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41.
Anurima Majumder Lakshmanan Govindasamy Andrew Magis Róbert Kiss Tímea Polgár Rebekah Baskin Robert W. Allan Mavis Agbandje-McKenna Gary W. Reuther Gy?rgy M. Keser? Kirpal S. Bisht Peter P. Sayeski 《The Journal of biological chemistry》2010,285(41):31399-31407
Somatic mutations in the Jak2 protein, such as V617F, cause aberrant Jak/STAT signaling and can lead to the development of myeloproliferative neoplasms. This discovery has led to the search for small molecule inhibitors that target Jak2. Using structure-based virtual screening, our group recently identified a novel small molecule inhibitor of Jak2 named G6. Here, we identified a structure-function correlation of this compound. Specifically, five derivative compounds of G6 having structural similarity to the original lead compound were obtained and analyzed for their ability to (i) inhibit Jak2-V617F-mediated cell growth, (ii) inhibit the levels of phospho-Jak2, phospho-STAT3, and phospho-STAT5; (iii) induce apoptosis in human erythroleukemia cells; and (iv) suppress pathologic cell growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Additionally, we computationally examined the interactions of these compounds with the ATP-binding pocket of the Jak2 kinase domain. We found that the stilbenoid core-containing derivatives of G6 significantly inhibited Jak2-V617F-mediated cell proliferation in a time- and dose-dependent manner. They also inhibited phosphorylation of Jak2, STAT3, and STAT5 proteins within cells, resulting in higher levels of apoptosis via the intrinsic apoptotic pathway. Finally, the stilbenoid derivatives inhibited the pathologic growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Collectively, our data demonstrate that G6 has a stilbenoid core that is indispensable for maintaining its Jak2 inhibitory potential. 相似文献
42.
Water-soluble quantum dots for biomedical applications 总被引:6,自引:0,他引:6
Yu WW Chang E Drezek R Colvin VL 《Biochemical and biophysical research communications》2006,348(3):781-786
Semiconductor nanocrystals are 1-10nm inorganic particles with unique size-dependent optical and electrical properties due to quantum confinement (so they are also called quantum dots). Quantum dots are new types of fluorescent materials for biological labeling with high quantum efficiency, long-term photostability, narrow emission, and continuous absorption spectra. Here, we discuss the recent development in making water-soluble quantum dots and related cytotoxicity for biomedical applications. 相似文献
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44.
Brennan RM Petersen J Neller MA Miles JJ Burrows JM Smith C McCluskey J Khanna R Rossjohn J Burrows SR 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(6):2742-2748
The TCR plays a critical role in recognizing intracellular pathogens and initiating pathways leading to the destruction of infected cells by the immune system. Although genetic variability is known to greatly impact on the human immune system and the outcome of infection, the influence of sequence variation leading to the inactivation or deletion of TCR gene segments is unknown. To investigate this issue, we examined the CD8(+) T cell response to an HLA-B7-restricted epitope ((265)RPHERNGFTVL(275)) from the pp65 Ag of human CMV that was highly biased and frequently dominated by a public TCR β-chain encoded by the variable gene segment TRBV4-3. Approximately 40% of humans lack T cells expressing TRBV4-3 because of a 21.5-kb insertion/deletion polymorphism, but these individuals remain responsive to this epitope, using a diverse T cell repertoire characterized by private TCR usage. Although most residues within the bulged 11-mer peptide were accessible for TCR contact, the public and private TCRs showed distinct patterns of sensitivity to amino acid substitution at different positions within the peptide, thereby suggesting that the repertoire diversity generated in the absence of the dominant public TRBV4-3(+) TCR could lead to better protection from viral escape mutation. Thus, variation in the size of the TRBV repertoire clearly contributes toward interindividual variability in immune responses and is presumably maintained in many ethnic groups to enhance the diversity of Ag-specific T cell responses. 相似文献
45.
Fadel HJ Saenz DT Guevara R von Messling V Peretz M Poeschla EM 《Journal of virology》2012,86(4):2312-2322
A rodent or other small animal model for HIV-1 has not been forthcoming, with the principal obstacles being species-specific restriction mechanisms and deficits in HIV-1 dependency factors. Some Carnivorans may harbor comparatively fewer impediments. For example, in contrast to mice, the domestic cat genome encodes essential nonreceptor HIV-1 dependency factors. All Feliformia species and at least one Caniformia species also lack a major lentiviral restriction mechanism (TRIM5α/TRIMCyp proteins). Here we investigated cells from two species in another carnivore family, the Mustelidae, for permissiveness to the HIV-1 life cycle. Mustela putorius furo (domesticated ferret) primary cells and cell lines did not restrict HIV-1, feline immunodeficiency virus (FIV), equine infectious anemia virus (EIAV), or N-tropic murine leukemia virus (MLV) postentry and supported late HIV-1 life cycle steps comparably to human cells. The ferret TRIM5α gene exon 8, which encodes the B30.2 domain, was found to be pseudogenized. Strikingly, ferret (but not mink) cells engineered to express human HIV-1 entry receptors supported productive spreading replication, amplification, and serial passage of wild-type HIV-1. Nevertheless, produced virions had relatively reduced infectivity and the virus accrued G→A hypermutations, consistent with APOBEC3 protein pressure. Ferret cell-passaged HIV-1 also evolved amino acid changes in the capsid cyclophilin A binding loop. We conclude that the genome of this carnivore can provide essential nonreceptor HIV-1 dependency factors and that ferret APOBEC3 proteins with activity against HIV-1 are likely. Even so, unlike in cat cells, HIV-1 can replicate in ferret cells without vif substitution. The virus evolves in this novel nonprimate cell adaptive landscape. We suggest that further characterization of HIV-1 adaptation in ferret cells and delineation of Mustelidae restriction factor repertoires are warranted, with a view to the potential for an HIV-1 animal model. 相似文献
46.
