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961.
Wolin RL Bembenek SD Wei J Crawford S Lundeen K Brunmark A Karlsson L Edwards JP Blevitt JM 《Bioorganic & medicinal chemistry letters》2008,18(9):2825-2829
Computer aided modeling guided the design of a series of diarylimidazole compounds (11–22) intended to interact with both the ATP and adjacent allosteric binding domains of B-RAF kinase. Their ability to inhibit the function of B-RAF kinase and intracellular ERK1/2 phosphorylation were evaluated. 相似文献
962.
Herrmann A Burman R Mylne JS Karlsson G Gullbo J Craik DJ Clark RJ Göransson U 《Phytochemistry》2008,69(4):939-952
The cyclotides are currently the largest known family of head-to-tail cyclic proteins. The complex structure of these small plant proteins, which consist of approximately 30 amino acid residues, contains both a circular peptide backbone and a cystine knot, the combination of which produces the cyclic cystine knot motif. To date, cyclotides have been found in plants from the Rubiaceae, Violaceace and Cucurbitaceae families, and are believed to be part of the host defence system. In addition to their insecticidal effect, cyclotides have also been shown to be cytotoxic, anti-HIV, antimicrobial and haemolytic agents. In this study, we show that the alpine violet Viola biflora (Violaceae) is a rich source of cyclotides. The sequences of 11 cyclotides, vibi A-K, were determined by isolation and MS/MS sequencing of proteins and screening of a cDNA library of V. biflora in parallel. For the cDNA screening, a degenerate primer against a conserved (AAFALPA) motif in the cyclotide precursor ER signal sequence yielded a series of predicted cyclotide sequences that were correlated to those of the isolated proteins. There was an apparent discrepancy between the results of the two strategies as only one of the isolated proteins could be identified as a cDNA clone. Finally, to correlate amino acid sequence to cytotoxic potency, vibi D, E, G and H were analysed using a fluorometric microculture cytotoxicity assay using a lymphoma cell line. The IC(50)-values of the bracelet cyclotides vibi E, G and H ranged between 0.96 and 5.0 microM while the M?bius cyclotide vibi D was not cytotoxic at 30 microM. 相似文献
963.
Repair of radiation-induced heat-labile sites is independent of DNA-PKcs, XRCC1 and PARP 总被引:1,自引:0,他引:1
Ionizing radiation induces a variety of different DNA lesions; in addition to the most critical DNA damage, the DSB, numerous base alterations, SSBs and other modifications of the DNA double-helix are formed. When several non-DSB lesions are clustered within a short distance along DNA, or close to a DSB, they may interfere with the repair of DSBs and affect the measurement of DSB induction and repair. We have shown previously that a substantial fraction of DSBs measured by pulsed-field gel electrophoresis (PFGE) are in fact due to heat-labile sites within clustered lesions, thus reflecting an artifact of preparation of genomic DNA at elevated temperature. To further characterize the influence of heat-labile sites on DSB induction and repair, cells of four human cell lines (GM5758, GM7166, M059K, U-1810) with apparently normal DSB rejoining were tested for biphasic rejoining after gamma irradiation. When heat-released DSBs were excluded from the measurements, the fraction of fast rejoining decreased to less than 50% of the total. However, the half-times of the fast (t(1/2) = 7-8 min) and slow (t(1/2) = 2.5 h) DSB rejoining were not changed significantly. At t = 0, the heat-released DSBs accounted for almost 40% of the DSBs, corresponding to 10 extra DSBs per cell per Gy in the initial DSB yield. These heat-released DSBs were repaired within 60-90 min in all cells tested, including M059K cells treated with wortmannin and DNA-PKcs-defective M059J cells. Furthermore, cells lacking XRCC1 or poly(ADP-ribose) polymerase 1 (PARP1) rejoined both total DSBs and heat-released DSBs similarly to normal cells. In summary, the presence of heat-labile sites has a substantial impact on DSB induction and DSB rejoining rates measured by pulsed-field gel electrophoresis, and heat-labile sites repair is independent of DNA-PKcs, XRCC1 and PARP. 相似文献
964.
