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41.
Claudia Karnthaler‐Benbakka Bettina Koblmüller Marlene Mathuber Katharina Holste Walter Berger Petra Heffeter Christian R. Kowol Bernhard K. Keppler 《化学与生物多样性》2019,16(1)
Since several decades, the prodrug concept has raised considerable interest in cancer research due to its potential to overcome common problems associated with chemotherapy. However, for small‐molecule tyrosine kinase inhibitors, which also cause severe side effects, hardly any strategies to generate prodrugs for therapeutic improvement have been reported so far. Here, we present the synthesis and biological investigation of a cathepsin B‐cleavable prodrug of the VEGFR inhibitor sunitinib. Cell viability assays and Western blot analyses revealed, that, in contrast to the non‐cathepsin B‐cleavable reference compound, the prodrug shows activity comparable to the original drug sunitinib in the highly cathepsin B‐expressing cell lines Caki‐1 and RU‐MH. Moreover, a cathepsin B cleavage assay confirmed the desired enzymatic activation of the prodrug. Together, the obtained data show that the concept of cathepsin B‐cleavable prodrugs can be transferred to the class of targeted therapeutics, allowing the development of optimized tyrosine kinase inhibitors for the treatment of cancer. 相似文献
42.
Marlene Jahnke Martin Gullstrm Josefine Larsson Maria E. Asplund Said Mgeleka Mathew Ogalo Silas Arielle Hoamby Jamal Mahafina Lina Mtwana Nordlund 《Ecology and evolution》2019,9(16):8953-8964
This study is the first large‐scale genetic population study of a widespread climax species of seagrass, Thalassia hemprichii, in the Western Indian Ocean (WIO). The aim was to understand genetic population structure and connectivity of T. hemprichii in relation to hydrodynamic features. We genotyped 205 individual seagrass shoots from 11 sites across the WIO, spanning over a distance of ~2,700 km, with twelve microsatellite markers. Seagrass shoots were sampled in Kenya, Tanzania (mainland and Zanzibar), Mozambique, and Madagascar: 4–26°S and 33–48°E. We assessed clonality and visualized genetic diversity and genetic population differentiation. We used Bayesian clustering approaches (TESS) to trace spatial ancestry of populations and used directional migration rates (DivMigrate) to identify sources of gene flow. We identified four genetically differentiated groups: (a) samples from the Zanzibar channel; (b) Mozambique; (c) Madagascar; and (d) the east coast of Zanzibar and Kenya. Significant pairwise population genetic differentiation was found among many sites. Isolation by distance was detected for the estimated magnitude of divergence (DEST), but the three predominant ocean current systems (i.e., East African Coastal Current, North East Madagascar Current, and the South Equatorial Current) also determine genetic connectivity and genetic structure. Directional migration rates indicate that Madagascar acts as an important source population. Overall, clonality was moderate to high with large differences among sampling sites, indicating relatively low, but spatially variable sexual reproduction rates. The strongest genetic break was identified for three sites in the Zanzibar channel. Although isolation by distance is present, this study suggests that the three regionally predominant ocean current systems (i.e., East African Coastal Current, North East Madagascar Current, and the South Equatorial Current) rather than distance determine genetic connectivity and structure of T. hemprichii in the WIO. If the goal is to maintain genetic connectivity of T. hemprichii within the WIO, conservation planning and implementation of marine protection should be considered at the regional scale—across national borders. 相似文献
43.
Internalization of weight bias: Implications for binge eating and emotional well-being 总被引:1,自引:0,他引:1
Objective: This study examined the relationship between internalization of negative weight‐based stereotypes and indices of eating behaviors and emotional well‐being in a sample of overweight and obese women. Research Method and Procedures: The sample was comprised of 1013 women who belonged to a national, non‐profit weight loss organization. Participants completed an on‐line battery of self‐report questionnaires measuring frequency of weight stigmatization and coping responses to deal with bias and symptoms of depression and self‐esteem, attitudes about weight and obesity, and binge eating behaviors. In addition, participants were asked to list the most common weight‐based stereotypes and whether they believed them to be true or false. Results: Participants who believed that weight‐based stereotypes were true reported more frequent binge eating and refusal to diet in response to stigma experiences compared with those who reported stereotypes to be false. The degree to which participants believed stereotypes to be true or false was not related to types or amount of stigma experiences reported, self‐esteem, depression, or attitudes toward obese persons. In addition, engaging in weight loss strategies as a response to bias was not predicted by stereotype beliefs or by actual stigma experiences, regardless of the amount or types of stigma reported. Discussion: These findings suggest that obese individuals who internalize negative weight‐based stereotypes may be particularly vulnerable to the negative impact of stigma on eating behaviors and also challenge the notion that stigma may motivate obese individuals to engage in efforts to lose weight. This study highlights a new area of research that warrants attention to better understand weight stigma and its potential consequences for health. 相似文献
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45.
