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31.
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As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5ad and 6d, showed excellent efficacy with a αmax close to 1. Selected compounds (2d, 3a, 3b, 5ad) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,29 are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs.  相似文献   
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The proteasome inhibitor bortezomib (Velcade) is prescribed for the treatment of multiple myeloma. Clinically achievable concentrations of bortezomib cause less than 85% inhibition of the chymotrypsin-like activity of the proteasome, but little attention has been paid as to whether in vitro studies are representative of this level of inhibition. Patients receive bortezomib as an intravenous or subcutaneous bolus injection, resulting in maximum proteasome inhibition within one hour followed by a gradual recovery of activity. In contrast, most in vitro studies use continuous treatment so that activity never recovers. Replacing continuous treatment with 1 h-pulse treatment increases differences in sensitivity in a panel of 7 multiple myeloma cell lines from 5.3-fold to 18-fold, and reveals that the more sensitive cell lines undergo apoptosis at faster rates. Clinically achievable inhibition of active sites was sufficient to induce cytotoxicity only in one cell line. At concentrations of bortezomib that produced similar inhibition of peptidase activities a different extent of inhibition of protein degradation was observed, providing an explanation for the differential sensitivity. The amount of protein degraded per number of active proteasomes correlated with sensitivity to bortezomib. Thus, (i) in vitro studies of proteasome inhibitors should be conducted at pharmacologically achievable concentrations and duration of treatment; (ii) a similar level of inhibition of active sites results in a different extent of inhibition of protein breakdown in different cell lines, and hence a difference in sensitivity.  相似文献   
35.
Buteoninae (Falconiformes, Accipitridae) consist of the widely distributed genus Buteo, and several closely related species in a group called “sub-buteonine hawks”, such as Buteogallus, Parabuteo, Asturina, Leucopternis and Busarellus, with unsolved phylogenetic relationships. Diploid number ranges between 2n = 66 and 2n = 68. Only one species, L. albicollis had its karyotype analyzed by molecular cytogenetics. The aim of this study was to present chromosomal analysis of three species of Buteoninae: Rupornis magnirostris, Asturina nitida and Buteogallus meridionallis using fluorescence in situ hybridization (FISH) experiments with telomeric and rDNA probes, as well as whole chromosome probes derived from Gallus gallus and Leucopternis albicollis. The three species analyzed herein showed similar karyotypes, with 2n = 68. Telomeric probes showed some interstitial telomeric sequences, which could be resulted by fusion processes occurred in the chromosomal evolution of the group, including the one found in the tassociation GGA1p/GGA6. In fact, this association was observed in all the three species analyzed in this paper, and also in L. albicollis, suggesting that it represents a cytogenetic signature which reinforces the monophyly of Neotropical buteoninae species.  相似文献   
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Primate populations, including Madagascar’s lemurs, are threatened worldwide and conservationists need accurate population estimates to develop targeted conservation plans. We sought to fill knowledge gaps for three lemur taxa —white-fronted brown lemur (Eulemur albifrons); eastern woolly lemur (Avahi laniger); and Allocebus/Microcebus, a category combining observations of hairy-eared dwarf lemurs (Allocebus trichotis) and mouse lemurs (Microcebus spp.)— in northeastern Madagascar by estimating their density, examining how their encounter rates and densities vary across three different forest types, and monitoring trends in encounter rates and densities at resurveyed sites, using data from surveys at six forest sites over a 4-year period (2010–2013). Landscape density for white-fronted brown lemur, eastern woolly lemur, and Allocebus/Microcebus was 21.5 (SE 3.67), 57.7 (SE 9.17), and 39.1 (SE 9.55) individuals/km2, respectively. There was no difference in density estimates at intact and intermediately degraded forest sites; however, we encountered white-fronted brown lemurs more often in intact forest (1.64 ± SE 0.40 individuals/km) than in intermediately degraded and degraded forest (0.15 ± SE 0.06 and 0.16 ± SE 0.06 individuals/km). In addition, we encountered white-fronted brown lemurs at lower rates in 2013 (0.15 ± SE 0.06 individuals/km) compared to 2010 (0.82 ± SE 0.12 individuals/km) at a resurveyed site. Our findings emphasize that primate researchers must account for variation in how lemur encounter rates and densities differ between intact and degraded forests, and although we observed a decline in white-fronted brown lemur encounter rate at our resurveyed site, we caution that changes in lemur encounter rates may simply reflect lower detection rates rather than lower density. Future research should focus on using conventional distance sampling techniques, which are infrequently used in primate studies, to provide more robust density estimates as a way to accurately assess trends and the effects of anthropogenic pressures on lemur populations.  相似文献   
38.
Tissue‐resident memory T (TRM) cells are abundant in the memory T cell pool and remain resident in peripheral tissues, such as the skin, where they act as alarm sensors or cytotoxic killers. TRM cells persist long after the pathogen is eliminated and can respond rapidly upon reinfection with the same antigen. When aberrantly activated, skin‐located TRM cells have a profound role in various skin disorders, including vitiligo and melanoma. Autoreactive TRM cells are present in human lesional vitiligo skin and mouse models of vitiligo, which suggests that targeting these cells could be effective as a durable treatment strategy for vitiligo. Furthermore, emerging evidence indicates that induction of melanoma‐reactive TRM cells is needed to achieve effective protection against tumor growth. This review highlights seminal reports about skin‐resident T cells, focusing mainly on their role in the context of vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases.  相似文献   
39.
Purpose

Life cycle assessment (LCA) is a data-intensive methodology; therefore, experts usually focus collection efforts on a few activities, while generic data on remaining activities are taken from databases. Even though increased availability of databases has facilitated LCA takeoff, assuring data quality is fundamental to ensure meaningful results and reliable interpretation.

Methods

Ecoinvent has become a global reference for inventory data. Its current version released three impact partition modeling options—the recycled content, “allocation at the point of substitution” (APOS), and consequential models—whose adequate choice is crucial for yielding meaningful assessments. Tutorials and manuals describe the distribution algorithm that backs each system model, to ground decision-making regarding the best fit to a study’s goals. We performed a systematic literature review to investigate—within the papers published on the International Journal of LCA (IJLCA)—how transparently authors addressed the system model choices.

Results and discussion

About 70% of LCA practitioners continued to use earlier versions of ecoinvent after version 3 was launched in 2013. The number of papers using versions 3.x only showed an increased growth trend 2 years later. Eighty-three papers actually adopted the newest version of the database. From those, only 29 papers clearly mentioned the adopted system model. Our SLR also suggests a trend regarding authorship profile of LCA-related studies: the number of studies conducted by practitioners aware of the intricacies of sound modeling of background and foreground data might have been surpassed by those conducted by non-LCA specialists who use LCA as a supporting tool for investigations in applied fields, and merely scratch the surface.

Conclusions

Our results point to a need for a caveat: ecoinvent users must take time to understand the general concept behind each system model and practice one of the most important actions when performing an LCA—state methodological choices clearly.

  相似文献   
40.
International Journal of Primatology - Interspecific hybridization allows the introgression or movement of alleles from one genome to another. While some genomic regions freely exchange alleles...  相似文献   
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