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991.
Williams SJ Sornaraj P deCourcy-Ireland E Menz RI Kobe B Ellis JG Dodds PN Anderson PA 《Molecular plant-microbe interactions : MPMI》2011,24(8):897-906
Resistance (R) proteins are key regulators of the plant innate immune system and are capable of pathogen detection and activation of the hypersensitive cell death immune response. To understand the molecular mechanism of R protein activation, we undertook a phenotypic and biochemical study of the flax nucleotide binding (NB)-ARC leucine-rich repeat protein, M. Using Agrobacterium-mediated transient expression in flax cotyledons, site-directed mutations of key residues within the P-loop, kinase 2, and MHD motifs within the NB-ARC domain of M were shown to affect R protein function. When purified using a yeast expression system and assayed for ATP and ADP, these mutated proteins exhibited marked differences in the quantity and identity of the bound nucleotide. ADP was bound to recombinant wild-type M protein, while the nonfunctional P-loop mutant did not have any nucleotides bound. In contrast, ATP was bound to an autoactive M protein mutated in the highly conserved MHD motif. These data provide direct evidence supporting a model of R protein function in which the "off" R protein binds ADP and activation of R protein defense signaling involves the exchange of ADP for ATP. 相似文献
992.
Biofouling of vessels is implicated as a high risk transfer mechanism of non-indigenous marine species (NIMS). Biofouling on international vessels is managed through stringent border control policies, however, domestic biofouling transfers are managed under different policies and legislative arrangements as they cross internal borders. As comprehensive guidelines are developed and increased compliance of international vessels with 'clean hull' expectations increase, vessel movements from port to port will become the focus of biosecurity management. A semi-quantitative port to port biofouling risk assessment is presented that evaluates the presence of known NIMS in the source port and determines the likelihood of transfer based on the NIMS association with biofouling and environmental match between source and receiving ports. This risk assessment method was used to assess the risk profile of a single dredge vessel during three anticipated voyages within Australia, resulting in negligible to low risk outcomes. This finding is contrasted with expectations in the literature, specifically those that suggest slow moving vessels pose a high to extreme risk of transferring NIMS species. 相似文献
993.
Covington HE Maze I Sun H Bomze HM DeMaio KD Wu EY Dietz DM Lobo MK Ghose S Mouzon E Neve RL Tamminga CA Nestler EJ 《Neuron》2011,71(4):656-670
Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression. 相似文献
994.
Garlic (Allium sativum) and its essential oil have long been used for their distinct flavour, therapeutic effects and as a topical and systemic insect repellent. We tested the hypothesis that the yellow fever mosquito, Aedes aegypti L. (Diptera: Culicidae), responds electrophysiologically and behaviourally to specific components of the steam‐distilled essential oil of garlic. In coupled gas chromatographic‐electroantennographic detection analyses of garlic oil, antennae of female Ae. aegypti responded to 14 compounds. Seven of them [diallyl disulphide, diallyl trisulphide, diallyl tetrasulphide, 2‐(2,3‐dithia‐5‐hexenyl)‐3,4‐dihydro‐2H‐thiopyran, 3‐(2,3‐dithia‐5‐hexenyl)‐3,4‐dihydro‐2H‐thiopyran, 6‐methyl‐4,5,8,9‐tetrathiadodeca‐1,11‐diene and 4,5,9,10‐tetrathiatrideca‐1,12‐diene] were isolated or synthesized and tested for their ability to repel host‐seeking female Ae. aegypti. A solution of diallyl trisulphide and diallyl tetrasulphide applied to a human forearm provided protection from female mosquitoes significantly longer than the paraffin oil control. All compounds had mean protection times significantly shorter than an equivalent dose of the ‘gold standard’N,N‐diethyl‐3‐methylbenzamide. Understanding the common moiety in organosulfur compounds that causes repellence could lead to the design of analogues that are more effective than their natural counterparts in repelling mosquitoes. 相似文献
995.
Akt signalling in health and disease 总被引:1,自引:0,他引:1
Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial. 相似文献
996.
Ratcliffe P Adam JM Baker J Bursi R Campbell R Clark JK Cottney JE Deehan M Easson AM Ecker D Edwards D Epemolu O Evans L Fields R Francis S Harradine P Jeremiah F Kiyoi T McArthur D Morrison A Passier P Pick J Schnabel PG Schulz J Steinbrede H Walker G Westwood P Wishart G de Haes JU 《Bioorganic & medicinal chemistry letters》2011,21(8):2541-2546
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development. 相似文献
997.
Jamieson C Maclean JK Brown CI Campbell RA Gillen KJ Gillespie J Kazemier B Kiczun M Lamont Y Lyons AJ Moir EM Morrow JA Pantling J Rankovic Z Smith L 《Bioorganic & medicinal chemistry letters》2011,21(2):805-811
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19. 相似文献
998.
Arbuckle W Baugh M Belshaw S Bennett DJ Bruin J Cai J Cameron KS Claxton C Dempster M Everett K Fradera X Hamilton W Jones PS Kinghorn E Long C Martin I Robinson J Westwood P 《Bioorganic & medicinal chemistry letters》2011,21(3):932-935
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pka of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pka 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen. 相似文献
999.
1000.
Lambert W Koeck PJ Ahrman E Purhonen P Cheng K Elmlund D Hebert H Emanuelsson C 《Protein science : a publication of the Protein Society》2011,20(2):291-301
Unfolding proteins are prevented from irreversible aggregation by small heat shock proteins (sHsps) through interactions that depend on a dynamic equilibrium between sHsp subunits and sHsp oligomers. A chloroplast-localized sHsp, Hsp21, provides protection to client proteins to increase plant stress resistance. Structural information is lacking concerning the oligomeric conformation of this sHsp. We here present a structure model of Arabidopsis thaliana Hsp21, obtained by homology modeling, single-particle electron microscopy, and lysine-specific chemical crosslinking. The model shows that the Hsp21 subunits are arranged in two hexameric discs, similar to a cytosolic plant sHsp homolog that has been structurally determined after crystallization. However, the two hexameric discs of Hsp21 are rotated by 25° in relation to each other, suggesting a role for global dynamics in dodecamer function. 相似文献