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71.
Spinks D Torrie LS Thompson S Harrison JR Frearson JA Read KD Fairlamb AH Wyatt PG Gilbert IH 《ChemMedChem》2012,7(1):95-106
Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62,000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids. 相似文献
72.
Julie K. Furmick Dr. Ichiro Kaneko Angela N. Walsh Joanna Yang Jaskaran S. Bhogal Geoffrey M. Gray Juan C. Baso Drew O. Browder Jessica L. S. Prentice Luis A. Montano Chanh C. Huynh Lisa M. Marcus Dorian G. Tsosie Jungeun S. Kwon Alexis Quezada Nicole M. Reyes Brittney Lemming Puneet Saini Dr. Arjan van der Vaart Dr. Thomas L. Groy Dr. Pamela A. Marshall Dr. Peter W. Jurutka Dr. Carl E. Wagner 《ChemMedChem》2012,7(9):1551-1566
73.
Rupert Andrew Hurley Rachel Randall Liam O'Hara Charles Tonkin Julie C. Rice 《Color research and application》2017,42(1):50-59
The goal of this research was to determine whether or not there was a difference between consumer preferences for color harmonies for products where external labels and visible product existed simultaneously. Using established color theory, transparent packages containing visible products with colored labels were evaluated. Eye tracking metrics and overall preference testing were used to assess these products. Eye tracking data yielded quantitative data that was statistically analyzed using analysis of variance. A post experiment survey was given to participants to collect demographics and additional data was completed through chi‐squared tests for association. No significant difference was found between color harmonies and preference, nor was there significance for the eye tracking metrics. These results of no significance are ideal for designers because it gives them the freedom to use their judgment when designing packaging labels. © 2016 Wiley Periodicals, Inc. Col Res Appl, 42, 50–59, 2017 相似文献
74.
Systematic studies have been performed to investigate the composition effects of ZrO2-based thermal barrier coating (TBC) ceramics on their interactions with molten Ca–Mg–Al–silicate (CMAS) glass. Porous ceramic pellets (~15% porosity), instead of actual TBCs, are used in these model studies, where the penetration of molten CMAS into the pellets is investigated. This study involves a total of six compositions of ZrO2-based ceramics: two containing low solute (Y3+ or Gd3+) concentration, three with high concentration of solute (Y3+, Gd3+ or Yb3+), and one containing a combined intermediate concentration of Y3++Al3++Ti4+ solutes. While both the type of the solute and its concentration in the ZrO2-based TBC ceramics have been found to influence the extent of molten CMAS penetration into the pellets, the solute concentration has the most dramatic effect. In particular, molten CMAS penetration is almost completely suppressed in porous TBC ceramic pellets containing a high concentration of Y3+ solute (Y2Zr2O7). Possible mechanisms governing these effects are presented, together with a discussion of guidelines for the chemical design of CMAS-resistant zirconate TBC ceramics. Generally, for a TBC ceramic to be highly effective against CMAS attack it must interact vigorously with the molten CMAS, which must result in the rapid crystallization of the refractory oxide phase(s) that form a sealing layer, arresting further penetration of the molten CMAS. The porous ceramic pellets approach used here could be developed into rapid-screening methodologies for the discovery of CMAS-resistant TBC ceramic compositions, and to study the effect of composition of CMAS glasses on their interactions with TBC ceramics of specific compositions. 相似文献
75.
76.
Stephen Patterson Dr. Deuan C. Jones Dr. Emma J. Shanks Dr. Julie A. Frearson Prof. Ian H. Gilbert Prof. Paul G. Wyatt Prof. Alan H. Fairlamb Prof. 《ChemMedChem》2009,4(8):1341-1353
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μM ) and biologically active against bloodstream T. brucei (EC50=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC50=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed. 相似文献
77.
78.
Luke Mansard David Baux Christel Vach Catherine Blanchet Isabelle Meunier Marjolaine Willems Valrie Faugre Corinne Baudoin Melody Moclyn Julie Bianchi Helene Dollfus Brigitte Gilbert-Dussardier Delphine Dupin-Deguine Dominique Bonneau Isabelle Drumare Sylvie Odent Xavier Zanlonghi Mireille Claustres Michel Koenig Vasiliki Kalatzis Anne-Franoise Roux 《International journal of molecular sciences》2021,22(24)
Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic MYO7A and USH2A genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in USH2A. Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed. 相似文献
79.
Sophia X. Sui Lana J. Williams Kara L. Holloway-Kew Natalie K. Hyde Julie A. Pasco 《International journal of molecular sciences》2021,22(1)
Sarcopenia is the loss of skeletal muscle mass and function with advancing age. It involves both complex genetic and modifiable risk factors, such as lack of exercise, malnutrition and reduced neurological drive. Cognitive decline refers to diminished or impaired mental and/or intellectual functioning. Contracting skeletal muscle is a major source of neurotrophic factors, including brain-derived neurotrophic factor, which regulate synapses in the brain. Furthermore, skeletal muscle activity has important immune and redox effects that modify brain function and reduce muscle catabolism. The identification of common risk factors and underlying mechanisms for sarcopenia and cognition may allow the development of targeted interventions that slow or reverse sarcopenia and also certain forms of cognitive decline. However, the links between cognition and skeletal muscle have not been elucidated fully. This review provides a critical appraisal of the literature on the relationship between skeletal muscle health and cognition. The literature suggests that sarcopenia and cognitive decline share pathophysiological pathways. Ageing plays a role in both skeletal muscle deterioration and cognitive decline. Furthermore, lifestyle risk factors, such as physical inactivity, poor diet and smoking, are common to both disorders, so their potential role in the muscle–brain relationship warrants investigation. 相似文献