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71.
Josef KA Aimone LD Lyons J Raddatz R Hudkins RL 《Bioorganic & medicinal chemistry letters》2012,22(12):4198-4202
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities. 相似文献
72.
Sundar BG Bailey TR Dunn D Hostetler GA Chatterjee S Bacon ER Yue C Schweizer D Aimone LD Gruner JA Lyons J Raddatz R Lesur B 《Bioorganic & medicinal chemistry letters》2012,22(4):1546-1549
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept. 相似文献
73.
One of the most popular and simple models for the calculation of pKas from a protein structure is the semi‐macroscopic electrostatic model MEAD. This model requires empirical parameters for each residue to calculate pKas. Analysis of current, widely used empirical parameters for cysteine residues showed that they did not reproduce expected cysteine pKas; thus, we set out to identify parameters consistent with the CHARMM27 force field that capture both the behavior of typical cysteines in proteins and the behavior of cysteines which have perturbed pKas. The new parameters were validated in three ways: (1) calculation across a large set of typical cysteines in proteins (where the calculations are expected to reproduce expected ensemble behavior); (2) calculation across a set of perturbed cysteines in proteins (where the calculations are expected to reproduce the shifted ensemble behavior); and (3) comparison to experimentally determined pKa values (where the calculation should reproduce the pKa within experimental error). Both the general behavior of cysteines in proteins and the perturbed pKa in some proteins can be predicted reasonably well using the newly determined empirical parameters within the MEAD model for protein electrostatics. This study provides the first general analysis of the electrostatics of cysteines in proteins, with specific attention paid to capturing both the behavior of typical cysteines in a protein and the behavior of cysteines whose pKa should be shifted, and validation of force field parameters for cysteine residues. Proteins 2012. © 2012 Wiley Periodicals, Inc. 相似文献
74.
Palaniappan R Singh S Singh UP Singh R Ades EW Briles DE Hollingshead SK Royal W Sampson JS Stiles JK Taub DD Lillard JW 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(4):2346-2356
Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Recently, it has been shown that genetic polymorphisms can result in diminished expression of CCL5, which results in increased susceptibility to and progression of infectious diseases. We show that CCL5, together with Th cytokine mRNA expression, is temporally up-regulated during pneumococcal carriage. To determine the contribution of CCL5 to pneumococcal surface antigen A-specific humoral and cellular pneumococcal immunity, mice were treated with anti-CCL5 or control Abs before and during Streptococcus pneumoniae strain EF3030-challenge for the initiation of carriage. CCL5 blockade resulted in a decrease of CD4(+) and CD8(+) T cells as well as CD11b(+) cells in the spleen, cervical lymph node, lung, and nasopharyngeal associated lymphoid tissue during the recognition phase of the pneumococcal adaptive immune response. CCL5 blockade significantly reduced the Ag-specific IgG2a and IgG1 Abs in serum and IgA Ab levels in nasal washes. These decreases also corresponded to reductions in Ag-specific T cell (mucosal and systemic) responses. CCL5 inhibition resulted in decreasing the quantity of IL-4- and IFN-gamma-secreting CD4(+) T cells and increasing the number of Ag-specific IL-10-producing CD4(+) T cells; these changes combined also corresponded with the transition from pneumococcal carriage to lethal pneumonia. These data suggest that CCL5 is an essential factor for the induction and maintenance of protective pneumococcal immunity. 相似文献
75.
Wang C McDonald KG McDonough JS Newberry RD 《American journal of physiology. Gastrointestinal and liver physiology》2006,291(4):G595-G604
Isolated lymphoid follicles (ILFs) are organized intestinal lymphoid structures whose formation can be induced by luminal stimuli. ILFs have been demonstrated to act as inductive sites for the generation of immune responses directed toward luminal stimuli; however, the phenotype of the immune response initiated within ILFs has largely been uninvestigated. To gain a better understanding of the immune responses initiated within ILFs, we examined phenotypic and functional aspects of the largest cellular component of the murine ILF lymphocyte population, B lymphocytes. We observed that murine ILF B lymphocytes are composed of a relatively homogenous population of follicular B-2 B lymphocytes. Consistent with their proximity to multiple stimuli, ILF B lymphocytes displayed a more activated phenotype compared with their counterparts in the spleen and Peyer's patch (PP). ILF B lymphocytes also expressed higher levels of immunomodulatory B7 and CD28 family members B7X and programmed death-1 compared with their counterparts in the spleen and PP. ILF B lymphocytes preferentially differentiate into IgA-producing plasma cells and produce more IL-4 and IL-10 and less interferon-gamma compared with their counterparts in the spleen. Immunoglobulin repertoire analysis from individual ILFs demonstrated that ILFs contain a polyclonal population of B lymphocytes. These findings indicate that murine ILFs contain a polyclonal population of follicular B-2 B lymphocytes with a phenotype similar to PP B lymphocytes and that, in unchallenged animals, ILFs promote immune responses with a homeostatic phenotype. 相似文献
76.
