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1.
Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis 总被引:2,自引:0,他引:2 下载免费PDF全文
Sutton VR Waterhouse NJ Browne KA Sedelies K Ciccone A Anthony D Koskinen A Mullbacher A Trapani JA 《The Journal of cell biology》2007,176(4):425-433
Cathepsin C activates serine proteases expressed in hematopoietic cells by cleaving an N-terminal dipeptide from the proenzyme upon granule packaging. The lymphocytes of cathepsin C-null mice are therefore proposed to totally lack granzyme B activity and perforin-dependent cytotoxicity. Surprisingly, we show, using live cell microscopy and other methodologies, that cells targeted by allogenic CD8(+) cytotoxic T lymphocyte (CTL) raised in cathepsin C-null mice die through perforin-dependent apoptosis indistinguishable from that induced by wild-type CTL. The cathepsin C-null CTL expressed reduced but still appreciable granzyme B activity, but minimal granzyme A activity. Also, in contrast to mice with inactivation of both their granzyme A/B genes, cathepsin C deficiency did not confer susceptibility to ectromelia virus infection in vivo. Overall, our results indicate that although cathepsin C clearly generates the majority of granzyme B activity, some is still generated in its absence, pointing to alternative mechanisms for granzyme B processing and activation. Cathepsin C deficiency also results in considerably milder immune deficiency than perforin or granzyme A/B deficiency. 相似文献
2.
Furuya Y Chan J Wan EC Koskinen A Diener KR Hayball JD Regner M Müllbacher A Alsharifi M 《PloS one》2011,6(10):e25765
Background
We have shown previously in mice, that infection with live viruses, including influenza/A and Semliki Forest virus (SFV), induces systemic partial activation of lymphocytes, characterized by cell surface expression of CD69 and CD86, but not CD25. This partial lymphocytes activation is mediated by type-I interferons (IFN-I). Importantly, we have shown that γ-irradiated SFV does not induce IFN-I and the associated lymphocyte activation.Principal Findings
Here we report that, in contrast to SFV, γ-irradiated influenza A virus elicits partial lymphocyte activation in vivo. Furthermore, we show that when using influenza viruses inactivated by a variety of methods (UV, ionising radiation and formalin treatment), as well as commercially available influenza vaccines, only γ-irradiated influenza virus is able to trigger IFN-I-dependent partial lymphocyte activation in the absence of the TLR7/MyD88 signalling pathways.Conclusions
Our data suggest an important mechanism for the recognition of γ-irradiated influenza vaccine by cytosolic receptors, which correspond with the ability of γ-irradiated influenza virus to induce cross-reactive and cross-protective cytotoxic T cell responses. 相似文献3.
Johan Björkqvist Anu-Katriina Pesonen Liisa Kuula Hanna-Maria Matinolli Aulikki Lano Marika Sipola-Leppänen 《Chronobiology international》2018,35(4):555-564
A preference for eveningness (being a “night owl”) and preterm birth (<37 weeks of gestation) are associated with similar adversities, such as elevated blood pressure, impaired glucose regulation, poorer physical fitness, and lower mood. Yet, it remains unclear if and how preterm birth is associated with circadian preference. The aim of this study was to assess this association across the whole gestation range, using both objective and subjective measurements of circadian preference.Circadian preference was measured among 594 young adults (mean age 24.3 years, SD 1.3) from two cohorts: the ESTER study and the Arvo Ylppö Longitudinal Study. We compared 83 participants born early preterm (<34 weeks) and 165 late preterm (34 to <37 weeks) with those born at term (≥37 weeks, n = 346). We also compared very low birth weight (VLBW, <1500 g) participants with term-born controls. We obtained objective sleep data with actigraphs that were worn for a mean period of 6.8 (SD 1.4) nights. Our primary outcome was sleep midpoint during weekdays and weekend. The sleep midpoint is the half-way time between falling asleep and waking up, and it represents sleep timing. We also investigated subjective chronotype with the Morningness–Eveningness Questionnaire (MEQ) in 688 (n = 138/221/329) ESTER participants. The MEQ consists of 19 questions, which estimates the respondent to be of a “morning”, “evening,” or “intermediate” chronotype, based on the Morningness–Eveningness Score (MES). We analyzed the data from the actigraphs and the MES with three linear regression models, and analyzed distribution of the chronotype class with Pearson χ2.There were no consistent differences across the study groups in sleep midpoint. As compared with those born at term, the mean differences in minutes:seconds and 95% confidence intervals for the sleep midpoint were: early preterm weekdays 11:47 (?8:34 to 32:08), early preterm weekend 4:14 (?19:45 to 28:13), late preterm weekdays ?10:28 (?26:16 to 5:21), and late preterm weekend ?1:29 (?20:36 to 17:37). There was no difference in sleep timing between VLBW-participants and controls either. The distribution of chronotype in the MEQ among all participants was 12.4% morningness, 65.4% intermediate, and 22.2% eveningness. The distribution of the subjective chronotype class did not differ between the three gestational age groups (p = 0.98). The linear regression models did not show any influence of gestational age group or VLBW status on the MES (all p > 0.5).We found no consistent differences between adults born early or late preterm and those born at term in circadian preference. The earlier circadian preference previously observed in those born smallest is unlikely to extend across the whole range of preterm birth. 相似文献
4.
