bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of Bap31 and MHC Class I Molecules and Their Traffic Out of the Endoplasmic Reticulum
Authors: Abe Fumiyoshi , Van Prooyen Nancy , Ladasky John J. , Edidin Michael
Published: April 2009

The endoplasmic reticulum (ER) protein Bap31 associates with nascent class I MHC molecules. It appears to mediate the export of class I MHC molecules from the ER and may also be involved in their quality control. In this study, we use Förster resonance energy transfer and quantitative fluorescence imaging to show that in human, HeLa cells, Bap31 clusters with MHC class I (HLA-A2) molecules in the ER, and traffics via export vesicles to the ER/Golgi intermediate compartment. Förster resonance energy transfer between Bap31 and HLA-A2 and forward traffic increases when MHC class I molecules are loaded with a pulse of peptide. The increased forward traffic is blocked by overexpression of Bap29, a partner protein for Bap31, which localizes to the ER. Thus, in HeLa cells, Bap31 is involved in the exit of peptide-loaded MHC class I from the ER, and its function is regulated by its interaction with its homologue, Bap29.
Heat Shock Protein 96 Is Elevated in Rheumatoid Arthritis and Activates Macrophages Primarily via TLR2 Signaling
Authors: Huang Qi-Quan , Sobkoviak Rudina , Jockheck-Clark Angela R. , Shi Bo , Mandelin Arthur M. , Tak Paul Peter , Haines G. Kennith , Nicchitta Christopher V. , Pope Richard M.
Published: April 2009

Macrophages are important mediators of chronic inflammation and are prominent in the synovial lining and sublining of patients with rheumatoid arthritis (RA). Recently, we demonstrated increased TLR2 and TLR4 expression and increased response to microbial TLR2 and TLR4 ligands in macrophages from the joints of RA. The current study characterized the expression of the 96-kDa heat shock glycoprotein (gp96) in the joints of RA and its role as an endogenous TLR ligand to promote innate immunity in RA. gp96 was increased in RA compared with osteoarthritis and arthritis-free control synovial tissues. The expression of gp96 strongly correlated with inflammation and synovial lining thickness. gp96 was increased in synovial fluid from the joints of RA compared with disease controls. Recombinant gp96 was a potent activator of macrophages and the activation was mediated primarily through TLR2 signaling. The cellular response to gp96 was significantly stronger with RA synovial macrophages compared with peripheral blood monocytes from RA or healthy controls. The transcription of TLR2, TNF-α, and IL-8, but not TLR4, was significantly induced by gp96, and the induction was significantly greater in purified RA synovial macrophages. The expression of TLR2, but not TLR4, on synovial fluid macrophages strongly correlated with the level of gp96 in the synovial fluid. The present study documents the potential role of gp96 as an endogenous TLR2 ligand in RA and provides insight into the mechanism by which gp96 promotes the chronic inflammation of RA, identifying gp96 as a potential new therapeutic target.
IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa
Authors: Steenwinckel Valérie , Louahed Jamila , Lemaire Muriel M. , Sommereyns Caroline , Warnier Guy , McKenzie Andrew , Brombacher Frank , Van Snick Jacques , Renauld Jean-Christophe
Published: April 2009

IL-9 contributes to lung inflammatory processes such as asthma, by promoting mast cell differentiation, B cell activation, eosinophilia, and mucus production by lung epithelial cells. The observation that IL-9 overexpressing mice show increased mast cell numbers in the intestinal mucosa suggests that this cytokine might also play a role in intestinal inflammation. In colons from IL-9 transgenic mice, the expression of Muc2, a major intestinal mucin gene, was up-regulated, together with that of CLCA3 chloride channel and resistin like α, which are goblet cell-associated genes. Additional IL-9 up-regulated genes were identified and included innate immunity genes such as angiogenin 4 and the PLA2g2a phospholipase A2, which are typical Paneth cell markers. Histochemical staining of Paneth cells by phloxine/tartrazine showed that IL-9 induces Paneth cell hyperplasia in Lieberkühn glands of the small intestine, and in the colonic mucosa, where this cell type is normally absent. Expression of Paneth cell markers, including angiogenin 4, PLA2g2a, and cryptdins, was induced in the colon of wild-type mice after two to four daily administrations of IL-9. By crossing IL-9 transgenic mice with IL-13−/− mice, or by injecting IL-9 into IL-4R−/− mice, we showed that IL-13 was required for the up-regulation of these Paneth cell-specific genes by IL-9. Taken together, our data indicate that Paneth cell hyperplasia and expression of their various antimicrobial products contribute to the immune response driven by TH2 cytokines, such as IL-9 and IL-13 in the intestinal mucosa.
Costimulation of Dendritic Epidermal γδ T Cells by a New NKG2D Ligand Expressed Specifically in the Skin
Authors: Whang Michael I. , Guerra Nadia , Raulet David H.
Published: April 2009

Dendritic epidermal T cells (DETCs) are a highly specialized population of γδ T cells that resides in the murine skin and participates in wound healing and tumor surveillance. Despite the expression of other stimulatory receptors on these cells, mechanisms involving activation have focused primarily on the invariant Vγ3-Vδ1 TCR expressed by DETCs. All DETCs also express the activating NKG2D receptor, but the role of NKG2D in DETC activation remains unclear, as does the identity of NKG2D ligands that are functionally expressed in the skin. In this study, we document the cloning of an NKG2D ligand H60c that is expressed specifically in the skin and in cultured keratinocytes and demonstrate its role in the activation of DETCs and NK cells. The ligand is unique among NKG2D ligands in being up-regulated in cultured keratinocytes, and its interaction with NKG2D is essential for DETC activation. Importantly, it is shown that engagement of NKG2D is not sufficient to activate DETCs, but instead provides a costimulatory signal that is nevertheless essential for activating DETCs in response to stimulation with keratinocytes.
IL-22-Dependent Attenuation of T Cell-Dependent (ConA) Hepatitis in Herpes Virus Entry Mediator Deficiency
Authors: Wahl Christian , Wegenka Ursula Maria , Leithäuser Frank , Schirmbeck Reinhold , Reimann Jörg
Published: April 2009

