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131.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
132.
A road map for molecular ecology 总被引:1,自引:0,他引:1
Rose L. Andrew Louis Bernatchez Aurélie Bonin C. Alex. Buerkle Bryan C. Carstens Brent C. Emerson Dany Garant Tatiana Giraud Nolan C. Kane Sean M. Rogers Jon Slate Harry Smith Victoria L. Sork Graham N. Stone Timothy H. Vines Lisette Waits Alex Widmer Loren H. Rieseberg 《Molecular ecology》2013,22(10):2605-2626
The discipline of molecular ecology has undergone enormous changes since the journal bearing its name was launched approximately two decades ago. The field has seen great strides in analytical methods development, made groundbreaking discoveries and experienced a revolution in genotyping technology. Here, we provide brief perspectives on the main subdisciplines of molecular ecology, describe key questions and goals, discuss common challenges, predict future research directions and suggest research priorities for the next 20 years. 相似文献
133.
Patricia L. Jones Michael J. Ryan Victoria Flores Rachel A. Page 《Proceedings. Biological sciences / The Royal Society》2013,280(1772)
Animals can use different sources of information when making decisions. Foraging animals often have access to both self-acquired and socially acquired information about prey. The fringe-lipped bat, Trachops cirrhosus, hunts frogs by approaching the calls that frogs produce to attract mates. We examined how the reliability of self-acquired prey cues affects social learning of novel prey cues. We trained bats to associate an artificial acoustic cue (mobile phone ringtone) with food rewards. Bats were assigned to treatments in which the trained cue was either an unreliable indicator of reward (rewarded 50% of the presentations) or a reliable indicator (rewarded 100% of the presentations), and they were exposed to a conspecific tutor foraging on a reliable (rewarded 100%) novel cue or to the novel cue with no tutor. Bats whose trained cue was unreliable and who had a tutor were significantly more likely to preferentially approach the novel cue when compared with bats whose trained cue was reliable, and to bats that had no tutor. Reliability of self-acquired prey cues therefore affects social learning of novel prey cues by frog-eating bats. Examining when animals use social information to learn about novel prey is key to understanding the social transmission of foraging innovations. 相似文献
134.
Anne Gro Vea Salvanes Olav Moberg Lars O. E. Ebbesson Tom Ole Nilsen Knut Helge Jensen Victoria A. Braithwaite 《Proceedings. Biological sciences / The Royal Society》2013,280(1767)
Different kinds of experience during early life can play a significant role in the development of an animal''s behavioural phenotype. In natural contexts, this influences behaviours from anti-predator responses to navigation abilities. By contrast, for animals reared in captive environments, the homogeneous nature of their experience tends to reduce behavioural flexibility. Studies with cage-reared rodents indicate that captivity often compromises neural development and neural plasticity. Such neural and behavioural deficits can be problematic if captive-bred animals are being reared with the intention of releasing them as part of a conservation strategy. Over the last decade, there has been growing interest in the use of environmental enrichment to promote behavioural flexibility in animals that are bred for release. Here, we describe the positive effects of environmental enrichment on neural plasticity and cognition in juvenile Atlantic salmon (Salmo salar). Exposing fish to enriched conditions upregulated the forebrain expression of NeuroD1 mRNA and improved learning ability assessed in a spatial task. The addition of enrichment to the captive environment thus promotes neural and behavioural changes that are likely to promote behavioural flexibility and improve post-release survival. 相似文献
135.
Pyridoxal 5′-phosphate is the active form of vitamin B6 and its deficiency is directly related with several human disorders, which make human pyridoxal kinase (hPLK) an important pharmacologic target. In spite of this, a carefully kinetic characterization of hPLK including the main species that regulates the enzymatic activity is at date missing. Here we analyse the catalytic and regulatory mechanisms of hPLK as a function of a precise determination of the species involved in metal–nucleotide equilibriums and describe new regulatory mechanisms for this enzyme. hPLK activity is supported by several metals, being Zn2+ the most effective, although the magnitude of the effect observed is highly dependent on the relative concentrations of metal and nucleotide used. The true substrate for the reaction catalyzed by hPLK is the metal nucleotide complex, while ATP4? and HATP3? did not affect the activity. The enzyme presents substrate inhibition by both pyridoxal (PL) and ZnATP2?, although the latter behaves as a weakly inhibitor. Our study also established, for the first time, a dual role for free Zn2+; as an activator at low concentrations (19 μM optimal concentration) and as a potent inhibitor with a IC50 of 37 μM. These results highlighted the importance of an accurate estimation of the actual concentration of the species involved in metal–nucleotide equilibriums in order to obtain reliable values for the kinetic parameters, and for determine the true regulators of the PLK activity. They also help to explain the dissimilar kinetic parameters reported in the literature for this enzyme. 相似文献
136.