Louise Bélanger Kristin A. Dimmick Jacquelyn S. Fleming Trevor C. Charles 《Molecular microbiology》2009,74(5):1223-1237
Exopolysaccharides, either succinoglycan or galactoglucan, are essential for the establishment of the symbiosis between Sinorhizobium meliloti and Medicago sativa (alfalfa). The ExoS/ChvI two‐component regulatory system is known as a regulator of succinoglycan production but the genes that are directly regulated by ChvI have not been determined. Difficulty isolating exoS and chvI null mutants has prompted the suggestion that these genes are essential for S. meliloti viability. We have successfully isolated exoS and chvI null mutants using a merodiploid‐facilitated strategy. We present evidence that the S. meliloti ExoS/ChvI two‐component regulatory system is essential for symbiosis with alfalfa. Phenotypic analyses of exoS and chvI null mutant strains demonstrate that ExoS/ChvI controls both succinoglycan and galactoglucan production and is required for growth on over 21 different carbon sources. These new findings suggest that the ExoS/ChvI regulatory targets might not be the exo genes that are specific for succinoglycan biosynthesis but rather genes that have common influence on both succinoglycan and galactoglucan production. Other studied alpha‐proteobacteria ExoS/ChvI orthologues are required for the bacteria to invade or persist in host cells and thus we present more evidence that this two‐component regulatory system is essential for alpha‐proteobacterial host interaction. 相似文献
77.
Jacquelyn A. Kallunki 《Brittonia》2009,61(1):28-34
The name Neoraputia was published without citation of the type, making it and the names of the four species transferred to it invalid. The genus
name and combinations are validated here. Lectotypes are chosen for the basionyms, Aruba alba, Raputia magnifica, R. paraensis, and Raputia trifoliata. Two new species, Neoraputia micrantha and N. calliantha, from forests of eastern Bahia, Brazil, are described. 相似文献
78.
Amyris amazonica, from the Amazonian forests of northeastern Ecuador, is described. This new species is characterized by a shrubby or arborescent
habit, very large unifoliolate leaves, long petioles, and fasciculate, pseudoracemose inflorescences.
Resumen Se describe Amyris amazonica, una nueva especie de arbusto o arbolillo de la selva Amazónica del nororiente de Ecuador. Esta nueva especie se caracteriza por presentar hojas unifolioladas con largos pecíolos y muy grandes láminas e inflorescencias pseudoracemosas fasciculadas.相似文献
79.
80.
Richard C. Crist Jacquelyn J. Roth Amy A. Baran Benjamin J. McEntee Linda D. Siracusa Arthur M. Buchberg 《Mammalian genome》2010,21(9-10):450-457
The adenomatous polyposis coli (APC) gene is known to act as a tumor suppressor gene in both sporadic and hereditary colorectal cancer by negatively regulating WNT signaling. Familial adenomatous polyposis (FAP) patients develop intestinal polyps due to the presence of a single germline mutation in APC. The severity of the FAP phenotype is a function of the position of the APC mutation, indicating a complex role for APC that extends beyond the canonical WNT pathway. APC encodes a large protein with multiple functional domains, including an armadillo repeat domain that has been linked to protein–protein interactions. To determine the effect of the armadillo repeat domain on intestinal tumorigenesis, we generated a congenic mouse line (Apc Δ242 ) carrying a gene trap cassette between exons 7 and 8 of the murine Apc gene. Apc Δ242/+ mice express a truncated Apc product lacking the armadillo repeat domain as part of a fusion protein with β-geo. Expression of the fusion product was confirmed by X-gal staining, ensuring that Apc Δ242 is not a null allele. In contrast, Apc Min/+ mice produce a truncated Apc product that contains an intact armadillo repeat domain. On the C57BL/6J background, Apc Δ242/+ mice develop more polyps than do Apc Min/+ mice along the entire length of the small intestine; however, polyps were significantly smaller in Apc Δ242/+ mice. In addition, polyp multiplicity in Apc Δ242/+ mice is affected by polymorphisms between inbred strains. These data suggest that the armadillo repeat domain of the Apc protein suppresses tumor initiation in the murine intestine while also promoting tumor growth. 相似文献