Coinhibitors and costimulators control intrahepatic T cell responses that trigger acute hepatitis. We used the ConA-induced hepatitis model in the mouse to test if the coinhibitor herpes virus entry mediator (HVEM) modulates hepatitis-inducing T cell responses. Compared with ConA-injected, wild-type (wt) C57BL/6 (B6) mice, HVEM-deficient (HVEM−/−) B6 mice showed lower serum transaminase levels and lower proinflammatory IFN-γ, but higher protective IL-22 serum levels and an attenuated liver histopathology. The liver type I invariant NKT cell population that initiates acute hepatitis in this model was reduced in HVEM−/− mice but their surface phenotype was similar to that of untreated or ConA-treated wt controls. In response to mitogen injection, liver invariant NKT cells from HVEM−/− B6 mice produced in vivo more IL-22 but lower amounts of IFN-γ and IL-4 than wt controls. Bone marrow chimeras showed that HVEM deficiency of the liver nonparenchymal cell population, but not of the parenchymal cell population, mediated the attenuated course of the dendritic cell- and T cell-dependent ConA hepatitis. IL-22 is produced more efficiently by liver NKT cells from HVEM−/− than from wt mice, and its Ab-mediated neutralization of IL-22 aggravated the course of hepatitis in wt and HVEM−/− mice. Hence, HVEM expression promotes pathogenic, proinflammatory Th1 responses but down-modulates protective IL-22 responses of T cells in this model of acute hepatitis.
Nerve Growth Factor and Neurotrophin-3 Mediate Survival of Pulmonary Plasma Cells during the Allergic Airway Inflammation
Authors: Abram Melanie , Wegmann Michael , Fokuhl Verena , Sonar Sanchaita , Luger Elke Olga , Kerzel Sebastian , Radbruch Andreas , Renz Harald , Zemlin Michael
Published: April 2009

Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-κB subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease.
Mitocryptide-2: Purification, Identification, and Characterization of a Novel Cryptide That Activates Neutrophils
Authors: Mukai Hidehito , Seki Tetsuo , Nakano Hiroko , Hokari Yoshinori , Takao Toshifumi , Kawanami Masanori , Tsukagoshi Hiroyuki , Kimura Hirokazu , Kiso Yoshiaki , Shimonishi Yasutsugu , Nishi Yoshisuke , Munekata Eisuke
Published: April 2009

Neutrophils are a class of leukocytes involved in innate immunity by monitoring and scavenging invading microorganisms and toxic substances. The actions of neutrophils in damaged tissues are still not well understood, particularly in the early stage of inflammation, and as-yet-unknown neutrophil-activating substances are proposed to induce their acute transmigration and activation. Here, we isolated and identified from porcine hearts a neutrophil-activating peptide. Structural analyses indicated that the primary structure of this peptide is formyl-Met-Thr-Asn-Ile-Arg-Lys-Ser-His-Pro-Leu-Met-Lys-Ile-Ile-Asn, which is identical to that of the N-terminal pentadecapeptide of porcine mitochondrial cytochrome b; we therefore named the newly isolated peptide “mitocryptide-2” (MCT-2), since we have recently purified and identified mitocryptide-1, a different class of a neutrophil-activating peptide. Synthetic MCT-2 and its human homolog hMCT-2 induced β-hexosaminidase release in and chemotaxis of HL-60 cells differentiated into neutrophilic/granulocytic cells. The induction of β-hexosaminidase release, chemotaxis, and the increase in the intracellular free Ca2+ concentration by hMCT-2 were completely suppressed by pertussis toxin, indicating the involvement of Gi- or Go-type G proteins in the signaling pathways. Moreover, MCT-2 and hMCT-2 also stimulated β-hexosaminidase secretion in human neutrophils isolated from peripheral blood in a concentration-dependent manner. Additionally, these peptides partially competed with [3H]formyl-Met-Leu-Phe binding to HL-60 cells differentiated into neutrophilic/granulocytic cells, presenting the possibility that the receptor for MCT-2 and hMCT-2 is one of the formyl peptide receptors. These results demonstrate that MCT-2 and its human homolog hMCT-2 are cryptides that activate neutrophils, thus suggesting the presence of regulatory mechanisms involving such mitocryptides in innate immunity.
Lipocalin 2 Is Required for Pulmonary Host Defense against Klebsiella Infection
Authors: Chan Yvonne R. , Liu Jessica S. , Pociask Derek A. , Zheng Mingquan , Mietzner Timothy A. , Berger Thorsten , Mak Tak W. , Clifton Matthew C. , Strong Roland K. , Ray Prabir , Kolls Jay K.
Published: April 2009

Antimicrobial proteins comprise a significant component of the acute innate immune response to infection. They are induced by pattern recognition receptors as well as by cytokines of the innate and adaptive immune pathways and play important roles in infection control and immunomodulatory homeostasis. Lipocalin 2 (siderocalin, NGAL, 24p3), a siderophore-binding antimicrobial protein, is critical for control of systemic infection with Escherichia coli; however, its role in mucosal immunity in the respiratory tract is unknown. In this study, we found that lipocalin 2 is rapidly and robustly induced by Klebsiella pneumoniae infection and is TLR4 dependent. IL-1β and IL-17 also individually induce lipocalin 2. Mucosal administration of IL-1β alone could reconstitute the lipocalin 2 deficiency in TLR4 knockout animals and rescue them from infection. Lipocalin 2-deficient animals have impaired lung bacterial clearance in this model and mucosal reconstitution of lipocalin 2 protein in these animals resulted in rescue of this phenotype. We conclude that lipocalin 2 is a crucial component of mucosal immune defense against pulmonary infection with K. pneumoniae.
Critical and Multiple Roles for the CD3ε Intracytoplasmic Tail in Double Negative to Double Positive Thymocyte Differentiation
Authors: Brodeur Jean-Francois , Li Samantha , Martins Maria da Silva , Larose Louise , Dave Vibhuti P.
Published: April 2009

