directed design of synthetic promoters utilizing CHO genomic sequence information. We designed promoters with two objective features, (i) constitutive high-level recombinant gene transcription, and (ii) upregulated transcription under mild hypothermia or late-stage culture. CHO genes varying in transcriptional activity were selected based on a comparative analysis of RNA-Seq transcript levels in normal and biphasic cultures in combination with estimates of mRNA half-life from published genome scale datasets. Discrete transcription factor regulatory elements (TFREs) upstream of these genes were informatically identified and functionally screened in vitro to identify a subset of TFREs with the potential to support high activity recombinant gene transcription during biphasic cell culture processes. Two libraries of heterotypic synthetic promoters with varying TFRE combinations were then designed in silico that exhibited a maximal 2.5-fold increase in transcriptional strength over the CMV-IE promoter after transient transfection into host CHO-K1 cells. A subset of synthetic promoters was then used to create stable transfectant pools using CHO-K1 cells under glutamine synthetase selection. Whilst not achieving the maximal 2.5-fold increase in productivity over stable pools harboring the CMV promoter, all stably transfected cells utilizing synthetic promoters exhibited increased reporter production - up to 1.6-fold that of cells employing CMV, both in the presence or absence of intron A immediately downstream of the promoter. The increased productivity of stably transfected cells harboring synthetic promoters was maintained during fed-batch culture, with or without a transition to mild hypothermia at the onset of stationary phase. Our data exemplify that it is important to consider both host cell and intended bioprocess contexts as design criteria in the de novo construction of synthetic genetic parts for mammalian cell engineering

A Multiple Commutator Formula for the Sum of Feynman Diagrams

In the presence of a large parameter, such as mass or energy, leading behavior of individual Feynman diagrams often get cancelled in the sum. This is known to happen in large-$N_c$ QCD in the presence of a baryon, and also in the case of high-energy electron-electron as well as quark-quark scatterings. We present an exact combinatorial formula, involving multiple commutators of the vertices, which can be used to compute such cancellations. It is a non-abelian generalization of the eikonal formula, and will be applied in subsequent publications to study the consistency of large-$N_c$ QCD involving baryons, as well as high-energy quark-quark scattering in ordinary QCD.Comment: uu-encoded latex file with two postscript figure

Loop effects and non-decoupling property of SUSY QCD in gb→tH−g b\to tH^{-}

One-loop SUSY QCD radiative correction to $gb \to tH^{-}$ cross section is calculated in the Minimal Supersymmetric Standard Model. We found that SUSY QCD is non-decoupling if the gluino mass and the parameter $\mu$, $A_t$ or $A_b$ are at the same order and get large. The non-decoupling contribution can be enhanced by large $\tan\beta$ and therefore large corrections to the hadronic production rates at the Tevatron and LHC are expected in the large $\tan\beta$ limit. The fundamental reason for such non-decoupling behavior is found to be some couplings in the loops being proportional to SUSY mass parameters.Comment: 15 pages, 5 PS figures. A proof of non-decouplings of SUSY-QCD, Comments on corresponding QCD correction and references adde