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1.
Byth KF Cooper N Culshaw JD Heaton DW Oakes SE Minshull CA Norman RA Pauptit RA Tucker JA Breed J Pannifer A Rowsell S Stanway JJ Valentine AL Thomas AP 《Bioorganic & medicinal chemistry letters》2004,14(9):2249-2252
Modification of imidazo[1,2-a]pyridine CDK inhibitors lead to identification of less lipophilic imidazo[1,2-b]pyridazine series of CDK inhibitors. Although several equivalent compounds from these two series have similar structure and show similar CDK activity, the SAR of the two series differs significantly. Protein inhibitor structure determination has confirmed differences in binding mode and given some understanding of these differences in SAR. Potent and selective imidazo[1,2-b]pyridazine inhibitors of CDK2 have been identified, which show >1 microM plasma levels following a 2mg/kg oral dose to mice. 相似文献
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We consider a two-dimensional model of cell-to-cell spread of HIV-1 in tissue cultures, assuming that infection is spread
directly from infected cells to healthy cells and neglecting the effects of free virus. The intracellular incubation period
is modeled by a gamma distribution and the model is a system of two differential equations with distributed delay, which includes
the differential equations model with a discrete delay and the ordinary differential equations model as special cases. We
study the stability in all three types of models. It is shown that the ODE model is globally stable while both delay models
exhibit Hopf bifurcations by using the (average) delay as a bifurcation parameter. The results indicate that, differing from
the cell-to-free virus spread models, the cell-to-cell spread models can produce infective oscillations in typical tissue
culture parameter regimes and the latently infected cells are instrumental in sustaining the infection. Our delayed cell-to-cell
models may be applicable to study other types of viral infections such as human T-cell leukaemia virus type 1 (HTLV-1).
Received: 18 November 2000 /
Published online: 28 February 2003
RID="*"
ID="*" Research was partially supported by the NSERC and MITACS of Canada and a start-up fund from the College of Arts and
Sciences at the University of Miami. On leave from Dalhousie University, Halifax, Nova Scotia, Canada.
Current address: Department of Mathematics, Clarke College, Dubuque, Iowa 52001, USA
Key words or phrases: HIV-1 – Cell-to-cell spread – Time delay – Stability – Hopf bifurcation – Periodicity 相似文献
3.
Ranasinghe SR Kramer HB Wright C Kessler BM di Gleria K Zhang Y Gillespie GM Blais ME Culshaw A Pichulik T Simmons A Rowland-Jones SL McMichael AJ Dong T 《PLoS pathogens》2011,7(5):e1001341
A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef90–97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A–H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses. 相似文献
4.
Roseane Borner Jo?o Bento-Torres Diego RV Souza Danyelle B Sadala Nonata Trevia José Augusto Farias Nara Lins Aline Passos Amanda Quintairos José Ant?nio Diniz Victor Hugh Perry Pedro Fernando Vasconcelos Colm Cunningham Cristovam W Pican?o-Diniz 《朊病毒》2011,5(3):215-227
Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.Key words: prion disease, optical fractionator, neuropathology, behavioral changes, albino Swiss mice 相似文献
5.
Irie O Kosaka T Kishida M Sakaki J Masuya K Konishi K Yokokawa F Ehara T Iwasaki A Iwaki Y Hitomi Y Toyao A Gunji H Teno N Iwasaki G Hirao H Kanazawa T Tanabe K Hiestand PC Malcangio M Fox AJ Bevan SJ Yaqoob M Culshaw AJ Hart TW Hallett A 《Bioorganic & medicinal chemistry letters》2008,18(19):5280-5284
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. 相似文献
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Anderson M Beattie JF Breault GA Breed J Byth KF Culshaw JD Ellston RP Green S Minshull CA Norman RA Pauptit RA Stanway J Thomas AP Jewsbury PJ 《Bioorganic & medicinal chemistry letters》2003,13(18):3021-3026
High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2. 相似文献
9.
A.S. Perelson, D.E. Kirschner and R. De Boer (Math. Biosci. 114 (1993) 81) proposed an ODE model of cell-free viral spread of human immunodeficiency virus (HIV) in a well-mixed compartment such as the bloodstream. Their model consists of four components: uninfected healthy CD4(+) T-cells, latently infected CD4(+) T-cells, actively infected CD4(+) T-cells, and free virus. This model has been important in the field of mathematical modeling of HIV infection and many other models have been proposed which take the model of Perelson, Kirschner and De Boer as their inspiration, so to speak (see a recent survey paper by A.S. Perelson and P.W. Nelson (SIAM Rev. 41 (1999) 3-44)). We first simplify their model into one consisting of only three components: the healthy CD4(+) T-cells, infected CD4(+) T-cells, and free virus and discuss the existence and stability of the infected steady state. Then, we introduce a discrete time delay to the model to describe the time between infection of a CD4(+) T-cell and the emission of viral particles on a cellular level (see A.V.M. Herz, S. Bonhoeffer, R.M. Anderson, R.M. May, M.A. Nowak [Proc. Nat. Acad. Sci. USA 93 (1996) 7247]). We study the effect of the time delay on the stability of the endemically infected equilibrium, criteria are given to ensure that the infected equilibrium is asymptotically stable for all delay. Numerical simulations are presented to illustrate the results. 相似文献
10.
A role for IL-18 in neutrophil activation 总被引:19,自引:0,他引:19
Leung BP Culshaw S Gracie JA Hunter D Canetti CA Campbell C Cunha F Liew FY McInnes IB 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(5):2879-2886
IL-18 expression and functional activity has been identified in several autoimmune and infectious diseases. To clarify the potential role of IL-18 during early innate immune responses, we have explored the capacity of IL-18 to activate neutrophils. Human peripheral blood-derived neutrophils constitutively expressed IL-18R (alpha and beta) commensurate with the capacity to rapidly respond to IL-18. IL-18 induced cytokine and chemokine release from neutrophils that was protein synthesis dependent, up-regulated CD11b expression, induced granule release, and enhanced the respiratory burst following exposure to fMLP, but had no effect upon the rate of neutrophil apoptosis. The capacity to release cytokine and chemokine was significantly enhanced in neutrophils derived from rheumatoid arthritis synovial fluid, indicating differential responsiveness to IL-18 dependent upon prior neutrophil activation in vivo. Finally, IL-18 administration promoted neutrophil accumulation in vivo, whereas IL-18 neutralization suppressed the severity of footpad inflammation following carrageenan injection. The latter was accompanied by reduction in tissue myeloperoxidase expression and suppressed local TNF-alpha production. Together, these data define a novel role for IL-18 in activating neutrophils and thereby promoting early innate immune responses. 相似文献