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11.
12.
Tomasz Borowski Valentin Georgiev Per E. M. Siegbahn 《Journal of molecular modeling》2010,16(11):1673-1677
Catalytic cycle intermediates of a representative extradiol dioxygenase, homoprotocatechuate 2,3-dioxygenase (HPCD), have
recently been characterized in crystallo by Kovaleva and Lipscomb. The structures of the identified species indicate that
the process of inserting oxygen into the catechol ring occurs stepwise, and involves an Fe(II)-alkylperoxo intermediate and
its O–O cleavage product: a gem diol species. In general, these findings corroborate the results of our previous computational
studies; however, the fact that the gem diol species is stable enough to be observed in the crystal form seems to be at odds
with the computational mechanistic data, which suggest that this intermediate should very readily and spontaneously convert
to the epoxide species. The key question then becomes what is actually observed in the X-ray experiments. Here we report additional
computational studies undertaken with the hope of clarifying this issue. The results obtained for active site models hosting
both the native and the alternative (4-sulfonylcatechol) substrate indicate that the stability of the gem diol species is
substantially increased if an electron and a proton are added. If this occurs somehow, the lifetime of the intermediate should
be sufficient to observe it. 相似文献
13.
John E. McKinnon Robbie B. Mailliard Susan Swindells Timothy J. Wilkin LuAnn Borowski Jillian M. Roper Barbara Bastow Mary Kearney Ann Wiegand John W. Mellors Charles R. Rinaldo for the A study team 《PloS one》2014,9(5)
Objectives
Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification.Methods
Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD''s 38/69/94/95/158/279).Results
Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92–55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels.Conclusions
Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring.Trial Registration
ClinicalTrials.gov NCT00084019相似文献14.
Borowski AB Boesteanu AC Mueller YM Carafides C Topham DJ Altman JD Jennings SR Katsikis PD 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(10):6494-6503
CD8(+) T cells are a critical component of the adaptive immune response against infections and tumors. A current paradigm in immunology is that naive CD8(+) T cells require CD28 costimulation, whereas memory CD8(+) T cells do not. We show here, however, that during viral infections of mice, costimulation is required in vivo for the reactivation of memory CD8(+) T cells. In the absence of CD28 costimulation, secondary CD8(+) T cell responses are greatly reduced and this impairs viral clearance. The failure of CD8(+) T cells to expand in the absence of CD28 costimulation is CD4(+) T cell help independent and is accompanied by a failure to down-regulate Bcl-2 and by cell cycle arrest. This requirement for CD28 costimulation was shown in both influenza A and HSV infections. Thus, contrary to current dogma, memory CD8(+) T cells require CD28 costimulation to generate maximal secondary responses against pathogens. Importantly, this CD28 requirement was shown in the context of real infections were multiple other cytokines and costimulators may be up-regulated. Our findings have important implications for pathogens, such as HIV and measles virus, and tumors that evade the immune response by failing to provide CD28 costimulation. These findings also raise questions about the efficacy of CD8(+) T cell-based vaccines against such pathogens and tumors. 相似文献
15.
Borowski Piotr Gawinecki Ryszard Miłaczewska Anna Skotnicka Agnieszka Woliński Krzysztof Brzyska Agnieszka 《Journal of molecular modeling》2011,17(4):857-868
The DFT calculations at the B3LYP level with 6-311G** basis set were carried out in order to reveal whether tautomerization
or decarboxylation is responsible for the instability of 2,2-di(pyridin-2-yl)acetic (DPA) and 1,8-diazafluorene-9-carboxylic
(DAF) acids. The carboxyl protons in both compounds are involved in the intramolecular hydrogen bonds (the pyridine nitrogen
atoms are the hydrogen bond acceptors). Although formation of two intramolecular OH···N hydrogen bonds in the enols of both
carboxylic acids enables effective electron delocalization within the quasi rings (···HO − C = C − C = N), only ene-1,1-diol
of DAF has somewhat lower energy than DAF itself (ΔE is ca. 7 kcal mol-1). DPA and its enediol have comparable energies. Migration of the methine proton toward the carbonyl oxygen atom (to form
enediols) requires overstepping the energy barriers of 55-57 kcal mol-1 for both DPA and DAF. The enaminone tautomers of the acids, formed by migration of this proton toward the pyridine nitrogen
atom, are thermodynamically somewhat more stable than the respective enediols. The energy barriers of these processes are
equal to ca. 44 and 62 kcal mol-1 for DPA and DAF, respectively. Thus, such tautomerization of the acids is not likely to proceed. On the other hand, the distinct
energetic effects (ca. 15 kcal mol-1) favor decarboxylation. This process involves formation of (E)-2-(pyridin-2(1H)-ylidenemethyl)pyridine and its cyclic analogue followed by their tautomerization to (dipyridin-2-yl)methane and 1,8-diazafluorene,
respectively. Although the later compound was found to be somewhat thermodynamically more stable, kinetic control of tautomerization
of the former is more distinct. 相似文献
16.