Julián Pardo Eva Ma Gálvez Aulikki Koskinen Markus M. Simon Mario Lobigs Matthias Regner Arno Müllbacher 《PloS one》2009,4(10)
Background
Ectromelia virus is a natural mouse pathogen, causing mousepox. The cytotoxic T (Tc) cell granule serine-protease, granzyme B, is important for its control, but the underlying mechanism is unknown. Using ex vivo virus immune Tc cells, we have previously shown that granzyme B is able to activate several independent pro-apoptotic pathways, including those mediated by Bid/Bak/Bax and caspases-3/-7, in target cells pulsed with Tc cell determinants.Methods and Findings
Here we analysed the physiological relevance of those pro-apoptotic pathways in ectromelia infection, by incubating ectromelia-immune ex vivo Tc cells from granzyme A deficient (GzmB+ Tc cells) or granzyme A and granzyme B deficient (GzmA×B−/− Tc cell) mice with ectromelia-infected target cells. We found that gzmB-induced apoptosis was totally blocked in ectromelia infected or peptide pulsed cells lacking caspases-3/-7. However ectromelia inhibited only partially apoptosis in cells deficient for Bid/Bak/Bax and not at all when both pathways were operative suggesting that the virus is able to interfere with apoptosis induced by gzmB in case not all pathways are activated. Importantly, inhibition of viral replication in vitro, as seen with wild type cells, was not affected by the lack of Bid/Bak/Bax but was significantly reduced in caspase-3/-7-deficient cells. Both caspase dependent processes were strictly dependent on gzmB, since Tc cells, lacking both gzms, neither induced apoptosis nor reduced viral titers.Significance
Out findings present the first evidence on the biological importance of the independent gzmB-inducible pro-apoptotic pathways in a physiological relevant virus infection model. 相似文献5.
Asen Daskalov Matthias Gantner Marielle Aulikki W?lti Thierry Schmidlin Celestine N. Chi Christian Wasmer Anne Schütz Johanna Ceschin Corinne Clavé Sandra Cescau Beat Meier Roland Riek Sven J. Saupe 《PLoS pathogens》2014,10(6)
The [Het-s] prion of the fungus Podospora anserina represents a good model system for studying the structure-function relationship in amyloid proteins because a high resolution solid-state NMR structure of the amyloid prion form of the HET-s prion forming domain (PFD) is available. The HET-s PFD adopts a specific β-solenoid fold with two rungs of β-strands delimiting a triangular hydrophobic core. A C-terminal loop folds back onto the rigid core region and forms a more dynamic semi-hydrophobic pocket extending the hydrophobic core. Herein, an alanine scanning mutagenesis of the HET-s PFD was conducted. Different structural elements identified in the prion fold such as the triangular hydrophobic core, the salt bridges, the asparagines ladders and the C-terminal loop were altered and the effect of these mutations on prion function, fibril structure and stability was assayed. Prion activity and structure were found to be very robust; only a few key mutations were able to corrupt structure and function. While some mutations strongly destabilize the fold, many substitutions in fact increase stability of the fold. This increase in structural stability did not influence prion formation propensity in vivo. However, if an Ala replacement did alter the structure of the core or did influence the shape of the denaturation curve, the corresponding variant showed a decreased prion efficacy. It is also the finding that in addition to the structural elements of the rigid core region, the aromatic residues in the C-terminal semi-hydrophobic pocket are critical for prion propagation. Mutations in the latter region either positively or negatively affected prion formation. We thus identify a region that modulates prion formation although it is not part of the rigid cross-β core, an observation that might be relevant to other amyloid models. 相似文献
6.
