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21.
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Qingqing Zhou Tristan A. Reekie Ramzi H. Abbassi Dinesh Indurthi Venkata Josep S. Font Renae M. Ryan Lenka Munoz Michael Kassiou 《Bioorganic & medicinal chemistry》2018,26(22):5852-5869
Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A. 相似文献
23.
Renae K. Barr Giuseppe Verdile Linda K. Wijaya Michael Morici Kevin Taddei Veer B. Gupta Steve Pedrini Liang Jin Joseph A. Nicolazzo Erin Knock Paul E. Fraser Ralph N. Martins 《The Journal of biological chemistry》2016,291(2):547-559
Although the formation of β-amyloid (Aβ) deposits in the brain is a hallmark of Alzheimer disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble Aβ oligomers is highly desirable for early diagnosis prior to the manifestation of a clinical AD phenotype and also more effective therapies. We have previously reported that a novel 15-amino acid peptide (15-mer), isolated via phage display screening, targeted Aβ and attenuated its neurotoxicity (Taddei, K., Laws, S. M., Verdile, G., Munns, S., D''Costa, K., Harvey, A. R., Martins, I. J., Hill, F., Levy, E., Shaw, J. E., and Martins, R. N. (2010) Neurobiol. Aging 31, 203–214). The aim of the current study was to generate and biochemically characterize analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15-amino acid peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t = 300 min, c.f. t = 30 min for the parent peptide). This candidate reduced the formation of soluble Aβ42 oligomers, with the concurrent generation of non-toxic, insoluble aggregates measuring up to 25–30 nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric Aβ42, as shown by coimmunoprecipitation and surface plasmon resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aβ42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aβ42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies. 相似文献
24.
Richard W Browne Michael S Bloom Enrique F Schisterman Kathy Hovey Maurizio Trevisan Chengqing Wu Aiyi Liu Jean Wactawski-Wende 《Biomarkers》2008,13(2):160-183
Little information is available on the intra-individual variability of oxidative stress biomarkers in healthy individuals and even less in the context of the menstrual cycle. The objective of this study was to characterize the analytical and biological variability of a panel of 21 markers of oxidative damage, antioxidant defence and micronutrients in nine healthy, regularly menstruating women aged 18-44 years. Analyses included measurement of lipid peroxidation, antioxidant enzymes and antioxidant vitamins. Blood specimens were collected, processed and stored using standardized procedures on days 2, 7, 12, 13, 14, 18, 22 and 28 in one cycle for each subject. Replicate analyses of markers were performed and two-way nested random effects ANOVA was used to describe analytical, intra-individual and inter-individual variability. No statistically significant differences at alpha=0.05, or temporal effects across the menstrual cycle were observed. Analytical variability was the smallest component of variance for all variables. The ICC among replicates ranged from 0.80 to 0.98. Imprecision based on quality control materials ranged from 1 to 11%. The critical differences between serial results varied greatly between assays ranging from 6 to 216% of the mean level. These results provide important initial information on the variability of biomarkers of oxidative stress, antioxidant defence and micronutrients across the menstrual cycle. 相似文献
25.
Eastern mosquitofish (Gambusia holbrooki) were introduced into Australia in 1925 and released to control mosquitoes. Gambusia holbrooki rapidly became invasive in recipient environments and now threaten native fauna. In this study, we used five polymorphic
microsatellite loci and sequence from two mitochondrial genes, cytochrome b and cytochrome oxidase I, to evaluate genetic
variation, colonisation and movement patterns of introduced G. holbrooki in the greater Melbourne area, and to assist in identifying the feasibility of local eradication. Microsatellite variation
was consistently low within populations and there was evidence of bottleneck events for several populations. Populations displayed
significant structuring associated with river basins rather than geographic distance, suggesting that habitat connectivity
is important for dispersal. However, a few populations within river basins were more closely related to populations in other
river basins than within their own basin, most likely reflecting a role of human-assisted dispersal in population establishment.
Mitochondrial sequencing revealed only a single haplotype and suggested all populations were founded by individuals from a
common source. These genetic data help delineate boundaries for local management strategies. 相似文献
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27.
