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961.
Ruchelman AL Man HW Chen R Liu W Lu L Cedzik D Zhang L Leisten J Collette A Narla RK Raymon HK Muller GW 《Bioorganic & medicinal chemistry》2011,19(21):6356-6374
A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ~1 μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd. 相似文献
962.
963.
Marcelo H Ratto Louis TJ Delbaere Yvonne A Leduc Roger A Pierson Gregg P Adams 《Reproductive biology and endocrinology : RB&E》2011,9(1):24
Background
The objective of the present study was to isolate and purify the protein fraction(s) of llama seminal plasma responsible for the ovulation-inducing effect of the ejaculate. 相似文献964.
965.
Critical oxygen pressure (P(C)) is used in respiratory physiology to measure the response to hypoxia. P(C) defines the partial pressure of oxygen (Po(2)) at which an oxygen regulator switches to a conformer. However, not all animals show such clear patterns in oxygen consumption rate (Mo2), and there are many methods for determining P(C). This study assesses two methods that determine regulatory ability and four that calculate P(C). A new method, the regulation index (RI), assigns to an animal a relative measure of regulatory ability by calculating the area under the Mo2 versus Po(2) curve that is greater than a linear trend. The six methods are applied to developmental Mo2 data of two amphibians, Pseudophryne bibronii and Crinia georgiana. The four methods used to determine P(C) produced similar results but failed to identify the increase in regulation on hatching in C. georgiana or the greater regulation in larval C. georgiana compared with P. bibronii. Of the two methods that evaluated regulation, only the RI satisfactorily represented the entire range of Po(2). The RI is advantageous because it has clearly defined limits and does not constrain data to fit any single pattern. The RI can be used in concert with P(C), which can be easily calculated during the RI analysis, to provide a clearer definition of the Mo2 response to environmental Po(2). 相似文献
966.
Although MDM2 is known to be a critical negative regulator of p53, MDM2 only catalyzes p53 mono- or multiple monoubiquitination in vitro and in vivo, which is insufficient for the initiation of proteasomal degradation. MDM2 does not polyubiquitinate p53 in vitro, however, which indicates that the activity of other ubiquitin ligase(s) or cofactor(s) is required for MDM2-mediated p53 polyubiquitination and degradation. In our recent study, we demonstrated that UBE4B, an E3 and E4 ubiquitin ligase with a U-box domain, interacts physically with both p53 and MDM2. Our findings revealed that UBE4B negatively regulates the level of p53 and inhibits p53-dependent transactivation and apoptosis. We propose that inhibition of MDM2 binding to UBE4B may provide another approach to inhibit MDM2 E3 ligase activity for tumor suppressor p53. It could lead to novel anticancer therapies, with the possibility of reducing the public health burden from cancer.Key words: ubiquitination, MDM2, UBE4B, p53, degradation 相似文献
967.
Bauman A Higdon R Rapson S Loiue B Hogan J Stacy R Napuli A Guo W van Voorhis W Roach J Lu V Landorf E Stewart E Kolker N Collart F Myler P van Belle G Kolker E 《Omics : a journal of integrative biology》2011,15(1-2):73-82
High-throughput (HTP) proteomics studies generate large amounts of data. Interpretation of these data requires effective approaches to distinguish noise from biological signal, particularly as instrument and computational capacity increase and studies become more complex. Resolving this issue requires validated and reproducible methods and models, which in turn requires complex experimental and computational standards. The absence of appropriate standards and data sets for validating experimental and computational workflows hinders the development of HTP proteomics methods. Most protein standards are simple mixtures of proteins or peptides, or undercharacterized reference standards in which the identity and concentration of the constituent proteins is unknown. The Seattle Children's 200 (SC-200) proposed proteomics standard mixture is the next step toward developing realistic, fully characterized HTP proteomics standards. The SC-200 exhibits a unique modular design to extend its functionality, and consists of 200 proteins of known identities and molar concentrations from 6 microbial genomes, distributed into 10 molar concentration tiers spanning a 1,000-fold range. We describe the SC-200's design, potential uses, and initial characterization. We identified 84% of SC-200 proteins with an LTQ-Orbitrap and 65% with an LTQ-Velos (false discovery rate?=?1% for both). There were obvious trends in success rate, sequence coverage, and spectral counts with protein concentration; however, protein identification, sequence coverage, and spectral counts vary greatly within concentration levels. 相似文献
968.
