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31.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
32.
Zhinxin Zhao Roberto Gambari Kenneth Ka-Ho Lee Stanton Hon-Lung Kok Raymond Siu-Ming Wong Fung-Yi Lau Johnny Cheuk-On Tang Kim-Hung Lam Chor-Hing Cheng Desmond Kwok Po Hau Chung-Hin Chui Wai-Yeung Wong Wai-Kwok Wong 《Bioorganic & medicinal chemistry letters》2013,23(8):2373-2376
We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified. 相似文献
33.
34.
Sarah E. Antinone Ghanashyam D. Ghadge Tukiet T. Lam Lijun Wang Raymond P. Roos William N. Green 《The Journal of biological chemistry》2013,288(30):21606-21617
Mutations in Cu,Zn-superoxide dismutase (mtSOD1) cause familial amyotrophic lateral sclerosis (FALS), a neurodegenerative disease resulting from motor neuron degeneration. Here, we demonstrate that wild type SOD1 (wtSOD1) undergoes palmitoylation, a reversible post-translational modification that can regulate protein structure, function, and localization. SOD1 palmitoylation was confirmed by multiple techniques, including acyl-biotin exchange, click chemistry, cysteine mutagenesis, and mass spectrometry. Mass spectrometry and cysteine mutagenesis demonstrated that cysteine residue 6 was the primary site of palmitoylation. The palmitoylation of FALS-linked mtSOD1s (A4V and G93A) was significantly increased relative to that of wtSOD1 expressed in HEK cells and a motor neuron cell line. The palmitoylation of FALS-linked mtSOD1s (G93A and G85R) was also increased relative to that of wtSOD1 when assayed from transgenic mouse spinal cords. We found that the level of SOD1 palmitoylation correlated with the level of membrane-associated SOD1, suggesting a role for palmitoylation in targeting SOD1 to membranes. We further observed that palmitoylation occurred predominantly on disulfide-reduced as opposed to disulfide-bonded SOD1, suggesting that immature SOD1 is the primarily palmitoylated species. Increases in SOD1 disulfide bonding and maturation with increased copper chaperone for SOD1 expression caused a decrease in wtSOD1 palmitoylation. Copper chaperone for SOD1 overexpression decreased A4V palmitoylation less than wtSOD1 and had little effect on G93A mtSOD1 palmitoylation. These findings suggest that SOD1 palmitoylation occurs prior to disulfide bonding during SOD1 maturation and that palmitoylation is increased when disulfide bonding is delayed or decreased as observed for several mtSOD1s. 相似文献
35.
Background and purpose
Rapid increases in atmospheric carbon dioxide concentration ([CO2]) may increase crop residue production and carbon: nitrogen (C:N) ratio. Whether the incorporation of residues produced under elevated [CO2] will limit soil N availability and fertilizer N recovery in the plant is unknown. This study investigated the interaction between crop residue incorporation and elevated [CO2] on the growth, grain yield and the recovery of 15N-labeled fertilizer by wheat (Triticum aestivum L. cv. Yitpi) under controlled environmental conditions.Methods
Residue for ambient and elevated [CO2] treatments, obtained from wheat grown previously under ambient and elevated [CO2], respectively, was incorporated into two soils (from a cereal-legume rotation and a cereal-fallow rotation) 1 month before the sowing of wheat. At the early vegetative stage 15N-labeled granular urea (10.22 atom%) was applied at 50 kg?N ha?1 and the wheat grown to maturity.Results
When residue was not incorporated into the soil, elevated [CO2] increased wheat shoot (16 %) and root biomass (41 %), grain yield (19 %), total N uptake (4 %) and grain N removal (8 %). However, the positive [CO2] fertilization effect on these parameters was absent in the soil amended with residue. In the absence of residue, elevated [CO2] increased fertilizer N recovery in the plant (7 %), but when residue was incorporated elevated [CO2] decreased fertilizer N recovery.Conclusions
A higher fertilizer application rate will be required under future elevated [CO2] atmospheres to replenish the extra N removed in grains from cropping systems if no residue is incorporated, or to facilitate the [CO2] fertilization effect on grain yield by overcoming N immobilization resulting from residue amendment. 相似文献36.
Abstract An efficient alternative which makes use of the reliable 3J1′2′. value to derive the endocyclic torsion angle constraints is proposed in this study. Based on the information embedded in the two plots, (i) the vicinal proton-proton J-couplings, 3J1′2′., 3J1′2″., 3J2′3′., 3J2”3′ and 3J3′4′ against the pseudorotation phase angle, and (ii) 3J1′2″, 3J2′3′., 3J2″3′ and 3J3′4′ against 3J1′2′; using the calculated J-couplings obtained for a range of sugar geometries of deoxyribose ring in nucleosides and nucleotides encountered along the pseudorotation itinerary [J. van Wijk, B.D. Huckriede, J.H. Ippel and C. Altona, Methods Enzymol. 211, 286–306 (1992)], it is suggested that the vicinal 3J1′2′ possesses structural information other than the vicinal torsion angle φ1′2′. This study is divided into two parts. In Part I, a correlation diagram between the endocyclic torsion angles vi (i=0,1,2,3,4) and the restrained vicinal torsion angle φ1′2′ is obtained through the use of the J-coupling restrained molecular mechanics (JrMM) protocol. The established φ1′2′.-vi correlation shows vi can be deduced from the reliable 3J1′2′. value and it forms the basis for developing an alternative protocol to derive endocyclic torsion angle constraints. In Part II of this series, extensive testing demonstrating the validity of the JrMM protocol to derive Vi for defining the sugar geometry of solution DNA molecules is presented. 相似文献
37.