Glutamate transport is coupled to the co-transport of 3 Na(+) and 1 H(+) followed by the counter-transport of 1 K(+). In addition, glutamate and Na(+) binding to glutamate transporters generates an uncoupled anion conductance. The human glial glutamate transporter EAAT1 (excitatory amino acid transporter 1) also allows significant passive and active water transport, which suggests that water permeation through glutamate transporters may play an important role in glial cell homoeostasis. Urea also permeates EAAT1 and has been used to characterize the permeation properties of the transporter. We have previously identified a series of mutations that differentially affect either the glutamate transport process or the substrate-activated channel function of EAAT1. The water and urea permeation properties of wild-type EAAT1 and two mutant transporters were measured to identify which permeation pathway facilitates the movement of these molecules. We demonstrate that there is a significant rate of L-glutamate-stimulated passive and active water transport. Both the passive and active L-glutamate-stimulated water transport is most closely associated with the glutamate transport process. In contrast, L-glutamate-stimulated [(14)C]urea permeation is associated with the anion channel of the transporter. However, there is also likely to be a transporter-specific, but glutamate independent, flux of water via the anion channel. 相似文献
28.
Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential 总被引:13,自引:0,他引:13
Bogoyevitch MA Boehm I Oakley A Ketterman AJ Barr RK 《Biochimica et biophysica acta》2004,1697(1-2):89-101
29.
Silvana Acevedo Stephen Saddlier Pam Clunie Renae Ayres 《Ecological Management & Restoration》2013,14(2):112-119
There are no national emergency response arrangements for freshwater pest fish incursions in Australia. Individual States and Territories vary widely in their current response arrangements to freshwater pest fish incursions, with many being dealt with on an ad‐hoc basis and with varying degrees of efficacy. In recognition of this, the Invasive Animals Cooperative Research Centre funded a project to ‘Advance the development of national emergency response arrangements for freshwater fish incursions in Australia’. One of the recommendations of this project was creating a web‐based support tool (DST) to provide direction and assistance in managing freshwater pest fish incursions. This article describes the DST created. The DST leads the user through a series of questions relating to the species sighting, details of the fish and its capture, and site information at a particular location. These questions address issues that managers must consider when choosing appropriate control techniques. Information entered in two sections (site details and fish details) influence the suggested control techniques. The final product of the DST is a standard online report that contains a summary of all information entered and a ranking of the most common control techniques used in Australia. The report is then submitted to and assessed by the relevant State Government authority responsible for the management of freshwater pest fish incursions. Managers are then able to consider their options, taking into consideration current permits, resources and capability. The DST is anticipated to maximize the speed and quality of freshwater pest fish incursion reporting and to help the responsible government agency decide on the most appropriate management action. The DST will also provide government agency staff access to other relevant information and facilitate consistency in the decision‐making approach by government agencies throughout Australia. 相似文献
30.
Esther Landesman-Bollag Anna Belkina Beth Hovey Edward Connors Charles Cox David C. Seldin 《Molecular and cellular biochemistry》2011,356(1-2):227-231
The CK2 α and α′ catalytic gene products have overlapping biochemical activity, but in vivo, their functions are very different. Deletion of both alleles of CK2α leads to mid-gestational embryonic lethality, while deletion of both alleles of CK2α′ does not interfere with viability or development of embryos; however, adult CK2α′?/?males are infertile. To further elucidate developmental roles of CK2, and analyze functional overlap between the two catalytic genes, mice with combined knockouts were bred. Mice bearing any two CK2 catalytic alleles were phenotypically normal. However, inheritance of a single CK2α allele, without either CK2α′ allele, resulted in partial embryonic lethality. Such mice that survived through embryogenesis were smaller at birth than littermate controls, and weighed less throughout life. However, their cardiac function and lifespan were normal. Fibroblasts derived from CK2α+/?CK2α′?/? embryos grew poorly in culture. These experiments demonstrate that combined loss of one CK2α allele and both CK2α′ alleles leads to unique abnormalities of growth and development. 相似文献