The preTCR is associated with signal-transducing CD3γ, δ, ε, and ζ polypeptides. It is generally agreed that CD3 chains play redundant roles in the receptor-mediated signal transduction. In the present study, we show that the intracytoplasmic (IC) domain of CD3ε is essential for early thymocyte maturation. We demonstrate that the IC domain-deleted CD3ε fails to restore the double negative (DN) to double positive (DP) thymocyte development in CD3ε-deficient mice. Additional experiments show that the membrane proximal basic amino acid rich sequence in the IC domain of CD3ε is sufficient for the DN to DP differentiation, whereas the proline rich sequence is required for efficient proliferation. This is probably due to impaired ligand independent recruitment of Nck to the proline rich sequence motif of CD3ε within the context of the preTCR. The data presented in this study elucidates mechanistic basis for the preTCR-induced proliferation of the DN thymocytes and have identified distinct roles for individual motifs of CD3ε in the preTCR-mediated differentiation and proliferation. These data provide the first genetic and phenotypic evidence for requirement of the IC domain of a CD3 chain in thymocyte development.
Association of HIV-Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point
Authors: Burgers Wendy A. , Riou Catherine , Mlotshwa Mandla , Maenetje Pholo , de Assis Rosa Debra , Brenchley Jason , Mlisana Koleka , Douek Daniel C. , Koup Richard , Roederer Mario , de Bruyn Guy , Karim Salim Abdool , Williamson Carolyn , Gray Clive M. ,   and the CAPRISA 002 Acute Infection Study Team
Published: April 2009

Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8+ T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-γ+ T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8+ T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8+ memory subpopulations. At 6–9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8+ cells of a central memory (CD45RO+CD27+CCR7+) and intermediate memory (CD45RO−CD27+CCR7−) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO+CD27−CCR7−) cells. The proportions of memory subsets significantly correlated with CD38+CD8+ T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8+ T cells.
Thrombin Binding Predicts the Effects of Sequence Changes in a Human Monoclonal Antiphospholipid Antibody on Its In Vivo Biologic Actions
Authors: Giles Ian , Pericleous Charis , Liu Xiaowei , Ehsanullah Jasmine , Clarke Lindsey , Brogan Paul , Newton-West Marvin , Swerlick Robert , Lambrianides Anastasia , Chen Pojen , Latchman David , Isenberg David , Pierangeli Silvia , Rahman Anisur
Published: April 2009

The mechanisms by which antiphospholipid Abs (aPL) cause thrombosis are not fully understood. It is clear that binding to a number of phospholipid-associated Ags is important but it is difficult to identify which Ag-binding properties are most closely linked to the ability to cause biologic effects such as promotion of thrombosis and activation of endothelial cells. We have previously used an in vitro expression system to produce a panel of human monoclonal IgG molecules between which we engineered small differences in sequence leading to significant well-defined changes in binding properties. In this study, we assess the properties of five of these IgG molecules in assays of biologic function in vitro and in vivo. The i.p. injection of these IgG into mice subjected to a femoral vein pinch stimulus showed that only those IgG that showed strong binding to thrombin promoted in vivo venous thrombosis and leukocyte adherence. However, this finding did not hold true for the effects of these IgG on activation of cultured endothelial cells in vitro, where there was a less clear relationship between binding properties and biologic effects.
Using PATIMDB to Create Bacterial Transposon Insertion Mutant Libraries
Authors: Urbach Jonathan M. , Wei Tao , Liberati Nicole , Grenfell‐Lee Daniel , Villanueva Jacinto , Wu Gang , Ausubel Frederick M.
Published: April 2009

PATIMDB is a software package for facilitating the generation of transposon mutant insertion libraries. The software has two main functions: process tracking and automated sequence analysis. The process tracking function specifically includes recording the status and fates of multiwell plates and samples in various stages of library construction. Automated sequence analysis refers specifically to the pipeline of sequence analysis starting with ABI files from a sequencing facility and ending with insertion location identifications. The protocols in this unit describe installation and use of PATIMDB software. Curr. Protoc. Mol. Biol. 86:19.7.1‐19.7.34. © 2009 by John Wiley & Sons, Inc.
Two‐Hybrid Dual Bait System
Authors: Kotova Elena , Coleman Thomas , Serebriiskii Ilya
Published: April 2009

The yeast two‐hybrid system, or interaction trap, is one of the most versatile methods available with which to identify and establish protein‐protein interactions. The dual bait system is one adaptation of the classic approach. This system facilitates the simultaneous comparison of two distinct baits with one prey. One protein of interest is expressed as a fusion to the DNA‐binding protein LexA (bait 1), while a second protein of interest is expressed as a fusion to the DNA‐binding protein cI (bait 2). Strains of yeast engineered for screening of these dual baits possess four separate reporter genes. A plasmid expressing an activation domain‐fused protein (prey), which can be either a defined protein interactor or a cDNA library, is also expressed to allow dual hybrid‐mediated transcriptional activation. Curr. Protoc. Mol. Biol. 86:20.7.1‐20.7.32. © 2009 by John Wiley & Sons, Inc.
Breaking the Dogma of the Metal‐Coordinating Carboxylate Group in Integrin Ligands: Introducing Hydroxamic Acids to the MIDAS To Tune Potency and Selectivity
Authors: Heckmann Dominik , Laufer Burkhardt , Marinelli Luciana , Limongelli Vittorio , Novellino Ettore , Zahn Grit , Stragies Roland , Kessler Horst
Published: April 2009

A suitable substitute: All integrin receptors bind their ligands, which contain an aspartate residue, in the metal‐ion‐ dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity. The picture shows one such ligand in the binding site of αvβ3.

