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81.
Johanna Haiko Liisa Laakkonen Katri Juuti Nisse Kalkkinen Timo K. Korhonen 《Journal of bacteriology》2010,192(18):4553-4561
Plasminogen activator inhibitor 1 (PAI-1) is a serine protease inhibitor (serpin) and a key molecule that regulates fibrinolysis by inactivating human plasminogen activators. Here we show that two important human pathogens, the plague bacterium Yersinia pestis and the enteropathogen Salmonella enterica serovar Typhimurium, inactivate PAI-1 by cleaving the R346-M347 bait peptide bond in the reactive center loop. No cleavage of PAI-1 was detected with Yersinia pseudotuberculosis, an oral/fecal pathogen from which Y. pestis has evolved, or with Escherichia coli. The cleavage and inactivation of PAI-1 were mediated by the outer membrane proteases plasminogen activator Pla of Y. pestis and PgtE protease of S. enterica, which belong to the omptin family of transmembrane endopeptidases identified in Gram-negative bacteria. Cleavage of PAI-1 was also detected with the omptins Epo of Erwinia pyrifoliae and Kop of Klebsiella pneumoniae, which both belong to the same omptin subfamily as Pla and PgtE, whereas no cleavage of PAI-1 was detected with omptins of Shigella flexneri or E. coli or the Yersinia chromosomal omptins, which belong to other omptin subfamilies. The results reveal a novel serpinolytic mechanism by which enterobacterial species expressing omptins of the Pla subfamily bypass normal control of host proteolysis.Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the mammalian fibrinolytic/plasminogen system (29, 37). The fibrinolytic system comprises the serine protease zymogen plasminogen, urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), PAI-1, and plasmin inhibitor α2-antiplasmin (α2AP) (for a review, see reference 52). Plasminogen is converted to plasmin, which is a broad-spectrum serine protease that dissolves fibrin in blood clots, degrades laminin of basement membranes, and activates matrix metalloproteinases that degrade collagens and gelatins in tissue barriers. Herewith, plasmin controls physiological processes such as fibrinolysis/coagulation, cell migration and invasion, and tumor metastasis (29, 37). PAI-1 maintains normal hemostasis by inhibiting the function of the plasminogen activators tPA and uPA, which are serine proteases and highly specific for cleavage of the plasminogen molecule. tPA binds to fibrin and is associated with plasmin-mediated breakdown of fibrin clots, whereas uPA has low affinity for fibrin and associates with cell surface proteolysis, cellular migration, and damage of tissue barriers (52).The mammalian fibrinolytic and coagulation systems are targeted by invasive bacterial pathogens during infection (reviewed in references 6, 11, 34, and 61). In bacterial sepsis, increased production of fibrin clots at a damaged endothelium results from enhanced thrombin-catalyzed fibrin generation and from an increased serum level of PAI-1. Coagulation can protect the host by activating immune systems or by physically restraining the bacteria (6, 15, 25, 41). On the other hand, several invasive bacterial pathogens enhance fibrinolysis either through direct plasminogen activation or by immobilizing plasminogen/plasmin on the surface (6, 34, 61). Activation of the plasminogen system by bacteria enhances bacterial dissemination and invasiveness through release of bacteria from fibrin deposits and through degradation of tissue barriers. Bacterial plasminogen activators and receptors have been under extensive structural and functional studies, but much less is known about interactions of bacteria with the regulatory proteins of fibrinolysis.PAI-1 is present in a large variety of tissues and is secreted by several human cells (37). In healthy individuals, the level of PAI-1 antigen in human plasma is low (6 to 85 ng/ml), but synthesis and secretion of PAI-1 are strongly elevated in disease states and induced by, e.g., inflammatory cytokines and endotoxin of Gram-negative bacteria (37). PAI-1 is a serine protease inhibitor (serpin), which exists in two forms. In its active form, PAI-1 rapidly inactivates both tPA and uPA by forming a covalent bond between the hydroxyl group of a catalytic serine residue of tPA/uPA and the carboxyl group of the residue R346 at the reactive center loop (RCL) of PAI-1 (52). The RCL of PAI-1 is a 19-amino-acid-long flexible loop which inserts into the catalytic center of tPA/uPA and contains the “bait” residues R346 and M347, which mimic the normal target of tPA/uPA. PAI-1 induces distortion of the active site of tPA/uPA, which prevents completion of the catalytic cycle (70). The active form of PAI-1 is unstable, with a half-life of 2 to 3 h at 37°C, and it changes spontaneously and irreversibly into a