Structure of the human histamine H1 receptor complex with doxepin

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.     

Cloning, sequencing and expression of cDNA for a novel subunit of acetylcholine receptor from calf muscle

The nicotinic acetylcholine receptor (AChR) from fish electric organ has a subunit structure of alpha 2 beta gamma delta, and this is thought to be also the case for the mammalian skeletal muscle AChR. By cloning and sequencing the complementary or genomic DNAs, we have previously elucidated the primary structures of all four subunits of the Torpedo californica electroplax and calf muscle AChR and of the alpha- and gamma-subunits of the human muscle AChR; the primary structures of the gamma-subunit of the T. californica AChR and the alpha-subunit of the Torpedo marmorata AChR have also been deduced elsewhere. We have now cloned DNA complementary to the calf muscle messenger RNA encoding a novel polypeptide (the epsilon-subunit) whose deduced amino-acid sequence has features characteristic of the AChR subunits and which shows higher sequence homology with the gamma-subunit than with the other subunits. cDNA expression studies indicate that the calf epsilon-subunit, as well as the calf gamma-subunit, can replace the Torpedo gamma-subunit to form the functional receptor in combination with the Torpedo alpha-, beta- and delta-subunits.     

内蒙古白绒山羊不同放牧期瘤胃甲烷菌mcrA基因的RFLP分析

分析不同放牧期内蒙古绒山羊瘤胃中甲烷细菌的种群组成.选取甲烷菌mcrA基因的特异性引物序列,对瘤胃液中提取的细菌总DNA进行PCR扩增,建立甲烷细菌特异性的mcrA基因文库.用限制性内切酶TapⅠ对该文库特异性片段进行限制性内切片段长度多态性分析(RFLP).结果表明牧草生长幼嫩期、旺盛期和枯草期随机挑选的特异性克隆片段分别为115、105和112,分成6个RFLP类型,每期的不同类型占了所有分析克隆子的比例分别为36%、28%、20%、3.5%、3.5%和9%;38%、27%、18%、7%、5.5%和4.5%;35%、24%、18%、6.5%、3%和13.5%.     

Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.     

Regulation of glucose transporter messenger RNA in insulin-deficient states

Recent studies have indicated that a family of structurally related proteins with distinct but overlapping tissue distributions are responsible for facilitative glucose transport in mammalian tissues. Insulin primarily stimulates glucose transport by inducing the redistribution of a unique glucose transporter protein from an intracellular pool to the plasma membrane. This 509-amino-acid integral membrane protein, termed GLUT-4, is the main insulin-responsive glucose transporter in adipose and muscle tissues. We have observed a dramatic decrease (tenfold) in the steady-state levels of GLUT-4 messenger RNA in adipose tissue from fasted rats or rats made insulin deficient with streptozotocin. Insulin treatment of the streptozotocin-diabetic rats or refeeding the fasted animals causes a rapid recovery of the GLUT-4 mRNA to levels significantly above those observed in untreated control animals. By contrast, the levels of the erythrocyte/HepG2/rat brain-type glucose transporter mRNA remain essentially unchanged under these conditions. These data suggest that the in vivo expression of GLUT-4 mRNA in rat adipose tissue is regulated by insulin.     

Multiple oncogenesis of neural crest cells by steroids in suckling mice.

In suckling mice injected with steroids, multiple tumors occurred in the sites where neural crest cells normally are present. It is speculated that the phase of the cell cycle of the neural crest cells may have something to do with its cell surface and cellular phenotypic expression in the system mediated by cyclic AMP.     

Multiple APUD system (neural crest) tumors caused by endotoxin in suckling mice

Summary In suckling mice injected i. p. with endotoxin on the 1st day after birth and surviving up to the 4th day, multiple tumors and heterotopic melanin pigmentation occurred in the sites where the neural crest cells may be present.     

Shadow free texture acquisition of a large scale scene for city modeling

Texture acquisition of a large scale scene is one of the critical research areas in computer vision and can be used in other application areas such as computer graphics (CG), the intelligent transportation system (ITS) and the 3D geographic information system (GIS). Moreover, to acquire texture without noise (e. g. , a shadow, an obstacle body) is vital for such work. Although obstacles can be removed by using 3D geometric data, shadow elimination is still a difficult problem and strongly required for the CG and ITS community, especially for city modeling and simulation purposes. In this paper, we propose an automatic multiple image fusion technique and an efficient and simple shadow removing technique to retrieve high quality texture images of an urban area. The image fusion can be efficiently achieved by epipolar plane image (EPI) analysis, and the shadow elimination can be successfully carried out by an illumination-independent color clustering technique. The strength of this algorithm is that we can successfully fuse multiple images and eliminate shadows from the fused single image, especially in low dynamic range images, which have proven difficult using previous techniques.     

Mastocytosis in suckling mice.

In suckling mice injected intraperitoneally with mitomycin C on the 1st to 5th day after birth and sacrificed in the course of 24 or 48 h after injection, mastocytosis occurred in the oral mucosa membrane, skin of the trunk or extremities and bone marrow of extremities.     

Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2

Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.