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Synthesis of highly efficient D‐naproxen imprinted polymer and investigation of their specific performance
Authors: Zhang Zhiliang , Wang Bing
Published: April 2009

D‐naproxen was selected as the imprinted molecule. An original ultraviolet spectrum analysis method based on proof of solvent effects was designed to verify the realization of the noncovalent self‐assembly between naproxen and functional monomers under the influence of the solvents with different nature. The facts proved that it is a more scientific way to effectively implement the pre‐selection of functional monomer. Then, a series of molecular imprinted polymers (MIPs) were synthesized by different ratios of raw materials. These products were detected by infrared spectroscopy as well as adsorption experimentation to analyze their structure and performance. Meanwhile, the transmission electron microscopy (TEM) was first used to observe the morphology of MIPs, by which the pore‐forming mechanism and the effect of the solvent (porogen) were investigated. The MIPs with morphology of different structure were also tested in the adsorption kinetics experiments to testify the influence of morphology factors on the materials' adsorption properties. Through the evaluation of the imprinting efficiency, the best condition accessing to the preparation of highly efficient D‐naproxen imprinted polymer was obtained. The apparent imprinting efficiency of the ultimate product was as high as 90.39%. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Melt electrospinning from poly(L‐lactide) rods coated with poly(ethylene‐co‐vinyl alcohol)
Authors: Tian Sheng , Ogata Nobuo , Shimada Naoki , Nakane Koji , Ogihara Takashi , Yu Muhuo
Published: April 2009

Rodlike poly(L‐lactide) (PLLA) samples coated with poly(ethylene‐co‐vinyl alcohol) (EVOH) were made. Fibers were produced from these rodlike samples by using a melt electrospinning system equipped with a laser irradiating device, and the effects of EVOH content and the processing parameters of the melt electrospinning on fiber diameters were investigated. We also studied the fiber formation mechanism from the rods during the laser melt electrospinning process. The following conclusions were reached: (i) coating of EVOH on PLLA rods has a remarkable effect on decreasing fiber diameter from 3 μm to around 1 μm; (ii) increases in the electric field strength and temperature of spinning space decrease the average diameter of fibers produced from pure PLLA rods, and longer collector distance leads to lager PLLA fiber diameter; and (iii) the migration of PLLA component from the core to the surface of electrospun fibers takes place during the fiber formation process. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Composition, thermal properties, and biodegradability of a new biodegradable aliphatic/aromatic copolyester
Authors: Han Ling , Zhu Guixiang , Zhang Wei , Chen Wei
Published: April 2009

A series of new aliphatic/aromatic copolyesters [poly(hexylene terephthalate‐co‐hexylene adipate) (PHTA)] were synthesized on the bases of 1,6‐hexanediol, adipic acid, and dimethyl terephthalate and characterized by gel permeation chromatography, 1H‐NMR, wide‐angle X‐ray diffraction (WAXD), differential scanning calorimetry (DSC), and compost testing. 1H‐NMR results show that the compositions of the copolyesters were in accordance with the feed molar ratios. The WAXD patterns indicated that the crystal structures of the PHTA copolyesters were determined by the dominant crystal units, and the copolyesters became less crystallizable, even amorphous, with increasing comonomer content. The DSC curves showed that the glass‐transition temperatures (Tg′s) of the PHTA copolyesters decreased linearly, and both the melting temperature (Tm) and heat of fusion decreased first and then increased with increasing hexylene adipate unit content. Under compost conditions, PHTA copolyesters with less than 60 mol % aromatic units were biodegradable. Particularly, compared with the copolyester poly(butylene terephthalate‐co‐butylene adipate), the PHTA copolyester with the same aliphatic/aromatic composition possessed a lower Tg and Tm and better biodegradability. Additionally, the biodegradability of the copolyesters could be predicted by the number‐average sequence length of aromatic units, Tg, and the temperature difference between Tm and the temperature at which biodegradation took place. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Oxidative ortho CC Coupling of 4‐Ethylphenol by Dual Substrate Activation at a Bioinspired Dicopper Complex—Trapping of an Unusual Oligophenolic Cu6 Species
Authors: Prokofieva Angelina , Dechert Sebastian , Große Christian , Sheldrick George M. , Meyer Franc
Published: April 2009

Bioinspired dual activation: Dual activation within the bimetallic pocket of a bioinspired dicopper(II) complex suitably places two phenolato substrates for preferred ortho–ortho coupling. Spectroscopic data and the molecular structure of a unique Cu6 complex isolated from the reaction mixture reveal a novel terphenolato ligand and provide a clue about the activation mechanism (see picture).

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Molecular Simulation Study of Hexane Diffusion in Dynamic Metal‐Organic Frameworks
Authors: XUE Chunyu , ZHONG Chongli
Published: April 2009

The modified MM3 force field for describing flexible IRMOF‐1 was extended to include other IRMOFs, and a molecular dynamics simulation study was performed on hexane diffusion in IRMOF‐1 and IRMOF‐16. The self‐diffusion coefficients and diffusion pathways of hexane, as well as the mobility of the frameworks were investigated, as a function of both temperature and loading. The results revealed that the diffusion pathway of hexane was largely influenced by loading, and the flexibility of IRMOF‐16 was much larger than that of IRMOF‐1. The microscopic information obtained is useful for understanding the diffusion mechanism of chain molecules in dynamic MOF.
Synthesis and Structural Characterization of a New 2D Coordination Polymer [Cu(pzta)2]n
Authors: HU Xin , LIU Cong , WANG Yongjiang , GUO Jixi
Published: April 2009

