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51.
52.
Lucie Guetzoyan Xiao-Min Yu Florence Ramiandrasoa Stéphanie Pethe Christophe Rogier Bruno Pradines Thierry Cresteil Martine Perrée-Fauvet Jean-Pierre Mahy 《Bioorganic & medicinal chemistry》2009,17(23):8032-8039
A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure–activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC50 ? 0.07 μM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC50 ? 0.3 μM. These acridine derivatives inhibited the formation of β-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains. 相似文献
53.
54.
Tilsner J Linnik O Christensen NM Bell K Roberts IM Lacomme C Oparka KJ 《The Plant journal : for cell and molecular biology》2009,57(4):758-770
We describe a method for localizing plant viral RNAs in vivo using Pumilio, an RNA-binding protein, coupled to bimolecular fluorescence complementation (BiFC). Two Pumilio homology domain (PUMHD) polypeptides, fused to either the N- or C-terminal halves of split mCitrine, were engineered to recognize two closely adjacent eight-nucleotide sequences in the genomic RNA of tobacco mosaic virus (TMV). Binding of the PUMHDs to their target sites brought the split mCitrine halves into close proximity, allowing BiFC to occur and revealing the localization of viral RNA within infected cells. The bulk of the RNA was sequestered in characteristic inclusion bodies known as viral replication complexes (VRCs), with a second population of RNA localized in discrete particles distributed throughout the peripheral cytoplasm. Transfer of the TMV Pumilio recognition sequences into the genome of potato virus X (PVX) allowed the PVX RNA to be localized. Unlike TMV, the PVX RNA was concentrated in distinctive 'whorls' within the VRC. Optical sectioning of the PVX VRCs revealed that one of the viral movement proteins was localized to the centres of the RNA whorls, demonstrating significant partitioning of viral RNA and proteins within the VRC. The utility of Pumilio as a fluorescence-based reporter for viral RNA is discussed. 相似文献
55.
Escoffier J Boisseau S Serres C Chen CC Kim D Stamboulian S Shin HS Campbell KP De Waard M Arnoult C 《Journal of cellular physiology》2007,212(3):753-763
In spermatozoa, voltage-dependent calcium channels (VDCC) have been involved in different cellular functions like acrosome reaction (AR) and sperm motility. Multiple types of VDCC are present and their relative contribution is still a matter of debate. Based mostly on pharmacological studies, low-voltage-activated calcium channels (LVA-CC), responsible of the inward current in spermatocytes, were described as essential for AR in sperm. The development of Ca(V)3.1 or Ca(V)3.2 null mice provided the opportunity to evaluate the involvement of such LVA-CC in AR and sperm motility, independently of pharmacological tools. The inward current was fully abolished in spermatogenic cells from Ca(V)3.2 deficient mice. This current is thus only due to Ca(V)3.2 channels. We showed that Ca(V)3.2 channels were maintained in sperm by Western-blot and immunohistochemistry experiments. Calcium imaging experiments revealed that calcium influx in response to KCl was reduced in Ca(V)3.2 null sperm in comparison to control cells, demonstrating that Ca(V)3.2 channels were functional. On the other hand, no difference was noticed in calcium signaling induced by zona pellucida. Moreover, neither biochemical nor functional experiments, suggested the presence of Ca(V)3.1 channels in sperm. Despite the Ca(V)3.2 channels contribution in KCl-induced calcium influx, the reproduction parameters remained intact in Ca(V)3.2 deficient mice. These data demonstrate that in sperm, besides Ca(V)3.2 channels, other types of VDCC are activated during the voltage-dependent calcium influx of AR, these channels likely belonging to high-voltage activated Ca(2+) channels family. The conclusion is that voltage-dependent calcium influx during AR is due to the opening of redundant families of calcium channels. 相似文献
56.
The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inhibitor at 2.5-Å resolution. The three subunits of AcrB are locked in different conformations revealing distinct channels in each subunit. There seems to be remote conformational coupling between the channel access, exit, and the putative proton-translocation site, explaining how the proton motive force is used for drug export. Thus our structure suggests a transport pathway not through the central pore but through the identified channels in the individual subunits, which greatly advances our understanding of the multidrug export mechanism. 相似文献
57.
Dussurget O Dumas E Archambaud C Chafsey I Chambon C Hébraud M Cossart P 《FEMS microbiology letters》2005,250(2):253-261
In this study, the role of Listeria monocytogenes ferritin was investigated. The fri gene encoding the ferritin was deleted and the phenotype of the mutant was analyzed demonstrating that ferritin is necessary for optimal growth in minimal medium in both presence and absence of iron, as well as after cold- and heat-shock. We also showed that ferritin provides protection against reactive oxygen species and is essential for full virulence of L. monocytogenes. A comparative proteomic analysis revealed an effect of the fri deletion on the levels of listeriolysin O and several stress proteins. Together, our study demonstrates that fri has multiple roles that contribute to Listeria virulence. 相似文献
58.
