196 research outputs found
On Oliver's p-group conjecture
Let S be a p-group for an odd prime p. Bob Oliver conjectures that a certain
characteristic subgroup X(S) always contains the Thompson subgroup J(S). We
obtain a reformulation of the conjecture as a statement about modular
representations of p-groups. Using this we verify Oliver's conjecture for
groups where S/X(S) has nilpotence class at most two.Comment: 9 pages; terminology altered to conform to current usag
Two-Dimensional 'H and 31P NMR Spectra and Restrained Molecular Dynamics Structure of a Covalent CPI-CDP12-Oligodeoxyribonucleotide Decamer Complex?
ABSTRACT: CPI-CDPI, is a synthetic analogue of CC-1065, which is a naturally occurring antitumor antibiotic. Assignment of the 'H N M R spectra of a CPI-CDP1,-oligodeoxyribonucleotide decamer, d-(CGCTTAAGCG),, complex has been made by two-dimensional 'H/*H spectroscopy. The solution structure of the complex was calculated by an iterative hybrid relaxation matrix method combined with NOESY distance restrained molecular dynamics. Refinement proceeded in two steps in which the decamer was initially refined alone and then CPI-CDPI, was added to the structure to allow initial estimates of drug-DNA contacts. A hybrid matrix/MD refinement was used to better take into account problems associated with spin diffusion. Thus the distances from the 2D NOESY spectra were calculated from the relaxation rate matrix which were evaluated from a hybrid NOESY volume matrix comprising elements from the experimental spectrum and those calculated from an initial structure. The hybrid matrix derived distances were then used in a restrained molecular dynamics procedure to obtain a new structure that better approximates the NOESY spectra. The resulting partially refined structure was then used to calculate an improved theoretical NOESY volume matrix which is once again merged with the experimental matrix until refinement is complete. The efficacy of CC-1065 has been attributed to its minor groove binding and alkylation to the N 3 position of adenosine. CPI-CDPI, appears to bind to the decamer in a similar manner. The effect of CPI-CDPI, on the decamer's 'H and 31P spectrum was consistent with a minor groove binding motif with the drug alkylating at A17 with the CDPI rings oriented toward the 5'-end of the alkylated strand. In addition, the N M R data support one major adduct but also indicate the presence of a minor adduct. The latter could represent a drug alkylation of the D N A at a secondary site (or alternative orientation of the rings). C C -1 0 6 5 is a naturally occurring antitumor antibiotic derived from Streptomyces zelensius The activity of CC-1065 has been attributed to an interaction with DNA at the cellular level. The CD differenc
Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer
Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift
Helical Stacking in DNA 3-Way Junctions Containing 2 Unpaired Pyrimidines - Proton NMR-Studies
The proton NMR spectra of DNA three-way junction complexes (TWJ) having unpaired pyrimidines, 5\u27-TT- and 5\u27-TC- on one strand at the junction site were assigned from 2D NOESY spectra acquired in H2O and D2O solvents and homonuclear 3D NOESY-TOCSY and 3D NOESY-NOESY in D2O solvent. TWJ are the simplest branched structures found in biologically active nucleic acids. Unpaired nucleotides are common features of such structures and have been shown to stabilize junction formation. The NMR data confirm that the component oligonucleotides assemble to form conformationally homogeneous TWJ complexes having three double-helical, B-form arms. Two of the helical arms stack upon each other. The unpaired pyrimidine bases lie in the minor groove of one of the helices and are partly exposed to solvent. The coaxial stacking arrangement deduced is different from that determined by Rosen and Patel (Rosen, M. A., and D. J. Patel. 1993. Biochemistry. 32:6576-6587) for a DNA three-way junction having two unpaired cytosines, but identical to that suggested by Welch et al. (Welch, J. B., D. R. Duckett, D. M. J. Lilley. 1993. Nucleic Acids Res. 21:4548-4555) on the basis of gel electrophoretic studies of DNA three-way junctions containing unpaired adenosines and thymidines
New Camptothecin and Ellagic Acid Analogues from the Root Bark of Camptotheca Acuminate (Abstract)
Glueballs amass at RHIC and LHC Colliders! - The early quarkless 1st order phase transition at MeV - from pure Yang-Mills glue plasma to GlueBall-Hagedorn states
The early stage of high multiplicity pp, pA and AA collider is represented by
a nearly quarkless, hot, deconfined pure gluon plasma. According to pure
Yang-Mills Lattice Gauge Theory, this hot pure glue matter undergoes, at a high
temperature, MeV, a first order phase transition into a confined
Hagedorn-GlueBall fluid. These new scenario should be characterized by a
suppression of high photons and dileptons, baryon suppression and
enhanced strange meson production. We propose to observe this newly predicted
class of events at LHC and RHIC.Comment: 7 pages, 6 figures
Proteomic Analysis of Pichindé virus
The arenaviruses include a number of important pathogens including Lassa virus and Junin virus. Presently, the only treatment is supportive care and the antiviral Ribavirin. In the event of an epidemic, patient triage may be required to more effectively manage resources; the development of prognostic biomarker signatures, correlating with disease severity, would allow rational triage. Using a pair of arenaviruses, which cause mild or severe disease, we analyzed extracts from infected cells using SELDI mass spectrometry to characterize potential biomarker profiles. EDGE analysis was used to analyze longitudinal expression differences. Extracts from infected guinea pigs revealed protein peaks which could discriminate between mild or severe infection, and between times post-infection. Tandem mass-spectrometry identified several peaks, including the transcriptional regulator prothymosin-α. Further investigation revealed differences in secretion of this peptide. These data show proof of concept that proteomic profiling of host markers could be used as prognostic markers of infectious disease
Identification of Thioaptamer Ligand against E-Selectin: Potential Application for Inflamed Vasculature Targeting
Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based TA binding selection from a combinatorial library followed by a cell-based TA binding selection using E-selectin expressing human microvascular endothelial cells. ESTA-1 selectively bound to E-selectin with nanomolar binding affinity (KD = 47 nM) while exhibiting minimal cross reactivity to P- and L-selectin. Furthermore, ESTA-1 binding to E-selectin on the endothelial cells markedly antagonized the adhesion (over 75% inhibition) of sLex positive HL-60 cells at nanomolar concentration. ESTA-1 also bound specifically to the inflamed tumor-associated vasculature of human carcinomas derived from breast, ovarian, and skin but not to normal organs, and this binding was highly associated with the E-selectin expression level. Similarly, intravenously injected ESTA-1 demonstrated distinct binding to the tumor vasculature in a breast cancer xenograft model. Together, our data substantiates the discovery of a thioaptamer (ESTA-1) that binds to E-selectin with high affinity and specificity, thereby highlighting the potential application of ESTA-1 for E-selectin targeted delivery
Thioaptamer Conjugated Liposomes for Tumor Vasculature Targeting
Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo, the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer for targeting and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agents
Weak closure and Oliver's p-group conjecture
To date almost all verifications of Oliver's p-group conjecture have
proceeded by verifying a stronger conjecture about weakly closed quadratic
subgroups. We construct a group of order 3^n for n = 49 which refutes the
weakly closed conjecture but satisfies Oliver's conjecture.Comment: 9 page
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