Kolker N Higdon R Broomall W Stanberry L Welch D Lu W Haynes W Barga R Kolker E 《Omics : a journal of integrative biology》2011,15(7-8):513-521
To address the monumental challenge of assigning function to millions of sequenced proteins, we completed the first of a kind all-versus-all sequence alignments using BLAST for 9.9 million proteins in the UniRef100 database. Microsoft Windows Azure produced over 3 billion filtered records in 6 days using 475 eight-core virtual machines. Protein classification into functional groups was then performed using Hive and custom jars implemented on top of Apache Hadoop utilizing the MapReduce paradigm. First, using the Clusters of Orthologous Genes (COG) database, a length normalized bit score (LNBS) was determined to be the best similarity measure for classification of proteins. LNBS achieved sensitivity and specificity of 98% each. Second, out of 5.1 million bacterial proteins, about two-thirds were assigned to significantly extended COG groups, encompassing 30 times more assigned proteins. Third, the remaining proteins were classified into protein functional groups using an innovative implementation of a single-linkage algorithm on an in-house Hadoop compute cluster. This implementation significantly reduces the run time for nonindexed queries and optimizes efficient clustering on a large scale. The performance was also verified on Amazon Elastic MapReduce. This clustering assigned nearly 2 million proteins to approximately half a million different functional groups. A similar approach was applied to classify 2.8 million eukaryotic sequences resulting in over 1 million proteins being assign to existing KOG groups and the remainder clustered into 100,000 functional groups. 相似文献
969.
Kouyos RD von Wyl V Hinkley T Petropoulos CJ Haddad M Whitcomb JM Böni J Yerly S Cellerai C Klimkait T Günthard HF Bonhoeffer S;Swiss HIV Cohort Study 《PLoS pathogens》2011,7(11):e1002321
HIV-1 replicative capacity (RC) provides a measure of within-host fitness and is determined in the context of phenotypic drug resistance testing. However it is unclear how these in-vitro measurements relate to in-vivo processes. Here we assess RCs in a clinical setting by combining a previously published machine-learning tool, which predicts RC values from partial pol sequences with genotypic and clinical data from the Swiss HIV Cohort Study. The machine-learning tool is based on a training set consisting of 65000 RC measurements paired with their corresponding partial pol sequences. We find that predicted RC values (pRCs) correlate significantly with the virus load measured in 2073 infected but drug na?ve individuals. Furthermore, we find that, for 53 pairs of sequences, each pair sampled in the same infected individual, the pRC was significantly higher for the sequence sampled later in the infection and that the increase in pRC was also significantly correlated with the increase in plasma viral load and with the length of the time-interval between the sampling points. These findings indicate that selection within a patient favors the evolution of higher replicative capacities and that these in-vitro fitness measures are indicative of in-vivo HIV virus load. 相似文献
970.
Nick?Dawnay Louise?Dawnay Roger?N.?Hughes Richard?Cove Martin?I.?TaylorEmail author 《Conservation Genetics》2011,12(3):731-744
While currently in a state of recovery in the United Kingdom (UK), the grayling (Thymallus thymallus) remains of conservation interest due to its historical decline, socio-economic value and the potential impact of hatchery-reared
stock fish on the genetic structure and diversity of wild populations. However, little is known about the levels and distribution
of genetic diversity among UK grayling populations. To this end, 27 UK populations of grayling were genotyped across 10 microsatellite
loci and sequenced at the mtDNA D-Loop. All populations clustered into four higher-level groups: Northern England, Southern
England, Wales, and group consisting of a mixture of native and introduced populations. Ten populations showed evidence of
bottleneck or founder effects, and the effective population size (Ne) was low in all populations. In most cases, historical
stocking records agreed with the genetic relationships revealed in the study. A D-Loop haplotype network supported the groupings
observed in the nuclear data, while phylogenetic inference places the UK populations amongst Central European samples. The
combined datasets demonstrate that many of the UK populations can be treated as separate Management Units and we recommend
that to preserve population specific genetic diversity, that stocking should be an intervention of last resort. However, if
stocking is deemed essential, brood stock should originate from the river to be stocked. 相似文献