Ryszard Grucza Heikki Pekkarinen Eeva-Kaisa Titov Aulikki Kononoff Osmo H?nninen 《European journal of applied physiology and occupational physiology》1993,67(3):279-285
Thermoregulatory responses to exercise in relation to the phase of the menstrual cycle were studied in ten women taking oral contraceptives (P) and in ten women not taking oral contraceptives (NP). Each subject was tested for maximal aerobic capacity (
) and for 50%
exercise in the follicular (F) and luteal (L) phases of the menstrual cycle. Since the oral contraceptives would have prevented ovulation a quasi-follicular phase (q-F) and a quasi-luteal phase (q-L) of the menstrual cycle were assumed for P subjects. Exercise was performed on a cycle ergometer at an ambient temperature of 24° C and relative air humidity of 50%. Rectal (T
re), mean skin (
), mean body (
) temperatures and heart rate (f
c) were measured. Sweat rate was estimated by the continuous measurement of relative humidity of air in a ventilated capsule placed on the chest, converted to absolute pressure (PH2Ochest). Gain for sweating was calculated as a ratio of increase inPH2Ochest to the appropriate increase inT
re for the whole period of sweating (G) and for unsteady-state (Gu) separately. The
did not differ either between the groups of subjects or between the phases of the menstrual cycle. In P, rectal temperature threshold for sweating (T
re, td) was 37.85° C in q-L and 37.60° C in q-F (P < 0.01) and corresponded to a significant difference fromT
re at rest. TheT
re,
andf
c increased similarly during exercise in q-F and q-L. No menstrual phase-related differences were observed either in the dynamics of sweating or in G. In NP,T
re, td was shorter in L than in F (37.70 vs 37.47° C,P<0.02) with a significantly greater value fromT
re at rest. The dynamics and G for sweating were also greater in L than in F. The Gu was 36.8 versus 16.6 kPa · ° C–1 (P<0.01) while G was 6.4 versus 3.8 kPa · ° C–1 (P<0.05), respectively. TheT
re,
andf
c increased significantly more in phase F than in phase L. It was concluded that in these women performing moderate exercise, there was a greater temperature threshold and larger gains for sweating in phase L than in phase F. Intake of oral contraceptives reduced the differences in the gains for sweating making the thermoregulatory responses to exercise more uniform. 相似文献
7.
Alsharifi M Lobigs M Regner M Lee E Koskinen A Müllbacher A 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(7):4635-4640
The vast majority of both T and B cells in mice were found to up-regulate cell surface expression of the early activation markers CD69 and CD86, but not CD25, within 24 h of infection with Semliki Forest virus. Kinetics and magnitude of activation marker expression was dependent on live virus, dose, and correlated with strain virulence. Activation marker expression declined to baseline levels over the next 96 h. This very early "activation" of such a high percentage of lymphocytes required the presence of type I IFN receptor genes, was inducible with poly(I:C), and correlated with IFN-I levels in serum. We conclude that virus-induced IFN-I release systemically affects most of the hosts T and B cells by triggering them rapidly and independently of Ag-reactivity into a semiactivated state. 相似文献
8.
Melo-Silva CR Tscharke DC Lobigs M Koskinen A Wong YC Buller RM Müllbacher A Regner M 《Journal of virology》2011,85(21):11170-11182
Ectromelia virus (ECTV) is a natural pathogen of mice that causes mousepox, and many of its genes have been implicated in the modulation of host immune responses. Serine protease inhibitor 2 (SPI-2) is one of these putative ECTV host response modifier proteins. SPI-2 is conserved across orthopoxviruses, but results defining its mechanism of action and in vivo function are lacking or contradictory. We studied the role of SPI-2 in mousepox by deleting the SPI-2 gene or its serine protease inhibitor reactive site. We found that SPI-2 does not affect viral replication or cell-intrinsic apoptosis pathways, since mutant viruses replicate in vitro as efficiently as wild-type virus. However, in the absence of SPI-2 protein, ECTV is attenuated in mousepox-susceptible mice, resulting in lower viral loads in the liver, decreased spleen pathology, and substantially improved host survival. This attenuation correlates with more effective immune responses in the absence of SPI-2, including an earlier serum gamma interferon (IFN-γ) response, raised serum interleukin 18 (IL-18), increased numbers of granzyme B(+) CD8(+) T cells, and, most notably, increased numbers and activation of NK cells. Both virus attenuation and the improved immune responses associated with SPI-2 deletion from ECTV are lost when mice are depleted of NK cells. Consequently, SPI-2 renders mousepox lethal in susceptible strains by preventing protective NK cell defenses. 相似文献
9.
Electron microscopic observations on the mitochondrial adenosinetriphosphatase in the rat spinal cord 总被引:1,自引:0,他引:1
Summary Nucleosidetriphosphatase activity of the rat spinal cord was studied with a modified Wachstein-Meisel method at ultrastructural level. A short formaldehyde perfusion fixation favoured the preservation of the mitochondrial activity.The reaction product was localized intramitochondrially in the neuropil, while the pericaryonal mitochondria were nonreactive. Similar results were obtained, when ITP was substituted for ATP. No membrane activity was observed by Mg++ activation only, but a certain membrane affinity was noticed in the neuropil, when Na+ and K+ were included.The specificity of the ATPase reaction reported in this paper is further discussed.Abbreviations used ATP
adenosinetriphosphate
- ATPase
adenosinetriphosphatase
- IDP
inosinediphosphate
- ITP
inosinetriphosphate
- TPP
thiaminepyrophosphate
- UDP
uridinediphosphate 相似文献
10.
The effect of regular or reduced‐fat distillers grains with solubles on rumen methanogenesis and the rumen bacterial community 下载免费PDF全文
E. Castillo‐Lopez C.J.R. Jenkins N.D. Aluthge W. Tom P.J. Kononoff S.C. Fernando 《Journal of applied microbiology》2017,123(6):1381-1395