Roni D. Gordon Wei Qiu Vladimir Romanov Kim Lam Maria Soloveychik Diana Benetteraj 《Journal of biomolecular structure & dynamics》2013,31(10):1057-1065
The nitrilases include a variety of enzymes with functional specificities of nitrilase, amidase, and hydrolase reactions. The crystal structure of the uncharacterized protein SA0302 from the pathogenic microorganism Staphylococcus aureus is solved at 1.7?Å resolution. The protein contains 261 amino acids and presents a four-layer αββα sandwich with a chain topology similar to that of a few known CN-hydrolase folds. In the crystal, the proteins are arranged as dimers whose monomers are related by a pseudo twofold rotation symmetry axis. Analysis of the sequences and structures of CN-hydrolases with known 3D structures shows that SA0302 definitely is a member of Branch 10 (Nit and NitFhit) of the nitrilase superfamily. Enzyme activities and substrate specificities of members of this branch are not yet characterized, in contrast to those of the members of Branches 1–9. Although the sequence identities between Branch 10 members are rather low, less than 30%, five conserved regions are common in this subfamily. Three of them contain functionally important catalytic residues, and the two other newly characterized ones are associated with crucial intramolecular and intermolecular interactions. Sequence homology of the area near the active site shows clearly that the catalytic triad of SA0302 is Glu41-Lys110-Cys146. We suggest also that the active site includes a fourth residue, the closely located Glu119. Despite an extensive similarity with other Nit-family structural folds, SA0302 displays an important difference. Protein loop 111–122, which follows the catalytic Lys110, is reduced to half the number of amino acids found in other Nit-family members. This leaves the active site fully accessible to solvent and substrates. We have identified conservative sequence motifs around the three core catalytic residues, which are inherent solely to Branch 10 of the nitrilase superfamily. On the basis of these new sequence fingerprints, 10 previously uncharacterized proteins also could be assigned to this hydrolase subfamily. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:19 相似文献
38.
Kwok Ho Lam Hsiu‐Sheng Hsu Ying Li Changyang Lee Anderson Lin Qifa Zhou Eun Sok Kim Kirk Koping Shung 《Biotechnology and bioengineering》2013,110(3):881-886
Similar to optical tweezers, a tightly focused ultrasound microbeam is needed to manipulate microparticles in acoustic tweezers. The development of highly sensitive ultrahigh frequency ultrasonic transducers is crucial for trapping particles or cells with a size of a few microns. As an extra lens would cause excessive attenuation at ultrahigh frequencies, two types of 200‐MHz lensless transducer design were developed as an ultrasound microbeam device for acoustic tweezers application. Lithium niobate single crystal press‐focused (PF) transducer and zinc oxide self‐focused transducer were designed, fabricated and characterized. Tightly focused acoustic beams produced by these transducers were shown to be capable of manipulating single microspheres as small as 5 µm two‐dimensionally within a range of hundreds of micrometers in distilled water. The size of the trapped microspheres is the smallest ever reported in the literature of acoustic PF devices. These results suggest that these lensless ultrahigh frequency ultrasonic transducers are capable of manipulating particles at the cellular level and that acoustic tweezers may be a useful tool to manipulate a single cell or molecule for a wide range of biomedical applications. Biotechnol. Bioeng. 2013; 110: 881–886. © 2012 Wiley Periodicals, Inc. 相似文献
39.
V KW Wong T Li B YK Law E DL Ma N C Yip F Michelangeli C KM Law M M Zhang K YC Lam P L Chan L Liu 《Cell death & disease》2013,4(7):e720
Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, leading to autophagy induction through the activation of the Ca2+/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells. 相似文献
40.
Lee A. Rollins Angela T. Moles Serena Lam Robert Buitenwerf Joanna M. Buswell Claire R. Brandenburger Habacuc Flores‐Moreno Knud B. Nielsen Ellen Couchman Gordon S. Brown Fiona J. Thomson Frank Hemmings Richard Frankham William B. Sherwin 《Ecology and evolution》2013,3(13):4501-4517
Some introduced populations thrive and evolve despite the presumed loss of diversity at introduction. We aimed to quantify the amount of genetic diversity retained at introduction in species that have shown evidence of adaptation to their introduced environments. Samples were taken from native and introduced ranges of Arctotheca populifolia and Petrorhagia nanteuilii. Using microsatellite data, we identified the source for each introduction, estimated genetic diversity in native and introduced populations, and calculated the amount of diversity retained in introduced populations. These values were compared to those from a literature review of diversity in native, confamilial populations and to estimates of genetic diversity retained at introduction. Gene diversity in the native range of both species was significantly lower than for confamilials. We found that, on average, introduced populations showing evidence of adaptation to their new environments retained 81% of the genetic diversity from the native range. Introduced populations of P. nanteuilii had higher genetic diversity than found in the native source populations, whereas introduced populations of A. populifolia retained only 14% of its native diversity in one introduction and 1% in another. Our literature review has shown that most introductions demonstrating adaptive ability have lost diversity upon introduction. The two species studied here had exceptionally low native range genetic diversity. Further, the two introductions of A. populifolia represent the largest percentage loss of genetic diversity in a species showing evidence of substantial morphological change in the introduced range. While high genetic diversity may increase the likelihood of invasion success, the species examined here adapted to their new environments with very little neutral genetic diversity. This finding suggests that even introductions founded by small numbers of individuals have the potential to become invasive. 相似文献