Vermeulen W Van Troys M Bourry D Dewitte D Rossenu S Goethals M Borremans FA Vandekerckhove J Martins JC Ampe C 《Journal of molecular biology》2006,359(5):1277-1292
The HeadPiece (HP) domain, present in several F-actin-binding multi-domain proteins, features a well-conserved, solvent-exposed PXWK motif in its C-terminal subdomain. The latter is an autonomously folding subunit comprised of three alpha-helices organised around a hydrophobic core, with the sequence motif preceding the last helix. We report the contributions of each conserved residue in the PXWK motif to human villin HP function and structure, as well as the structural implications of the naturally occurring Pro to Ala mutation in dematin HP. NMR shift perturbation mapping reveals that substitution of each residue by Ala induces only minor, local perturbations in the full villin HP structure. CD spectroscopic thermal analysis, however, shows that the Pro and Trp residues in the PXWK motif afford stabilising interactions. This indicates that, in addition to the residues in the hydrophobic core, the Trp-Pro stacking within the motif contributes to HP stability. This is reinforced by our data on isolated C-terminal HP subdomains where the Pro is also essential for structure formation, since the villin, but not the dematin, C-terminal subdomain is structured. Proper folding can be induced in the dematin C-terminal subdomain by exchanging the Ala for Pro. Conversely, the reverse substitution in the villin C-terminal subdomain leads to loss of structure. Thus, we demonstrate a crucial role for this proline residue in structural stability and folding potential of HP (sub)domains consistent with Pro-Trp stacking as a more general determinant of protein stability. 相似文献
59.
Leif Egil Loe Christophe Bonenfant Erling L. Meisingset Atle Mysterud 《European Journal of Wildlife Research》2012,58(1):195-203
Species distribution models (SDMs) are popular in conservation and management of a wide array of taxa. Often parameterized
with coarse GIS-based environmental maps, they perform well in macro-ecological settings but it is debated if the models can
predict distribution within broadly suitable “known” habitats of interest to local managers. We parameterized SDMs with GIS-derived
environmental variables and location data from 82 GPS-collared female red deer (Cervus elaphus) from two study areas in Norway. Candidate GLM models were fitted to address the effect of spatial scale (landscape vs. home
range), sample size, and transferability between study areas, with respect to predictability (AUC) and explained variance
(Generalized R
2 and deviance). The landscape level SDM captured variation in deer distribution well and performed best on all diagnostic
measures of model quality, caused mainly by a trivial effect of avoidance of non-habitat (barren mountains). The home range
level SDMs were far less predictable and explained comparatively little variation in space use. Landscape scale models stabilized
at the low sample size of 5–10 individuals and were highly transferrable between study areas implying a low degree of individual
variation in habitat selection at this scale. It is important to have realistic expectations of SDMs derived from digital
elevation models and coarse habitat maps. They do perform well in highlighting potential habitat on a landscape scale, but
often miss nuances necessary to predict more fine-scaled distribution of wildlife populations. Currently, there seems to be
a trade-off between model quality and usefulness in local management. 相似文献
60.
Shinichi Sunagawa Jens Roat Kultima Paul I Costea Aurélien Amiot Jürgen Böhm Francesco Brunetti Nina Habermann Rajna Hercog Moritz Koch Alain Luciani Daniel R Mende Martin A Schneider Petra Schrotz‐King Christophe Tournigand Jeanne Tran Van Nhieu Takuji Yamada Jürgen Zimmermann Vladimir Benes Matthias Kloor Cornelia M Ulrich Magnus von Knebel Doeberitz Iradj Sobhani Peer Bork 《Molecular systems biology》2014,10(11)
Several bacterial species have been implicated in the development of colorectal carcinoma (CRC),
but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be
explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that
distinguished CRC patients from tumor-free controls in a study population of 156 participants.
Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and
when both approaches were combined, sensitivity improved > 45% relative to the FOBT,
while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ
significantly between early- and late-stage cancer and could be validated in independent patient and
control populations (N = 335) from different countries. CRC-associated
changes in the fecal microbiome at least partially reflected microbial community composition at the
tumor itself, indicating that observed gene pool differences may reveal tumor-related
host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in
controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an
increase of lipopolysaccharide metabolism. 相似文献