Rebekah E. Ruzicka Michael R. Conover 《Ethology : formerly Zeitschrift fur Tierpsychologie》2012,118(2):187-196
Olfactory predators and scavengers rely on odors to locate food, and they forage primarily at night. We hypothesized that weather (e.g. wind speed, humidity, and temperature), vegetation, and landscape features affect the dissipation of odors in the atmosphere and, thus, impact the foraging efficiency of olfactory predators. We tested this hypothesis by assessing what conditions were correlated with the persistence of bait along the dike surrounding Willard Bay Reservoir, Utah. We distributed 124 chicken eggs and 199 dead European starlings (Sturnus vulgaris) as bait over 21 separate occasions spanning from May 21, 2009, to August 18, 2009. We used timers to record the time of consumption and cameras to identify which species ate the bait. Sixty‐six eggs and 87 dead European starlings were consumed. The bait was consumed mostly at night (83%) and by striped skunks (Mephitis mephitis), raccoons (Procyon lotor), and red foxes (Vulpes vulpes). We used nest survival models in program MARK to determine which covariates influenced bait persistence. We tested nine variables and found that bait persistence was influenced by section of the dike, time since study initiation, temperature, humidity, and wind speed but not bait type (egg or dead European starling), terrain, or visual cover. How quickly scavengers were able to locate food, which was inversely related to rates of bait persistence, decreased with higher temperatures and wind speeds and increased with higher humidity. Our results support the hypothesis that weather and micro‐habitat characteristics impact the ability of olfactory predators and scavengers to locate food. 相似文献
47.
Higgins J Stuber T Quance C Edwards WH Tiller RV Linfield T Rhyan J Berte A Harris B 《Applied and environmental microbiology》2012,78(10):3674-3684
A variable-number tandem repeat (VNTR) protocol targeting 10 loci in the Brucella abortus genome was used to assess genetic diversity among 366 field isolates recovered from cattle, bison, and elk in the Greater Yellowstone Area (GYA) and Texas during 1998 to 2011. Minimum spanning tree (MST) and unweighted-pair group method with arithmetic mean (UPGMA) analyses of VNTR data identified 237 different VNTR types, among which 14 prominent clusters of isolates could be identified. Cattle isolates from Texas segregated into three clusters: one comprised of field isolates from 1998 to 2005, one comprised of vaccination-associated infections, and one associated with an outbreak in Starr County in January 2011. An isolate obtained from a feral sow trapped on property adjacent to the Starr County herd in May 2011 clustered with the cattle isolates, suggesting a role for feral swine as B. abortus reservoirs in Starr County. Isolates from a 2005 cattle outbreak in Wyoming displayed VNTR-10 profiles matching those of strains recovered from Wyoming and Idaho elk. Additionally, isolates associated with cattle outbreaks in Idaho in 2002, Montana in 2008 and 2011, and Wyoming in 2010 primarily clustered with isolates recovered from GYA elk. This study indicates that elk play a predominant role in the transmission of B. abortus to cattle located in the GYA. 相似文献
48.
Picou RA Schrum DP Ku G Cerqua RA Kheterpal I Gilman SD 《Analytical biochemistry》2012,425(2):104-112
The separation and detection of individual amyloid beta (Aβ) aggregates by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was demonstrated. Samples were prepared with either Aβ (1-40) or Aβ (1-42) peptides and were characterized by CE with ultraviolet (UV) absorbance detection and transmission electron microscopy (TEM). Using thioflavin T (ThT) in the electrophoresis buffer, electrophoresis of aggregate-containing samples (5.0-s injection) produced up to several hundred narrow (< 20 ms FWHM [full width at half maximum]) fluorescence peaks. Injection of Aβ (1-40) monomer samples resulted in no additional peaks compared with controls. The CE-LIF results were validated by bulk ThT fluorescence measurements for the same samples. The potential of laser-induced fluorescence anisotropy (LIFA) with CE to characterize individual Aβ aggregates also was investigated. 相似文献
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50.
Baskin R Gali M Park SO Zhao ZJ Keseru GM Bisht KS Sayeski PP 《Bioorganic & medicinal chemistry letters》2012,22(3):1402-1407
In this study, we analyzed the structure-activity relationship properties of the small molecule Jak2 inhibitor G6. We synthesized a set of derivatives containing the native para-hydroxyl structure or an alternative meta-hydroxyl structure and examined their Jak2 inhibitory properties. We found that the para-hydroxyl derivative known as NB15 had excellent Jak2 inhibitory properties in silico, in vitro, and ex vivo when compared with meta-hydroxyl derivatives. These results indicate that NB15 is a potent derivative of the Jak2 inhibitor G6, and that maintaining the para-hydroxyl orientation of G6 is critical for its Jak2 inhibitory potential. 相似文献