Jessie C. Tanner Elizabeth Swanger Marlene Zuk 《Evolution; international journal of organic evolution》2019,73(7):1482-1489
Evolutionary biologists commonly seek explanations for how selection drives the emergence of novel traits. Although trait loss is also predicted to occur frequently, few contemporary examples exist. In Hawaii, the Pacific field cricket (Teleogryllus oceanicus) is undergoing adaptive sexual signal loss due to natural selection imposed by eavesdropping parasitoids. Mutant male crickets (“flatwings”) cannot sing. We measured the intensity of sexual selection on wing phenotype in a wild population. First, we surveyed the relative abundance of flatwings and “normal‐wings” (nonmutants) on Oahu. Then, we bred wild‐mated females’ offspring to determine both female genotype with respect to the flatwing mutation and the proportion of flatwing males that sired their offspring. We found evidence of strong sexual selection favoring the production of song: females were predominantly homozygous normal‐wing, their offspring were sired disproportionately by singing males, and at the population level, flatwing males became less common following a single sexual selection event. We report a selection coefficient describing the total (pre‐ and postcopulatory) sexual selection favoring normal‐wing males in nature. Given the maintenance of the flatwing phenotype in Hawaii in recent years, this substantial sexual selection additionally suggests an approximate strength of opposing natural selection that favors silent males. 相似文献
46.
C. Seth Pearson Reza Nemati Binbin Liu Jing Zhang Matteo Scalabrin Zhong Li Hongmin Li Dan Fabris Marlene Belfort Georges Belfort 《Biotechnology and bioengineering》2019,116(4):709-721
We have engineered an intein which spontaneously and reversibly forms a thiazoline ring at the native N-terminal Lys-Cys splice junction. We identified conditions to stablize the thiazoline ring and provided the first crystallographic evidence, at 1.54 Å resolution, for its existence at an intein active site. The finding bolsters evidence for a tetrahedral oxythiazolidine splicing intermediate. In addition, the pivotal mutation maps to a highly conserved B-block threonine, which is now seen to play a causative role not only in ground-state destabilization of the scissile N-terminal peptide bond, but also in steering the tetrahedral intermediate toward thioester formation, giving new insight into the splicing mechanism. We demonstrated the stability of the thiazoline ring at neutral pH as well as sensitivity to hydrolytic ring opening under acidic conditions. A pH cycling strategy to control N-terminal cleavage is proposed, which may be of interest for biotechnological applications requiring a splicing activity switch, such as for protein recovery in bioprocessing. 相似文献
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48.
Charles E. Linn Marlene G. Campbell Wendell L. Roelofs 《Archives of insect biochemistry and physiology》1992,20(4):265-284
Experiments were conducted to determine whether the biogenic amines octopamine (OA) and 5-hydroxytryptamine (5-HT) exert modulatory effects on pheromone responsiveness and random locomotor activity in male gypsy moths. When injected into males, OA significantly enhanced sensitivity to pheromone, while 5-HT enhanced general locomotor activity, results that were very similar to those previously shown for the cabbage looper. Maximal effect of the amines, however, was observed when injection occurred just prior to the onset of scotophase, rather than photophase, as we had originally hypothesized for this diurnally active insect. Male gypsy moths also displayed a prominent scotophase response, with sensitivity to pheromone greater in the scotphase compared with photophase, but with the level of random locomotor activity lower in scotophase than in photophase. The upwind flight behavior of males to a pheromone source in a wind tunnel, as well as the time spent at the source, were also significantly different in the two light regimes. Furthermore, when exposed to a 1 h scotophase (instead of the normal 8), or to continuous dark conditions, while males exhibited response to pheromone and locomotor activity during the same scotophase and photophase periods as observed in a 16:8 light : dark cycle, the levels of response, as well as qualitative aspects of the upwind flight behaviors in both periods were a function of the light intensity. Our combined results suggest that male gypsy moths display a bimodal rhythm of locomotor and pheromone response over the diel cycle, with light intensity and scotophase onset providing critical cues for the expression of behaviors, as well as the modulatory action of the amines. © 1992 Wiley-Liss, Inc. 相似文献
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50.
Centrin in Giardia lamblia - ultrastructural localization 总被引:2,自引:0,他引:2
Giardia lamblia is a multiflagellar parasite and one of the earliest diverging eukaryotic cells. It possesses a complex cytoskeleton based on different groups of microtubular structures - a ventral adhesive disc, four pairs of flagella, a median body and funis. Centrin is an important member of the EF-hand family of calcium-binding proteins, and it is known to show calcium-sensitive contractile behaviour. In the present study, we performed an ultrastructural localization of centrin in G. lamblia using several monoclonal antibodies to centrin. Microtubular structures such as the basal bodies, all the flagella axonemes, the adhesive disc, funis, and the median bodies presented positive labelling to centrin. In addition, the dense rods also demonstrated positive labelling. These results show that centrin is located in key positions related to microtubules. The role of centrin in these dynamic regions is discussed. 相似文献