A new copper(II) tetrazolate coordination polymer [Cu(pzta)2]n (1) (pzta=5‐pyrazinyltetrazolate) was prepared from the hydrothermal reaction of Cu(OAc)2·H2O with NaN3 and pyrazinecarbonitrile (pzCN) in the presence of ethanol, and characterized by elemental analysis, IR, TGA and X‐ray crystallography. The X‐ray diffraction analysis of 1 shows that the compound crystallizes in the monoclinic system with space group P2(1)/c and Cu(II) ion center is six‐coordinated by four different pzta ligands. The complex 1 features a 2D tetrazole coordination polymer. The thermal analysis of 1 shows that the decomposition of the complex occurs in two regions.
Homology Model Adjustment and Ligand Screening with a Pseudoreceptor of the Human Histamine H4 Receptor
Authors: Tanrikulu Yusuf , Proschak Ewgenij , Werner Tim , Geppert Tim , Todoroff Nickolay , Klenner Alexander , Kottke Tim , Sander Kerstin , Schneider Erich , Seifert Roland , Stark Holger , Clark Timothy , Schneider Gisbert
Published: April 2009

A new pseudoreceptor modeling method (PRPS) was applied to the refinement of a homology model of the human histamine H4 receptor (H4R), the prediction of a ligand binding site, and virtual screening. Retrieval of two new H4R ligands demonstrates the biological relevance of the pseudoreceptor model and provides a means for finding new hits and leads in the early phases of drug discovery.

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A computer‐assisted method for the generation of pseudoreceptor models is presented together with two practical applications. From a three‐dimensional alignment of known histamine H4 receptor ligands, a pseudoreceptor model of the putative ligand binding site was constructed and used for virtual screening of a large collection of commercially available compounds. Two bioactive chemotypes were retrieved, demonstrating the general applicability of the approach. The pseudoreceptor model was also used to find the putative ligand binding pocket within the transmembrane receptor domain. For each frame of a molecular dynamics simulation of a homology‐based H4 receptor model, we automatically extracted potential ligand binding pockets and used their compatibility with the pseudoreceptor as a selection criterion. The best‐matching pocket fits perfectly with existing mutation data and previously published hypotheses suggesting Glu1825.46 as the preferred binding partner of a positively charged moiety of H4 receptor ligands. This new pseudoreceptor approach has demonstrated its suitability for both structure‐based prioritization of protein receptor models, and ligand‐based virtual screening with the aim to perform scaffold hopping.
Ultrafast Dynamics of o‐Bromofluorobenzene Studied by Time‐Resolved Photoelectron Imaging
Authors: Cao Zhen‐Zhou , Wei Zheng‐Rong , Hua Lin‐Qiang , Hu Chang‐Jin , Zhang Song , Zhang Bing
Published: April 2009

Photodissociation dynamics and rotational wave packet coherences of o‐bromofluorobenzene are studied by femtosecond time‐resolved photoelectron imaging (see figure). The decay of different photoelectron rings shows the population decay of states from which the lifetimes of different states are determined. The variation of photoelectron angular distributions reflects the evolution of rotational coherences.

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Photodissociation dynamics and rotational wave packet coherences of o‐bromofluorobenzene are studied by femtosecond time‐resolved photoelectron imaging (TR‐PEI) spectroscopy combined with the (1+2′) resonance‐enhanced multiphoton ionization (REMPI). Photoelectron kinetic energy and angular distributions indicate ionization dynamics from some Rydberg states at the (1+1′) photon energy. The lifetimes of the S1 (A′) and T2 (A′) states are determined from the decay of the photoelectron signals to be 38 ps and 27 ps. The electron population decay of the two states is attributed to predissociation and tunneling dissociation. The variation of time‐dependent anisotropy parameters in the first 5 ps shows the rotational wave coherences of molecule.
Heat shock factor 1 deficiency via its downstream target gene αB‐crystallin (Hspb5) impairs p53 degradation
Authors: Jin Xiongjie , Moskophidis Demetrius , Hu Yanzhong , Phillips Andrew , Mivechi Nahid F.
Published: April 2009

Heat shock factor Hsf1 regulates the stress‐inducibility of heat shock proteins (Hsps) or molecular chaperones. One of the functions attributed to Hsps is their participation in folding and degradation of proteins. We recently showed that hsf1−/− cells accumulate ubiquitinated proteins. However, a direct role for Hsf1 in stability of specific proteins such as p53 has not been elucidated. We present evidence that cells deficient in hsf1 accumulate wild‐type p53 protein. We further show that hsf1−/− cells express lower levels of αB‐crystallin and cells deficient in αB‐crystallin also accumulate p53 protein. Reports indicate that αB‐crystallin binds to Fbx4 ubiquitin ligase, and they target cyclin D1 for degradation through a pathway involving the SCF (Skp1‐Cul1‐F‐box) complex. Towards determining a mechanism for p53 degradation involving αB‐crystallin and Hsf1, we have found that ectopic expression of Fbx4 in wild‐type mouse embryo fibroblasts (MEFs) expressing mutant p53 (p53R175H) leads to increase in its degradation, while MEFs deficient in hsf1 or αBcry are defective in degradation of this p53 protein. In addition, immunoprecipitated p53R175H from wild‐type MEFs is able to pull‐down both αB‐crystallin and Fbx4. Finally, immunoprecipitated wild‐type p53 from doxorubicin treated U2OS cells can pull‐down endogenous αB‐crystallin and Fbx4. These results indicate that hsf1‐ and αBcry‐deficient cells accumulate p53 due to reduced levels of αB‐crystallin in these cells. Elevated levels of p53 in hsf1‐ and αBcry‐deficient cells lead to their increased sensitivity to DNA damaging agents. These data reveal a novel mechanism for protein degradation through Hsf1 and αB‐crystallin. J. Cell. Biochem. 107: 504–515, 2009. © 2009 Wiley‐Liss, Inc.
Synthesis and properties of 1,4‐dimethylpyridazino[4,5‐d] pyridazines
Authors: Adembri G. , De Sio F. , Nasi R. , Scotton M.
Published: April 2009