Victoria Hritonenko 《Molecular membrane biology》2013,30(5-6):395-406
The Escherichia coli K-12 outer membrane protein OmpT is a prototype of a unique family of bacterial endopeptidases known as the omptins. This family includes OmpT and OmpP of E. coli, SopA of Shigella flexneri, PgtE of Salmonella enterica, and Pla of Yersinia pestis. Despite their sequence similarities, the omptins vary in their reported functions. The OmpT protease is characterized by narrow cleavage specificity defined by the extracellular loops of the β-barrel protruding above the lipid bilayer. It employs a distinct proteolytic mechanism that involves a histidine and an aspartate residue. Most of the omptin proteins have been implicated in bacterial pathogenesis. As a result, the omptins are potential targets for antimicrobial drug and vaccine development. This review summarizes recent developments in omptins structure and function, emphasizes their role in pathogenesis, proposes evolutionary relation among the existing omptins, and offers possible directions for future research. 相似文献
137.
The temperature-sensitive hemagglutinin (Tsh) is a representative of the growing subfamily of secreted bacterial virulence factors, known as serine protease autotransporters of the Enterobacteriaceae (SPATEs). Expressed by avian and human pathogenic strains of Escherichia coli Tsh acts as a serine protease and an adhesin to erythrocytes, hemoglobin, and extracellular matrix proteins. Mature Tsh is comprised of a 106-kDa secreted domain (Tshs) and a 33-kDa outer membrane β-domain (Tshβ). Based on the size of β-domains and functional properties of their passenger domains, all SPATEs are considered to be conventional autotransporters. However, it is unsettled if the conventional autotransporters exist as monomers, oligomers, or multimers (e.g., hexamers). To determine the quaternary structure of Tsh in vitro, we purified Tshβ from the outer membranes and showed that it is natively folded because it is heat modifiable and resistant to protease digestion. Blue-native polyacrylamide gel electrophoresis of Tshβ indicated that Tshβ exists as a monomer or a dimer. The cross-linking analysis demonstrated that purified Tshβ exists as a monomer. The size-exclusion chromatography and cross-linking analyses of purified Tshs also showed that the passenger domain of Tsh is a monomer. Overall, our data indicated that Tsh is a monomeric protein in vitro and support the concept that the SPATE autotransporters exist as monomers rather than as multimers. Implications of our findings on the mechanism of autotransporter secretion across the outer membrane are discussed. 相似文献
138.
Victoria Magrioti Aikaterini Nikolaou Annetta Smyrniotou Ishita Shah Violetta Constantinou-Kokotou Edward A. Dennis George Kokotos 《Bioorganic & medicinal chemistry》2013,21(18):5823-5829
Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2. 相似文献
139.
Alba Naudí Mariona Jové Daniel Cacabelos Victoria Ayala Rosanna Cabre Pilar Caro José Gomez Manuel Portero-Otín Gustavo Barja Reinald Pamplona 《Amino acids》2013,44(2):361-371
Maillard reaction contributes to the chemical modification and cross-linking of proteins. This process plays a significant role in the aging process and determination of animal longevity. Oxidative conditions promote the Maillard reaction. Mitochondria are the primary site of oxidants due to the reactive molecular species production. Mitochondrial proteome cysteine residues are targets of oxidative attack due to their specific chemistry and localization. Their chemical, non-enzymatic modification leads to dysfunctional proteins, which entail cellular senescence and organismal aging. Previous studies have consistently shown that caloric and methionine restrictions, nutritional interventions that increase longevity, decrease the rate of mitochondrial oxidant production and the physiological steady-state levels of markers of oxidative damage to macromolecules. In this scenario, we have detected S-(carboxymethyl)-cysteine (CMC) as a new irreversible chemical modification in mitochondrial proteins. CMC content in mitochondrial proteins significantly correlated with that of the lysine-derived analog N ε-(carboxymethyl)-lysine. The concentration of CMC is, however, one order of magnitude lower compared with CML likely due in part to the lower content of cysteine with respect to lysine of the mitochondrial proteome. CMC concentrations decreases in liver mitochondrial proteins of rats subjected to 8.5 and 25 % caloric restriction, as well as in 40 and 80 % methionine restriction. This is associated with a concomitant and significant increase in the protein content of sulfhydryl groups. Data presented here evidence that CMC, a marker of Cys-AGE formation, could be candidate as a biomarker of mitochondrial damage during aging. 相似文献
140.