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991.
Brown DG Maier DL Sylvester MA Hoerter TN Menhaji-Klotz E Lasota CC Hirata LT Wilkins DE Scott CW Trivedi S Chen T McCarthy DJ Maciag CM Sutton EJ Cumberledge J Mathisen D Roberts J Gupta A Liu F Elmore CS Alhambra C Krumrine JR Wang X Ciaccio PJ Wood MW Campbell JB Johansson MJ Xia J Wen X Jiang J Wang X Peng Z Hu T Wang J 《Bioorganic & medicinal chemistry letters》2011,21(11):3399-3403
Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (sc 60 mg/kg). 相似文献
992.
Marjenberg ZR Ellis IR Hagan RM Prabhakaran S Höök M Talay SR Potts JR Staunton D Schwarz-Linek U 《The Journal of biological chemistry》2011,286(3):1884-1894
Integrin-dependent cell invasion of some pathogenic bacteria is mediated by surface proteins targeting the extracellular matrix protein fibronectin (FN). Although the structural basis for bacterial FN recognition is well understood, it has been unclear why proteins such as streptococcal SfbI contain several FN-binding sites. We used microcalorimetry to reveal cooperative binding of FN fragments to arrays of binding sites in SfbI. In combination with thermodynamic analyses, functional cell-based assays show that SfbI induces conformational changes in the N-terminal 100-kDa region of FN (FN100kDa), most likely by competition with intramolecular interactions defining an inactive state of FN100kDa. This study provides insights into how long range conformational changes resulting in FN activation may be triggered by bacterial pathogens. 相似文献
993.
Vazquez V Liang X Horndahl JK Ganesh VK Smeds E Foster TJ Hook M 《The Journal of biological chemistry》2011,286(34):29797-29805
Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) are bacterial surface proteins mediating adherence of the microbes to components of the extracellular matrix of the host. On Staphylococci, the MSCRAMMs often have multiple ligands. Consequently, we hypothesized that the Staphylococcus aureus MSCRAMM bone sialoprotein-binding protein (Bbp) might recognize host molecules other than the identified bone protein. A ligand screen revealed that Bbp binds human fibrinogen (Fg) but not Fg from other mammals. We have characterized the interaction between Bbp and Fg. The binding site for Bbp was mapped to residues 561-575 in the Fg Aα chain using recombinant Fg chains and truncation mutants in Far Western blots and solid-phase binding assays. Surface plasmon resonance was used to determine the affinity of Bbp for Fg. The interaction of Bbp with Fg peptides corresponding to the mapped residues was further characterized using isothermal titration calorimetry. In addition, Bbp expressed on the surface of bacteria mediated adherence to immobilized Fg Aα. Also, Bbp interferes with thrombin-induced Fg coagulation. Together these data demonstrate that human Fg is a ligand for Bbp and that Bbp can manipulate the biology of the Fg ligand in the host. 相似文献
994.
Forshammar J Block L Lundborg C Biber B Hansson E 《The Journal of biological chemistry》2011,286(36):31586-31597
Astrocytes respond to inflammatory stimuli and may be important modulators of the inflammatory response in the nervous system. This study aimed first to assess how astrocytes in primary culture behave in response to inflammatory stimuli concerning intracellular Ca(2+) responses, expression of Toll-like receptor 4 (TLR4), Na(+)/K(+)-ATPase, actin filament organization, and expression of cytokines. In a cell culture model with lipopolysaccharide (LPS), astrocyte response was assessed first in the acute phase and then after incubation with LPS for 1-48 h. The concentration curve for LPS-stimulated Ca(2+) responses was bell-shaped, and the astrocytes expressed TLR4, which detects LPS and evokes intracellular Ca(2+) transients. After a long incubation with LPS, TLR4 was up-regulated, LPS-evoked Ca(2+) transients were expressed as oscillations, Na(+)/K(+)-ATPase was down-regulated, and the actin filaments were disorganized. Interleukin-1β (IL-1β) release was increased after 24 h in LPS. A second aim was to try to restore the LPS-induced changes in astrocytes with substances that may have dose-dependent anti-inflammatory properties. Naloxone and ouabain were tested separately in ultralow or high concentrations. Both substances evoked intracellular Ca(2+) transients for all of the concentrations from 10(-15) up to 10(-4) M. Neither substance blocked the TLR4-evoked Ca(2+) responses. Naloxone and ouabain prevented the LPS-induced down-regulation of Na(+)/K(+)-ATPase and restored the actin filaments. Ouabain, in addition, reduced the IL-1β release from reactive astrocytes. Notably, ultralow concentrations (10(-12) M) of naloxone and ouabain showed these qualities. Ouabain seems to be more potent in these effects of the two tested substances. 相似文献
995.