Label-free primary screening and affinity ranking of fragment libraries using parallel analysis of protein panels 总被引:1,自引:0,他引:1
Hämäläinen MD Zhukov A Ivarsson M Fex T Gottfries J Karlsson R Björsne M 《Journal of biomolecular screening》2008,13(3):202-209
The authors present fragment screening data obtained using a label-free parallel analysis approach where the binding of fragment library compounds to 4 different target proteins can be screened simultaneously using surface plasmon resonance detection. They suggest this method as a first step in fragment screening to identify and select binders, reducing the demanding requirements on subsequent X-ray or nuclear magnetic resonance studies, and as a valuable "clean-up" tool to eliminate unwanted promiscuous binders from libraries. A small directed fragment library of known thrombin binders and a general 500-compound fragment library were used in this study. Thrombin, blocked thrombin, carbonic anhydrase, and glutathione-S-transferase were immobilized on the sensor chip surface, and the direct binding of the fragments was studied in real time. Only 12 microg of each protein is needed for screening of a 3000-compound fragment library. For screening, a binding site-blocked target as reference facilitates the identification of binding site-selective hits and the signals from other reference proteins for the elimination of false positives. The scope and limitations of this screening approach are discussed for both target-directed and general fragment libraries. 相似文献
965.
McGaha TL Karlsson MC Ravetch JV 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(8):5670-5679
Data suggests that modulation of FcgammaRIIB expression represents a significant risk factor for the development of autoimmunity. In this study, we investigated this notion in mice that possess genetics permissible for the development of autoimmunity. To this end, Mrl-MpJ Fcgr2b-/- mice were monitored for the development of autoreactivity. We found that FcgammaRIIB deficiency led to chronic B cell activation associated with increased germinal center and plasma cell accumulation in the spleen. Likewise, Mrl-MpJ Fcgr2b-/- mice exhibited significant serum IgG reactivity against DNA. We further analyzed the IgG isotype contribution to the anti-dsDNA response and found increases in all subtypes with the exception of IgG3. In particular, we found large increases in IgG1 and IgG2b autoreactivity correlating with significant increases in immune complex deposition and kidney pathology. Finally, we found dendritic cells derived from Mrl-MpJ Fcgr2b-/- mice greatly increased IL-12 expression upon coincubation with apoptotic thymocytes compared with wild-type controls. The results indicate that FcgammaRIIB is an important regulator of peripheral tolerance and attenuation of the inhibitory signal it provides enhances autoimmune disease on susceptible backgrounds. Additionally, the data indicates FcgammaRIIB function has a significant impact on APC activity, suggesting a prominent role in dendritic cell activity in response to interaction with particulate autoantigens. 相似文献
966.
Hannes Eichner Jens Karlsson Laura Spelmink Anuj Pathak Lok-To Sham Birgitta Henriques-Normark Edmund Loh 《PLoS pathogens》2021,17(4)
Bacterial meningitis is a major cause of death and disability in children worldwide. Two human restricted respiratory pathogens, Streptococcus pneumoniae and Haemophilus influenzae, are the major causative agents of bacterial meningitis, attributing to 200,000 deaths annually. These pathogens are often part of the nasopharyngeal microflora of healthy carriers. However, what factors elicit them to disseminate and cause invasive diseases, remain unknown. Elevated temperature and fever are hallmarks of inflammation triggered by infections and can act as warning signals to pathogens. Here, we investigate whether these respiratory pathogens can sense environmental temperature to evade host complement-mediated killing. We show that productions of two vital virulence factors and vaccine components, the polysaccharide capsules and factor H binding proteins, are temperature dependent, thus influencing serum/opsonophagocytic killing of the bacteria. We identify and characterise four novel RNA thermosensors in S. pneumoniae and H. influenzae, responsible for capsular biosynthesis and production of factor H binding proteins. Our data suggest that these bacteria might have independently co-evolved thermosensing abilities with different RNA sequences but distinct secondary structures to evade the immune system. 相似文献
967.
968.
Comparison of the myelin period of peripheral and central origin by electron microscopy 总被引:1,自引:0,他引:1
U Karlsson 《Journal of ultrastructure research》1966,15(3):451-468
969.
Electron microscopy of ribosomes isolated from tobacco leaves 总被引:2,自引:0,他引:2