17.
Amphotericin B (AmB)--a polyene macrolide antibiotic--exhibits strong antifungal activity, however, is known to be very toxic to mammalian cells. In order to decrease AmB toxicity, a number of its derivatives have been synthesized. Basing on in vitro and in vivo research, it was evidenced that one of AmB derivatives, namely N-methyl-N-D-fructopyranosylamphotericin B methyl ester (in short MF-AME) retained most of the antifungal activity of the parent antibiotic, however, exhibited dramatically lower animal toxicity. Therefore, MF-AME seems to be a very promising modification product of AmB. However, further development of this derivative as potential new antifungal drug requires the elucidation of its molecular mechanism of reduced toxicity, which was the aim of the present investigations. Our studies were based on examining the binding energies by determining the strength of interaction between MF-AME and membrane sterols (ergosterol-fungi sterol, and cholesterol-mammalian sterol) and DPPC (model membrane phospholipid) using the Langmuir monolayer technique, which serves as a model of cellular membrane. Our results revealed that at low concentration the affinity of MF-AME to ergosterol is considerably stronger as compared to cholesterol, which correlates with the improved selective toxicity of this drug. It is of importance that the presence of phospholipids is essential since--due to very strong interactions between MF-AME and DPPC--the antibiotic used in higher concentration is "immobilized" by DPPC molecules, which reduces the concentration of free antibiotic, thus enabling it to selectively interact with both sterols. 相似文献
18.
Rappocciolo G Jenkins FJ Hensler HR Piazza P Jais M Borowski L Watkins SC Rinaldo CR 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(3):1741-1749
Human herpesvirus 8 (HHV-8) causes Kaposi's sarcoma and pleural effusion lymphoma. In this study, we show that dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN; CD209) is a receptor for HHV-8 infection of myeloid DCs and macrophages. DC-SIGN was required for virus attachment to these cells and DC-SIGN-expressing cell lines. HHV-8 binding and infection were blocked by anti-DC-SIGN mAb and soluble DC-SIGN, and mannan, a natural ligand for DC-SIGN. Infection of DCs and macrophages with HHV-8 led to production of viral proteins, with little production of viral DNA, similar to HHV-8 infection of vascular endothelial cells. Infection of DCs resulted in down-regulation of DC-SIGN, a decrease in endocytic activity, and an inhibition of Ag stimulation of CD8+ T cells. We propose that DC-SIGN serves as a portal for immune dysfunction and oncogenesis caused by HHV-8 infection. 相似文献
19.
Borowski A Dirksen U Lixin L Shi RL Göbel U Schneider EM 《Cancer immunology, immunotherapy : CII》2006,55(4):363-374
Immunoscreening of an Ewing’s family of tumour (EFT)-derived cDNA library using formerly described EFT-specific antibodies
led to the isolation of a 3.5 kb cDNA, named Ewing’s tumour-associated antigen 16 (ETAA16). The ETAA16 cDNA shows no homology to any functionally characterised human gene. Only a bovine cDNA expressed in bovine testis and hepatocytes
is functionally characterised as it encodes for a junction plaque associated protein and showed a homology of 69.9% at amino
acid level to ETAA16. The human cDNA encodes for a 926 amino acid tumour antigen with a calculated molecular weight of 103 kDa. The epitope of
the ETAA16-specific antibody, Ak16, covers the central region of the protein which is part of an extra cellular domain. The human ETAA16 gene locus has been assigned to chromosome 2p13-15 by FISH analyses and is confirmed by the human genome sequencing project.
As demonstrated by flow cytometry, the cell surface expression of ETAA16 antigen is restricted to ET cell lines and not expressed on other small blue round cell tumours or other kind of tumour.
RT-PCR analysis revealed a high expression of ETAA16 in brain, liver and kidney while lung and heart were negative. Immunohistochemistry showed an intracellular expression of
ETAA16 in different kind of non-Ewing tumour tissues. These results suggest that ETAA16 may function as a tumour-specific cell surface antigen in EFTs. 相似文献
20.