Computational simulations of tissue differentiation have been able to capture the main aspects of tissue formation/regeneration observed in animal experiments-except for the considerable degree of variability reported. Understanding and modelling the source of this variability is crucial if computational tools are to be developed for clinical applications. The objective of this study was to test the hypothesis that differences in cell mechano-sensitivity between individuals can explain the variability of tissue differentiation patterns observed experimentally. Simulations of an experiment of tissue differentiation in a mechanically loaded bone chamber were performed. Finite element analysis was used to determine the biophysical environment, and a lattice-modelling approach was used to simulate cell activity. Differences in cell mechano-sensitivity among individuals were modelled as differences in cell activity rates, with the activation of cell activities regulated by the mechanical environment. Predictions of the tissue distribution in the chambers produced the two different classes of results found experimentally: (i) chambers with a layer of bone across the chamber covered by a layer of cartilage on top and (ii) chambers with almost no bone, mainly fibrous tissue and small islands of cartilage. This indicates that the differing cellular response to the mechanical environment (i.e., subject-specific mechano-sensitivity) could be a reason for the different outcomes found when implants (or tissue engineered constructs) are used in a population. 相似文献
996.
Pollination is often regarded as a mutualistic relationship between flowering plants and insects. In such a relationship, both partners gain a fitness benefit as a result of their interaction. The flower gets pollinated and the insect typically gets a food-related reward. However, flower-insect communication is not always a mutualistic system, as some flowers emit deceitful signals. Insects are thus fooled by irresistible stimuli and pollination is accomplished. Such deception requires very fine tuning, as insects in their typically short life span, try to find mating/feeding breeding sites as efficiently as possible, and following deceitful signals thus is both costly and time-consuming. Deceptive flowers have thus evolved the ability to emit signals that trigger obligate innate or learned responses in the targeted insects. The behavior, and thus the signals, exploited are typically involved in reproduction, from attracting pheromones to brood/food-site cues. Chemical mimicry is one of the main modalities through which flowers trick their pollen vectors, as olfaction plays a pivotal role in insect-insect and insect-plant interactions. Here we focus on floral odors that specifically mimic an oviposition substrate, i.e., brood-site mimicry. The phenomenon is wide spread across unrelated plant lineages of Angiosperm, Splachnaceae and Phallaceae. Targeted insects are mainly beetles and flies, and flowers accordingly often emit, to the human nose, highly powerful and fetid smells that are conversely extremely attractive to the duped insects. Brood-site deceptive plants often display highly elaborate flowers and have evolved a trap-release mechanism. Chemical cues often act in unison with other sensory cues to refine the imitation. 相似文献
997.
Skov C Baktoft H Brodersen J Brönmark C Chapman BB Hansson LA Nilsson PA 《Proceedings. Biological sciences / The Royal Society》2011,278(1710):1414-1418
Partial migration, in which a fraction of a population migrate and the rest remain resident, occurs in an extensive range of species and can have powerful ecological consequences. The question of what drives differences in individual migratory tendency is a contentious one. It has been shown that the timing of partial migration is based upon a trade-off between seasonal fluctuations in predation risk and growth potential. Phenotypic variation in either individual predation risk or growth potential should thus mediate the strength of the trade-off and ultimately predict patterns of partial migration at the individual level (i.e. which individuals migrate and which remain resident). We provide cross-population empirical support for the importance of one component of this model--individual predation risk--in predicting partial migration in wild populations of bream Abramis brama, a freshwater fish. Smaller, high-risk individuals migrate with a higher probability than larger, low-risk individuals, and we suggest that predation risk maintains size-dependent partial migration in this system. 相似文献
998.
