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961.
von Löhneysen K Noack D Hayes P Friedman JS Knaus UG 《The Journal of biological chemistry》2012,287(12):8737-8745
Redox regulation of signaling molecules contributes critically to propagation of intracellular signals. The main source providing reactive oxygen species (ROS) for these physiological processes are activated NADPH oxidases (Nox/Duox family). In a pathophysiological context, some NADPH oxidase complexes produce large amounts of ROS either as part of the antimicrobial immune defense or as pathologic oxidative stress in many chronic diseases. Thus, understanding the switch from a dormant, inactive conformation to the active state of these enzymes will aid the development of inhibitors. As exogenously expressed Nox4 represents the only constitutively active enzyme in this family, analysis of structural determinants that permit this active conformation was undertaken. Our focus was directed toward a cell-based analysis of the first intracellular loop, the B-loop, and the C-terminus, two regions of Nox family enzymes that are essential for electron transfer. Mutagenesis of the B-loop identified several unique residues and a polybasic motif that contribute to the catalytic activity of Nox4. By using a multifaceted approach, including Nox4-Nox2 chimeras, mutagenesis, and insertion of Nox2 domains, we show here that the penultimate 22 amino acids of Nox4 are involved in constitutive ROS generation. The appropriate spacing of the C-terminal Nox4 sequence may cooperate with a discrete arginine-based interaction site in the B-loop, providing an intrinsically active interface that could not be disrupted by peptides derived from the Nox4 C-terminus. These results indicate that accessibility for a Nox4-specific peptide inhibitor might be difficult to achieve in vivo. 相似文献
962.
María Busch Carol Knight Cristina Noemí Mazía Karina Hodara Emiliano Muschetto Enrique Chaneton 《Ecological Research》2012,27(2):369-376
Woody plant invasion in grassland ecosystems is a worldwide phenomenon, and biotic interactions as competition and predation
have been invoked as a possible barrier to woody encroachment in many ecosystems. We evaluated the role of rodents as seed
predators in Pampean grasslands, and we assessed the differences in removal by rodents between one native species, Prosopis caldenia (Caldén) and one exotic species, Gleditisia triacanthos (Honey locust). The experiment was conducted at different phases of the rodent population cycle in two grassland communities,
a remnant of a native grassland and a post agriculture grassland (old field). The amount of seed loss caused by predation
was estimated by a bait-removal experiment in foraging stations. We estimated the frequency of foraging stations with consumption,
the overall amount of seed predation and the individual rate of seed predation. The total amount of seed removal and the individual
rate of seed removal were higher for P. caldenia than for G. triacanthos, in the native grassland than in the old field, and in autumn when rodent density was maximum. Overall, the role of rodents
on woody seed removal varied according to the plant species and depending on the local conditions that vary through time and
space. 相似文献
963.
The saltwater mosquito, Aedes vigilax, is prolific in coastal wetlands including mangroves and saltmarshes. Ae. vigilax is a vector for arboviruses such as Ross River and Barmah Forest viruses, with significant consequences for human health and economic productivity. In Australia the dominant form of mosquito control is chemicals. For mangroves, this is because there is a critical lack of knowledge supporting alternative approaches, such as environmental modification or biological control using larvivorous fish. This review examines the potential of fish as biological agents for the control of mosquito larvae in mangroves. We consider two key aspects: how larvivorous fish use mangroves; and can larvivorous fish reduce larval mosquito populations sufficiently to provide effective mosquito control? The link between fish and mangroves is reasonably well established, where mangroves act as refuge habitat for small and juvenile fish. Also, research has established that fish can be significant predators of mosquitoes, and therefore may be effective control agents. However, studies of fish activity within mangroves are limited to study of the fringe of the mangroves and not the internal structure of mangrove basins and as a result, fish populations within these areas remain unstudied. Also, until recently there was little appreciation of the mangrove-mosquito habitat relationship and, as a consequence, the importance of the mangrove basin as the key mosquito habitat has also been overlooked in the literature. Similarly, the predator/prey relationships between fish and mosquitoes within mangrove basin environments also remain unstudied, and therefore the importance of fish for mosquito management in mangrove basins is not known. There are substantial knowledge gaps regarding the potential of fish in controlling larval mosquitoes in mangroves. The gaps include: understanding of how larvivorous fish use mangrove basins; the nature of the fish-mosquito predator/prey relationship in mangrove basins; and whether larvivorous fish are effective as a mosquito control option in mangroves. 相似文献
964.
965.
The vast number of microbial sequences resulting from sequencing efforts using new technologies require us to re-assess currently available analysis methodologies and tools. Here we describe trends in the development and distribution of software for analyzing microbial sequence data. We then focus on one widely used set of methods, dimensionality reduction techniques, which allow users to summarize and compare these vast datasets. We conclude by emphasizing the utility of formal software engineering methods for the development of computational biology tools, and the need for new algorithms for comparing microbial communities. Such large-scale comparisons will allow us to fulfill the dream of rapid integration and comparison of microbial sequence data sets, in a replicable analytical environment, in order to describe the microbial world we inhabit. 相似文献
966.
Skidmore J Atcha Z Boucherat E Castelletti L Chen DW Coppo FT Cutler L Dunsdon RM Heath BM Hutchings R Hurst DN Javed S Martin S Maskell ES Norton D Pemberton DJ Redshaw S Rutter R Sehmi SS Scoccitti T Temple HE Theobald P Ward RW Wilson DM 《Bioorganic & medicinal chemistry letters》2012,22(10):3560-3563
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement. 相似文献
967.
Hilinski MK Mrozowski RM Clark DE Lannigan DA 《Bioorganic & medicinal chemistry letters》2012,22(9):3244-3247
The Ser/Thr protein kinase, RSK, is important in the etiology of tumor progression including invasion and motility. The natural product kaempferol-3-O-(3″,4″-di-O-acetyl-α-l-rhamnopyranoside), called SL0101, is a highly specific RSK inhibitor. Acylation of the rhamnose moiety is necessary for high affinity binding and selectivity. However, the acetyl groups can be cleaved by esterases, which accounts for the poor in vitro biological stability of SL0101. To address this problem a series of analogs containing acetyl group replacements were synthesized and their in vitro stability evaluated. Monosubstituted carbamate analogs of SL0101 showed improved in vitro biological stability while maintaining specificity for RSK. These results should facilitate the development of RSK inhibitors derived from SL0101 as anticancer agents. 相似文献
968.
Bode CM Boezio AA Albrecht BK Bellon SF Berry L Broome MA Choquette D Dussault I Lewis RT Lin MH Rex K Whittington DA Yang Y Harmange JC 《Bioorganic & medicinal chemistry letters》2012,22(12):4089-4093
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model. 相似文献
969.
Leyi Gong Yun-Chou Tan Genevieve Boice Sarah Abbot Kristen McCaleb Pravin Iyer Fengrong Zuo Joseph Dal Porto Brian Wong Sue Jin Alice Chang Patricia Tran Gary Hsieh Linghao Niu Ada Shao Deborah Reuter Christine M. Lukacs R. Ursula Kammlott Andreas Kuglstatter David Goldstein 《Bioorganic & medicinal chemistry letters》2012,22(24):7381-7387
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC50 of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model. 相似文献
970.
Han X Civiello RL Conway CM Cook DA Davis CD Macci R Pin SS Ren SX Schartman R Signor LJ Thalody G Widmann KA Xu C Chaturvedula PV Macor JE Dubowchik GM 《Bioorganic & medicinal chemistry letters》2012,22(14):4723-4727
We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3-1 mg/kg (s.c.), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate. 相似文献