The synthesis and properties of several 1,4‐dimethylpyridazino[4,5‐d]pyridazines are described. Treatment of diethyl 3,6‐dimethylpyridazine‐4,5‐dicarboxylate (1a) with lithium aluminium hydride and hydrazine did not afford the expected 1,4‐dimethylpyridazino[4,5‐d]pyridazine (21b) but a mixture of compounds 13, 18, 19, and 20, whose structures were deduced from spectroscopic data.
Etudes en série indolique: VII Synthèse de nouveaux pyridocarbazoles obtenus par photocyclisation de (β‐indolyl)‐1 (pyridyl)‐2 acrylonitriles
Authors: Dieng C. , Thal C. , Husson H.‐P. , Potier P.
Published: April 2009

La photochime des (β‐indolyl)‐1 (α‐, β‐ and γ‐ pyridyl)‐2 acrylonitriles a permis de réaliser la synthèse de différents pyrido[a]carbazoles isomères. Des différences de réactivité ont été observées selon la place qu'occupe l'atome d'azote Nb du cycle pyridinique. La diversité des résultats obtenus montre, de plus, que le processus photochimique ne peut se ramener à celui connu dans le cas des stilbènes.
Solvent shifts in the NMR spectra of monomethoxyflavones a comparison of four solvent systems
Authors: Looker James H. , Mader J. Woodson , Kingsbury Charles A.
Published: April 2009

Nmr chemical shifts of methoxyl protons are reported for the eight monomethoxyflavones in four solvents: deuteriochloroform, benzene, dimethylsulfoxide, and pyridine. Benzene shift data are presented, and Δ values interpreted on the basis of a preferential approach of benzene molecules near the positive end (hetero oxygen atom) of a large pyrone dipole. Pyridine shifts, relative to deuteriochloroform and dimethylsulfoxide, are reported. The Δ values for monomethoxyflavones indicate that only in 2′‐methoxyflavone is the shift value positive.
A novel synthesis of 2‐(disubstituted amino)‐5(4)phenylimidazoles
Authors: Nishimura Tamio , Nakano Katsuo , Shibamoto Shinji , Kitajima Koji
Published: April 2009

The reaction of 1‐phenyl‐1,2‐propanedione with 1,1‐disubstituted guanidines in methanol yielded 2‐(disubstituted amino)‐4‐hydroxy‐4‐methyl‐4H‐imidazoles (III). Compound III produced 5(4)methylimidazoles by catalytic hydrogenation and 5(4)chloromethylimidazoles (IV) by concentrated hydrochloric acid treatment. Solvolysis of IV in water and alcohols gave 5(4)hydroxymethyl‐ and 5(4)alkoxymethylimidazoles, respectively.
New routes to the v‐triazolo[1,5‐a]pyridine and pyrazolo[1,5‐a]pyridine ring systems
Authors: Tamura Yasumitsu , Kim Joong‐Hyup , Miki Yasuyoshi , Hayashi Hironori , Ikeda Masazumi
Published: April 2009

New routes to the v‐triazolo[1,5‐a]pyridine and pyrazolo[1,5‐a]pyridine ring systems are described. Treatment of the N‐amine salts of 2‐picolinealdehyde oxime or 2‐pyridyl ketone oximes with polyphosphoric acid gave v‐triazolo[1,5‐a]pyridines in fair yields. Treatment of 2‐picolyl ketones or their oximes with O‐mesitylenesulfonylhydroxylamine produced directly pyrazolo‐[1,5‐a]pyridines. These reactions were extended to the quinoline cases.
Additions radicalaires du tétrahydrothiophène à des dérivés éthyléniques: Préparation de tétrahydrothiophènes substitués en 2
Authors: Lalande Robert , Bourgeois Marie‐Josèphe , Maillard Bernard
Published: April 2009

L'addition radicalaire du tétrahydrothiophène à des dérivés éthyléniques, sous amorçage peroxydique conduit à des tétrahydrothiophènes substitués en 2. Cette réaction semble être une voie synthétique intéressante de ces hétérocycles.
Studies of thieno[2,3‐b]pyrazines in preparation of pyrazino[2′,3′:4,5]thieno[3,2‐d]pyrimidines and related molecules
Authors: Schneller S. W. , Clough F. W.
Published: April 2009

A variety of 2,3‐disubstituted derivatives of the previously unknown thieno[2,3‐b]pyrazine ring system have been employed as a synthetic foundation for pyrazino[2′,3′:4,5]thieno[3,2‐d]‐pyrimidine and several of its derivatives.
Chemistry of thienopyridines. XX. The relation of dipole moment to molecular structure
Authors: Klemm L. H. , Jacquot R. D.
Published: April 2009

Dipole moments were measured for three bicyclic thienopyridines and three tetracyclic diben‐zothienopyridines in benzene solution at 25°. Results agreed closely with predicted values based on vector addition of dipole moments for reference constituent compounds.
Massenspektrometrische untersuchung organischer stickstoffverbindungen ‐ XVI: Elektronenstossinduzierte fragmentierungen von α‐pyridiyl‐ω‐phenylalkanonen und α‐phenyl‐ω‐pyridylalkanen
Authors: Schwarz Helmut , Herrmann Rupert , Wolfschütz Roland
Published: April 2009

The electron impact induced fragmentations of twelve pyridine derivatives are discussed. The fragmentation pattern of these compounds is strongly influenced by the number of methylene groups as well as the position of substitution in the pyridine nucleus. By means of mass spectrometry a differentiation between the 2‐pyridyl and the 4‐pyridyl derivatives is possible and this fact could be important with respect to an analytical identification of the compounds.
Electrophilic substitution of furo[3,2‐c] pyridine
Authors: Mcfarland John W. , Essary William A. , Cilenti Lale , Cozart William , Mcfarland Philip E.
Published: April 2009

