Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor

Comparisons between structures of the b1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3 (tertbutylamino)-2-hydroxypropoxy]-1H-indole-2 carbonitrile (cyanopindolol) is a weak partial agonist of b1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3 (tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2 carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7- methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both b1AR and b2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey b1AR and an inverse agonist of human b2AR. The structure of 7-methylcyanopindolol–bound b1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound b1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol–bound b1AR and the hydroxyl group of Ser5.46 is positioned 0.8 Å further from the ligand, with respect to the position of the Ser5.46 side chain in cyanopindololbound b1AR. Thus, the molecular basis for the reduction in efficacy of 7 methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists

Bubbling AdS Black Holes

We explore the non-BPS analog of `AdS bubbles', which are regular spherically symmetric 1/2 BPS geometries in type IIB supergravity. They have regular horizons and can be thought of as bubbling generalizations of non-extremal AdS black hole solutions in five-dimensional gauged supergravity. Due to the appearance of the Heun equation even at the linearized level, various approximation and numerical methods are needed in order to extract information about this system. We study how the vacuum expectation value and mass of a particular dimension two chiral primary operator depend on the temperature and chemical potential of the thermal Yang-Mills theory. In addition, the mass of the bubbling AdS black holes is computed. As is shown numerically, there are also non-BPS solitonic bubbles which are completely regular and arise from continuous deformations of BPS AdS bubbles.Comment: 37 pages, 2 figure

An intimate collaboration between peroxisomes and lipid bodies

Although peroxisomes oxidize lipids, the metabolism of lipid bodies and peroxisomes is thought to be largely uncoupled from one another. In this study, using oleic acid–cultured Saccharomyces cerevisiae as a model system, we provide evidence that lipid bodies and peroxisomes have a close physiological relationship. Peroxisomes adhere stably to lipid bodies, and they can even extend processes into lipid body cores. Biochemical experiments and proteomic analysis of the purified lipid bodies suggest that these processes are limited to enzymes of fatty acid β oxidation. Peroxisomes that are unable to oxidize fatty acids promote novel structures within lipid bodies (“gnarls”), which may be organized arrays of accumulated free fatty acids. However, gnarls are suppressed, and fatty acids are not accumulated in the absence of peroxisomal membranes. Our results suggest that the extensive physical contact between peroxisomes and lipid bodies promotes the coupling of lipolysis within lipid bodies with peroxisomal fatty acid oxidation

Implications of the Muon Anomalous Magnetic Moment for Supersymmetry

We re-examine the bounds on supersymmetric particle masses in light of the E821 data on the muon anomalous magnetic moment. We confirm, extend and supersede previous bounds. In particular we find (at one sigma) no lower limit on tan(beta) or upper limit on the chargino mass implied by the data at present, but at least 4 sparticles must be lighter than 700 to 820 GeV and at least one sparticle must be lighter than 345 to 440 GeV. However, the E821 central value bounds tan(beta) > 4.7 and the lighter chargino mass by 690 GeV. For tan(beta) < 10, the data indicates a high probability for direct discovery of SUSY at Run II or III of the Tevatron.Comment: 20 pages LaTeX, 14 figures; references adde

String Tensions and Three Dimensional Confining Gauge Theories

In the context of gauge/gravity duality, we try to understand better the proposed duality between the fractional D2-brane supergravity solutions of (Nucl. Phys. B 606 (2001) 18, hep-th/0101096) and a confining 2+1 dimensional gauge theory. Based on the similarities between this fractional D2-brane solution and D3-brane supergravity solutions with more firmly established gauge theory duals, we conjecture that a confining q-string in the 2+1 dimensional gauge theory is dual to a wrapped D4-brane. In particular, the D4-brane looks like a string in the gauge theory directions but wraps a S**3 in S**4 in the transverse geometry. For one of the supergravity solutions, we find a near quadratic scaling law for the tension: $T \sim q (N-q)$. Based on the tension, we conjecture that the gauge theory dual is SU(N) far in the infrared. We also conjecture that a quadratic or near quadratic scaling is a generic feature of confining 2+1 dimensional SU(N) gauge theories.Comment: 23 pages, 2 figure

Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation

The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EglN prolyl 4-hydroxylases that mark the HIF transcription factor for polyubiquitylation and proteasomal degradation 1. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumors but can suppress tumor growth in some other contexts. IDH1 and IDH2, which catalyze the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumors and leukemias. The resulting mutants display the neomorphic ability to convert 2-OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG) 2, 3. Here we show that R-2HG, but not S-2HG, stimulates EglN activity leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes

Environmental SLAPPs in the UK: threat or opportunity?

Strategic lawsuits against public participation (SLAPPs) brought against the environmental movement in the UK since the 1990s are examined. SLAPPs, a form of Green backlash, have been mobilised across a wide range of policy areas that have seen vigorous campaigning and protest by the movement, including roads, GMOs and, more recently, climate change. SLAPPs are typically regarded as a threat, designed to close down democratic free speech and protest. However, in the UK, there are some notable cases where the environmental movement has been able to use agency to convert what may appear as a legal threat into a positive legal or media opportunity

The split property for locally covariant quantum field theories in curved spacetime

The split property expresses the way in which local regions of spacetime define subsystems of a quantum field theory. It is known to hold for general theories in Minkowski space under the hypothesis of nuclearity. Here, the split property is discussed for general locally covariant quantum field theories in arbitrary globally hyperbolic curved spacetimes, using a spacetime deformation argument to transport the split property from one spacetime to another. It is also shown how states obeying both the split and (partial) Reeh–Schlieder properties can be constructed, providing standard split inclusions of certain local von Neumann algebras. Sufficient conditions are given for the theory to admit such states in ultrastatic spacetimes, from which the general case follows. A number of consequences are described, including the existence of local generators for global gauge transformations, and the classification of certain local von Neumann algebras. Similar arguments are applied to the distal split property and circumstances are exhibited under which distal splitting implies the full split property

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies