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41.
Frederique M Moret Kim MG van der Wurff-Jacobs Johannes WJ Bijlsma Floris PJG Lafeber Joel AG van Roon 《Arthritis research & therapy》2014,16(6)
Introduction
The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)–primed CD1c myeloid dendritic cells (mDCs).Methods
Expression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression.Results
PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation.Conclusion
SF T cell hyporesponsiveness upon (TSLP-primed) mDC stimulation in RA joints is partially dependent on PD-1/PD-L1 interactions, as PD-1 and PD-L1 are both highly expressed on SF T cells and mDCs, respectively, and inhibiting PD-1 availability restores T cell proliferation. The potential of IL-7 to robustly reverse this hyporesponsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation. 相似文献42.
Matthew C. Clifton David M. Dranow Alison Leed Ben Fulroth James W. Fairman Jan Abendroth Kateri A. Atkins Ellen Wallace Dazhong Fan Guoping Xu Z. J. Ni Doug Daniels John Van Drie Guo Wei Alex B. Burgin Todd R. Golub Brian K. Hubbard Michael H. Serrano-Wu 《PloS one》2015,10(4)
Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors. 相似文献
43.
E Del Poggetto M Tanturli N Ben-Califa A Gozzini I Tusa G Cheloni I Marzi MG Cipolleschi Y Kashman D Neumann E Rovida P Dello Sbarba 《Cell cycle (Georgetown, Tex.)》2015,14(19):3146-3154
We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors 相似文献
44.
45.
Mário C BarrosoJúnior Guilherme P Esteves Thiago P Nunes Lucia MG Silva Alvaro CD Faria Pedro L Melo 《Biomedical engineering online》2011,10(1):14
Introduction
A novel system that combines a compact mobile instrument and Internet communications is presented in this paper for remote evaluation of tremors. The system presents a high potential application in Parkinson's disease and connects to the Internet through a TCP/IP protocol. Tremor transduction is carried out by accelerometers, and the data processing, presentation and storage were obtained by a virtual instrument. The system supplies the peak frequency (fp), the amplitude (Afp) and power in this frequency (Pfp), the total power (Ptot), and the power in low (1-4 Hz) and high (4-7 Hz) frequencies (Plf and Phf, respectively). 相似文献46.
Molecular characterization of a dimeric intracellular maltogenic amylase of Bacillus subtilis SUH4-2
Cho HY Kim YW Kim TJ Lee HS Kim DY Kim JW Lee YW Leed S Park KH 《Biochimica et biophysica acta》2000,1478(2):333-340
An additional amylase besides the typical alpha-amylase was detected in the cytoplasm of Bacillus subtilis SUH4-2, an isolate from Korean soil. The corresponding gene encoded a maltogenic amylase, which hydrolyzed cyclodextrin or starch to maltose and glucose; pullulan to panose; acarbose to glucose and acarviosine-glucose. Maltogenic amylase of B. subtilis SUH4-2 transferred sugar molecules to form various branched oligosaccharides upon the hydrolysis of substrates. The enzyme existed in a monomer-dimer equilibrium with a molar ratio of 3:2 in 50 mM KH(2)PO(4)-NaOH buffer (pH 7.0). The maltogenic amylase is most likely to be associated with carbohydrate metabolism in the cytoplasm, since the nucleotide sequence of the gene was highly homologous to the yvdF gene of B. subtilis 168, which is located in a gene cluster involved in maltose/maltodextrin utilization. 相似文献
47.
Approximately 100 strains derived from natural populations of Drosophila
melanogaster were tested for the presence or absence of P- element
sequences by using two molecular probes derived from internal regions of a
full-sized P element. Strains that had been collected from several
continents at varying times during the past 60 years were examined. The
oldest available strains, representing most major geographical regions of
the world, exhibited no detectable hybridization to the P-element probes.
In contrast, all recently collected natural populations that were tested
carried P-element sequences. The earliest appearance of P elements occurred
in collections made during the 1950s and early 1960s in the Americas and
during the late 1960s on other continents. The youngest strains that were
completely devoid of P elements originated in populations sampled during
the mid-1960s in America, but as late as 1974 in populations from the USSR.
There are differences in the patterns of hybridization to the two P-element
probes between populations from different geographical regions. These
differences are consistent with the varying P-M phenotypic properties of
these populations. Taken together with the results of phenotypic tests
reported in earlier studies, the available evidence is consistent with the
hypothesis of a worldwide P-element invasion of D. melanogaster during the
past 30 years and suggests that the putative invasion of the Americas
possibly preceded by approximately a decade that in Europe, Africa, and the
rest of the world.
相似文献
48.
Mitochondrial control-region sequences in two shorebird species, the turnstone and the dunlin, and their utility in population genetic studies 总被引:12,自引:0,他引:12
We determined the mitochondrial control-region sequences of five turnstones
(Arenaria interpres) and three dunlins (Calidris alpina). Comparisons
revealed that the central part (part II) is conserved relative to much more
variable parts at the beginning (part I) and the end (part III). This
pattern of sequence conservation is also found in the control regions of
other vertebrates. The average sequence divergence between turnstone and
dunlin was 21.8% for part I, 7.5% for part II, and 29.5% for part III.
Within-species sequence divergence over the entire control region was much
lower, at 0.9% for turnstones and 2.0% for dunlins. In both shorebird
species, part III contains a repetitive sequence composed only of A and C
nucleotides, which has not been found in the control regions of other
birds. A survey of the part I sequences of 25 turnstones and 25 dunlins
sampled around the world revealed that these species have very different
population genetic structures. Dunlins are not only much more
differentiated in their sequences but also have a strongly subdivided
population genetic structure. Pleistocene vicariant events combined with
strong natal philopatry and high mutation rates of the sequences are likely
responsible for this population genetic subdivision. Conversely, part I
sequences of turnstones are weakly differentiated and are geographically
unstructured. We argue that this is not the result of global gene flow but
that, instead turnstones have recently expanded from a refugial population
that was bottlenecked.
相似文献
49.
Johanna H Kattenberg Eleanor A Ochodo Kimberly R Boer Henk DFH Schallig Petra F Mens Mariska MG Leeflang 《Malaria journal》2011,10(1):1-18
Background
To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays.Methods
In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart.Results
In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivo ELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants.Conclusions
All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between samples taken two weeks apart, indicating significant biological variability over short intervals. 相似文献50.
Phylogenetic relationships among prokaryotic and eukaryotic catalases 总被引:13,自引:1,他引:12
Seventy-four catalase protein sequences, including 29 bacterial, 8 fungal,
7 animal, and 30 plant sequences, were compiled, and 70 were used for
phylogenetic reconstruction. The core of the resulting tree revealed
unique, separate groups of plant and animal catalases, two groups of fungal
catalases, and three groups of bacterial catalases. The only overlap of
kingdoms occurred within one branch and involved fungal and bacterial
large-subunit enzymes. The other fungal branch was closely linked to the
group of animal enzymes. Group I bacterial catalases were more closely
related to the plant enzymes and contained such diverse taxa as the
Gram-positive Listeria seeligeri, Deinocococcus radiodurans, and
gamma-proteobacteria. Group III bacterial sequences were more closely
related to fungal and animal sequences and included enzymes from a broad
range of bacteria including high- and low-GC Gram positives,
proteobacteria, and a bacteroides species. Group II was composed of
large-subunit catalases from diverse sources including Gram positives
(low-GC Bacilli and high-GC Mycobacteria), proteobacteria, and species of
the filamentous fungus Aspergillus. These data can be interpreted in terms
of two gene duplication events that produced a minimum of three catalase
gene family members that subsequently evolved in response to environmental
demands. Horizontal gene transfer may have been responsible for the group
II mixture of bacterial and fungal large-subunit catalases.
相似文献