Furo[3,2‐c] pyridine (I) was nitrated to give 2‐nitrofuro[3,2‐c]pyridine (II). Bromination and chlorination of I gave, respectively, 2,3‐dibromo‐2,3‐dihydrofuro[3,2‐c]pyridine (III) and 2,3‐dichloro‐2,3‐dihydrofuro[3,2‐c]pyridine (IV). Oxidation of I with hydrogen peroxide afforded furo[3,2‐c]pyridine 5‐oxide (V) which was converted to I by phosphorus trichloride and to 4‐chlorofuro[3,2‐c]pyridine (VI) by phosphorus oxychloride.
Synthèse de 2H ‐furo[3,4‐b] (3H, 5H, 7H) pyrannediones‐4,5. Acylation de (2H, 5H) furannediones‐2,4 (acides tétroniques) par les chlorures d'acides α‐éthyléniques
Authors: Celin Suzanne , Pollet Patrick
Published: April 2009

Direct acylation of tetronic acids by α,β‐ethylenic acid chlorides with tin tetrachloride gave a new type of fused heterocyclic compounds: 2H‐furo[3,4‐b] pyran‐4,5‐diones. Acylation in alkaline medium gave enol esters which could be transposed in furopyrandiones. However, the first route was more satisfactory.
Heterocyclic compounds from 3,3‐dimercapto‐1‐aryl‐2‐propen‐1‐ones. Note 3. Condensation with N‐methyl‐o‐phenylenediamine and N‐benzyl‐o‐phenylenediamine
Authors: Nardi D. , Pennini R. , Tajana A.
Published: April 2009

Two seven‐membered ring compounds and three five‐membered ring compounds were obtained by reaction in hot xylene of 3,3‐dimercapto‐l‐phenyl‐2‐propen‐1‐one (1) with N‐alkyl‐o‐phenylenediamines (2). Compounds isolated were the 4‐phenyl‐5‐alkyl‐1,5‐dihydro‐2H‐1,5‐benzodiazepine‐2‐thiones (3) the 1‐alkyl‐4‐phenyl‐1,3‐dihydro‐2H‐1,5‐benzodiazepine‐2‐thiones (4), the 1‐alkyl‐2‐phenacylbenzimidazoles (5), the 1‐alkyl‐2‐phenylbenzimidazoles (6) and the 1‐alkyl‐2‐methylbenzimidazoles (7). The structures of these compounds were elucidated from their chemical reactivity and their nmr and ir spectra.
The use of amino acids in the mannich reaction
Authors: Short James H. , Ours C. Wayne
Published: April 2009

Amino acids have been found to participate as the amine component in the Mannich reaction with both ketones and phenols. The phenolic Mannich bases may be cyclized with sulfuric acid to 1,2‐dihydro‐4(3/H)isoquinolones. In the presence of thionyl chloride the same Mannich bases undergo lactonization to benz[f]‐1,4‐oxazepin‐4(3H)ones.
Synthesis of pyrazolo[1′,5′:1,2]‐1,3,5‐triazino[5,6‐a]benzimidazoles
Authors: Senga Keitaro , Robins Roland K. , O'Brien Darrell E.
Published: April 2009

The synthesis of a new class of tetracyclic bridgehead heterocycle pyrazolo[1′,5′:1,2]‐1,3,5‐triazino[5,6‐a] benzimidazoles is reported. The key intermediate 2‐(3‐aminopyrazol‐2‐yl)benzimidazoles were prepared by the reaction of 2‐hydrazinobenzimidazole with an appropriate reagent such as ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalononitrile, β‐cyanoacetophenone or α‐formylphenylacetonitrile. The treatment of these key intermediates with triethylorthoesters afforded the corresponding pyrazolo[1′,5′:1,2]‐1,3,5‐triazino[5,6‐a]benzimidazoles.
Studies on quinoline derivatives and related compounds. III. A novel pyridine synthesis to give substituted 1,4‐dihydro‐4‐oxonicotinic acids
Authors: Agui Hideo , Tobiki Hisao , Nakagome Takenari
Published: April 2009

A variety of 5‐mono‐ and 5,6‐disubstituted 1,4‐dihydro‐4‐oxonicotinates were prepared by a novel pyridine synthesis which involves thermal cyclisation of enaminomethylenemalonates 9. The intermediates 9 were readily prepared through a few steps from commercially available starting materials.
Mass spectra of substituted pyrazolo[1,5‐a]‐1,3,5‐triazines
Authors: El Khadem Hassan S. , Foltz Rodger L. , Novinson Thomas , Senga Keitaro
Published: April 2009

High resolution electron impact mass spectrometric measurements have been made on twelve pyrazolo[1,5‐a]‐1,3,5‐triazines. Substituents attached to carbon atoms 2, 4, 7, and 8 were used to label the various fragments. Three major ions were observed (a) the molecular ion, (b) an ion corresponding to M‐RCN where R is the substituent attached to C‐4 and (c) an aryl cyclopropenyl cation which was observed in 7‐aryl derivatives. Intensities and accurate mass‐measurements are given for all ions having intensities exceeding 2% of the base peak. Nine of the twelve pyrazolo‐[1,5‐a]‐1,3,5‐triazines included in this study are described here for the first time.
The stobbe condensation with substituted succinic esters. II A synthesis of benzothiophene derivatives
Authors: El‐Rayyes N. R. , Al‐Salman (Mrs.) N. A.
Published: April 2009

The condensation of some thienyl carbonyl compounds with dimethyl phenylsuccinate using either sodium hydride or potassium t‐butoxide as condensing agents, gave a stereoisomeric mixture of (E)‐ and (Z)‐half‐esters (3). The (E)‐half‐esters la‐c were either cyclised to the corresponding benzothiophene derivatives or hydrolysed to the (E)‐dibasic acids VIa‐e, which were cyclised to the corresponding anhydrides VIIa‐c. Methylation of VIIa,c gave the isomeric half‐esters VIIIa,c. The (Z)‐half‐ester Id can cyclise easily to the lactone IX.
Synthesis of 1,2,3‐thiadiazolo[4,5‐d] pyridazines, A new heterocyclic ring system
Authors: Shafiee Abbas
Published: April 2009