Aim To test whether species richness of Sphagnum mosses on islands in a land uplift archipelago is related to island age, area or connectivity, and whether the frequency of different species can be predicted by their life history and autecology. Location The northern Stockholm archipelago in the Baltic Sea, east‐central Sweden, with a current land uplift rate of 4.4 mm year?1. Methods We sampled 17 islands differing in area (0.55–55 ha), height (3.6–18 m, representing c. 800–4000 years of age) and distance from mainland (1.6–41 km). For each Sphagnum patch we measured area, height above sea level, horizontal distance from the shore and shading from vascular plants. Factors affecting island species richness, species frequency and habitats on the islands were tested by stepwise regressions. Species frequency was tested on nine life history and autecological variables, including estimated abundance and spore output on the mainland, habitat preference and distribution. Results We recorded 500 patches of 19 Sphagnum species, distributed in 83 rock pools on 14 islands. Island species richness correlated positively with island area and with degree of shelter by surrounding islands, while distance from the mainland, connectivity, height or age did not add to the model. Species frequency (number of colonized islands and rock pools) was mainly predicted by spore output on the mainland and by habitat preference (swamp forest species were more frequent than others), while spore size, for example, did not add to the model. Species differed in mean height above and horizontal distance from the shore, area of occupied rock pools and in the degree of shading of patches. The mean horizontal distance from the shore and the area of occupied rock pools correlated positively with the normal growth position above the water table among species. Spore capsules were found in only 2% of patches, mostly in the bisexual Sphagnum fimbriatum. Main conclusions The presence of Sphagnum in the Stockholm archipelago seems to be governed by regional spore production and habitat demands. Sphagnum does not appear to be dispersal limited at distances up to 40 km and time spans of centuries. Species with a high regional spore output have had a higher colonization rate, which, together with the rarity of spore capsules on the islands, indicate the mainland as a source for colonization rather than dispersal among islands. Swamp forest species seem more tolerant to the island conditions (summer droughts and some salt spray) than open mire species. The different distances from the sea occupied by the species indicate a slow, continuous succession and species replacement towards the island interior as islands are being uplifted and thus expand in area. This partly explains why larger islands harbour more species. Our results thus support some of the island biogeographical theories related to the species–area relationship. 相似文献
999.
Persson E Löfgren L Hansson G Abrahamsson B Lennernäs H Nilsson R 《Journal of lipid research》2007,48(1):242-251
The purpose of the study reported here was to develop a method for the determination of lipid classes in intestinal fluids, including bile acids (BAs). A solid-phase extraction (SPE) method using C18 and silica columns for the separation of BAs, phospholipids (PLs), and neutral lipids (NLs), including free fatty acids, has been developed and validated. Fed-state small intestinal fluid collected from humans was treated with orlistat to inhibit lipolysis and mixed with acetic acid and methanol before SPE to maximize lipid recoveries. BAs, PLs, and NLs were isolated using lipophilic and polar solvents to promote elution from the SPE columns. The different lipid classes were subsequently analyzed using three separately optimized HPLC methods with evaporative light-scattering detectors. High recoveries (>90%) of all lipids evaluated were observed, with low coefficients of variation (<5%). The HPLC methods developed were highly reproducible and allowed baseline separation of nearly all lipid classes investigated. In conclusion, these methods provide a means of lipid class analysis of NLs, PLs, and BAs in human fed-state small intestinal fluid, with potential use in other fluids from the intestinal tract and animals. 相似文献
1000.
Olofsson M Hansson S Hedberg L Logan DT Oliveberg M 《Journal of molecular biology》2007,365(1):237-248
Studies of circular permutants have demonstrated that the folding reaction of S6 from Thermus thermophilus (S6T) is malleable and responds in an ordered manner to changes of the sequence separation between interacting residues: the S6T permutants retain a common nucleation pattern in the form of a two-strand-helix motif that can be recruited from different parts of the structure. To further test the robustness of the two-strand-helix nucleus we have here determined the crystal structure and folding reaction of an evolutionary divergent S6 protein from the hyperthermophilic bacterium Aquifex aeolicus (S6A). Although the overall topology of S6A is very similar to that of S6T the architecture of the hydrophobic core is radically different by containing a large proportion of stacked Phe side-chains. Despite this disparate core composition, the folding rate constant and the kinetic m values of S6A are identical to those of S6T. The folding nucleus of S6A is also found to retain the characteristic two-strand-helix motif of the S6T permutants, but with a new structural emphasis. The results suggest that the protein folding reaction is linked to topology only in the sense that the native-state topology determines the repertoire of accessible nucleation motifs. If the native structure allows several equivalent ways of recruiting a productive nucleus the folding reaction is free to redistribute within these topological constraints. 相似文献