A method was developed for the synthesis of 5‐carbethoxy‐4‐formyl‐1,2,3‐thiadiazole (I), its isomer (II); 5‐benzoyl‐4‐formyl‐1,2,3‐thiadiazole (III), and its isomer (IV). It was demonstrated that although compounds I, III and IV with hydrazine gave 7H‐1,2,3‐thiadiazolo[4,5‐d]‐pyridazin‐7‐one (XXII), 7‐phenyl‐1,2,3‐thiadiazolo[4,5‐d]pyridazine (XXIII) and 4‐phenyl‐1,2,3‐thiadiazolo[4,5‐d]pyridazine (XXV), respectively; however, compound I gave its corresponding hydrazone (XXIV).
Intramolecular diels‐alder reactions. XI. Modal selectivity in the syntheses of some parent cyclolignan lactones
Authors: Klemm L. H. , Tran Vinh Tan , Olson D. R.
Published: April 2009

Ph(C2)CH2Cl and Ph(C2)'CO2Na [where (C2) = ‐C=C‐ or trans‐CH=CH‐, (C2)' = ‐C=C‐ or cis‐CH=CH‐] reacted in refluxing dimethylformamide to yield unsaturated esters Ph(C2)'CO2‐CH2(C2)Ph and/or their intramolecular Diels‐Alder cyclization products (cyclolignan lactones). It was found that modal selectivity for cyclization in DMF sometimes varies from that found previously with acetic anhydride as solvent. Two new parent tetrahydrocyclolignan lactones were synthesized.
Tetrahydro‐ and octahydropyrido[1,2‐a]pyrimidin‐4‐ones
Authors: Yale Harry L. , Spitzmiller Ervin R.
Published: April 2009

The catalytic hydrogenation of 2‐methyl‐, 1 2,8‐dimethyl‐, 2, 2,9‐dimethyl‐, 3, 9‐methyl‐2‐propyl‐, 4, 2,3,9‐trimethyl‐, 5, 9‐methyl‐2‐phenyl‐, 6, 9‐hydroxy‐2‐methyl‐, 7, 9‐acetoxy‐2‐methyl, 8, 9‐carboxy‐2‐methyl‐, 16, 9‐carboethoxy‐2‐methyl‐, 17, 9‐carbomethoxy‐2‐methyl‐, 18, and several 9‐carboxamido‐2‐methyl‐, 19, 20, and 21, derivatives of the pyrido[1,2‐a]pyrimidin‐4‐one heterocycle has led to a series of novel 6,7,8,9‐tetrahydro‐ and fully saturated, octahydro analogs. In deuteriochloroform or DMSO‐d6 solution, the pmr spectra of the tetrahydro derivatives derived from 1‐7 revealed only the 6,7,8,9‐tetrahydro structures. In the pmr spectra of 16‐21, there was evidence of a facile 1,3‐prototropic shift of the proton from position‐9 to position‐1, resulting in equilibria between tautomeric species, i.e., magnified image. The ratio of tautomers present at equilibrium, with the esters, favored the enamine conformation, whereas, with both the carboxylic acid and the amides, the imine structure predominated. Supportive evidence for the enamine structure with the esters was derived also from the ir spectra. Alkylation of the anion derived from the tetrahydro 9‐carbomethoxy derivative with sodium hydride led exclusively to derivatives of 6,7,8,9‐tetrahydro system.
The reaction of 1‐azirines with 2‐pyridyl isothiocyanate: Possible approaches to benzodiazepine and benzodiazepine derivatives
Authors: Nair V. , Kim K. H.
Published: April 2009

The structure of the dimer (5) from 2‐pyridyl isothiocyanate (1) has been confirmed by 13C nmr spectral studies. The cycloaddition of 2‐pyridyl isothiocyanate with 1‐azirines results in the formation of thiazoles (10). Thermal decomposition of the vinyl azide (14) gives the pyrrole (15) and the pyridazine (16) instead of 2‐(2‐pyridyl)‐1‐azirine (12).
The synthesis and spectroscopic properties of 3‐(2′,4′‐Xylyl)‐1H,3H‐quinazoline‐2,4‐diones
Authors: Vigne Christian , Buti Marielle , Montginoul Claude , Torreilles Eliane , Giral Louis
Published: April 2009

The synthesis of 3‐(2′,4′‐xylyl)‐1H,3H‐quinazoline‐2,4‐diones (1a, 9a‐j) has been accomplished. Their pmr and ir spectra data for all compounds are presented.
Model reactions in the pseudonucleoside series
Authors: Fissekis John D. , Lehnberg James W. , Sweet Frederick , Lipnick Robert L.
Published: April 2009

A series of pseudonucleoside analogs has been prepared from the base‐catalyzed condensation of methyl 3,3‐dimelhoxy‐2‐(telrahydrofuran‐2‐yl)propionate with urea and thiourea, followed by cyclization(s) with acid, bromine and peroxyformic acid. Some of their reactions which lead to other model pseudonucleosides are reported.
Carbon‐13 NMR investigation of the protonation and quaternization of azoloazines with a bridgehead nitrogen
Authors: Pugmire Ronald J. , Smith James C. , Grant David M. , Stanovnik Branko , Tišler Miha
Published: April 2009

Carbon‐13 nmr techniques have been employed to study imidazo[1,2‐a]pyridine, imidazo‐[ 1,2‐b]pyridazine, s‐triazolo[4,3‐b]pyridazine, and s‐triazolo[ 1,5‐b]pyridazine and their N‐1 quaternized derivatives. The data on quaternized derivatives have been analyzed to determine the tautomeric structures possible in the protonated derivatives. The data suggest that protonation at the bridgehead nitrogen does not occur in these compounds and, of the possible tautomerie forms, the N‐1 tautomer predominates.