latent form, where the RCL is incorporated into a central β-sheet of the PAI-1 molecule and therefore cannot react with tPA or uPA. This conformational change takes place also after proteolytic cleavage of PAI-1 at the R346-M347 bond. The active form of PAI-1 binds with high affinity to vitronectin (Vn), and PAI-1/Vn complex formation increases the half-life of PAI-1 2- to 4-fold (10, 46, 69). Most circulating PAI-1 is thought to be in a complex with Vn, and the complex serves as the reservoir of physiologically active PAI-1 (44).Plague disease caused by Yersinia pestis is associated with imbalance of the fibrinolytic system, and decreased fibrin(ogen) deposition has been observed in both bubonic and pneumonic plague (11, 36). The plasminogen activator Pla, which is encoded by a Y. pestis-specific 9.5-kb virulence plasmid, pPCP1 (59), does not degrade fibrin directly but mimics the action of tPA and uPA in converting plasminogen to plasmin by cleavage at R561-V562. Pla also degrades the serpin α2AP and thus creates uncontrolled plasmin activity (32, 60). Pla belongs to the omptin superfamily of bacterial β-barrel outer membrane proteases (for reviews of omptins, see references 21 and 23). The omptins share molecular size and transmembrane fold but differ markedly in their substrate selectivities. In their catalytic centers, omptins combine structural features of aspartic and serine proteases (66).Increased fibrinolysis observed in plague led us to investigate whether Y. pestis increases plasminogen activation also indirectly by controlling the activity of PAI-1. We compared Y. pestis to Salmonella enterica serovar Typhimurium and Yersinia pseudotuberculosis, and the study also included omptins of other enterobacterial species. 相似文献
82.
Katri Kivinen Pekka Taimen Markku Kallajoki 《Apoptosis : an international journal on programmed cell death》2010,15(8):936-945
One main feature of apoptosis is the sequential degradation of the nuclear structure, including the fragmentation of chromatin
and caspase-mediated cleavage of various nuclear proteins. Among these proteins is the Nuclear Mitotic Apparatus protein (NuMA)
which plays a specific role in the organization of the mitotic spindle. The exact function of NuMA in the interphase nucleus
is unknown, but a number of reports have suggested that it may play a role in chromatin organization and/or gene expression.
Here we show that upon cleavage in apoptotic cells, the N-terminal cleavage fragment of NuMA is solubilized while the C-terminal
fragment remains associated with the condensed chromatin. Using pancaspase inhibitor z-VAD-fmk and caspase-3 deficient MCF-7
cells, we further show that the solubilization is dependent on caspase-mediated cleavage of NuMA. Finally, the silencing of
NuMA by RNAi accelerated nuclear breakdown in apoptotic MCF-7 cells. These results suggest that NuMA may provide structural
support in the interphase nucleus by contributing to the organization of chromatin. 相似文献
83.
Green tea extract and its major polyphenol (-)-epigallocatechin gallate improve muscle function in a mouse model for Duchenne muscular dystrophy 总被引:2,自引:0,他引:2
Dorchies OM Wagner S Vuadens O Waldhauser K Buetler TM Kucera P Ruegg UT 《American journal of physiology. Cell physiology》2006,290(2):C616-C625
Duchenne muscular dystrophy is a frequent muscular disorder caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that contributes to the stabilization of muscle fiber membrane during muscle activity. Affected individuals show progressive muscle wasting that generally causes death by age 30. In this study, the dystrophic mdx5Cv mouse model was used to investigate the effects of green tea extract, its major component ()-epigallocatechin gallate, and pentoxifylline on dystrophic muscle quality and function. Three-week-old mdx5Cv mice were fed for either 1 or 5 wk a control chow or a chow containing the test substances. Histological examination showed a delay in necrosis of the extensor digitorum longus muscle in treated mice. Mechanical properties of triceps suræ muscles were recorded while the mice were under deep anesthesia. Phasic and tetanic tensions of treated mice were increased, reaching values close to those of normal mice. The phasic-to-tetanic tension ratio was corrected. Finally, muscles from treated mice exhibited 3050% more residual force in a fatigue assay. These results demonstrate that diet supplementation of dystrophic mdx5Cv mice with green tea extract or ()-epigallocatechin gallate protected muscle against the first massive wave of necrosis and stimulated muscle adaptation toward a stronger and more resistant phenotype. pharmacotherapy; muscular disorders; dystrophic mdx5cv mouse; muscle mechanical properties; muscle histology 相似文献
84.
85.
Alan M. Pittman Silvia Naranjo Sanni E. Jalava Philip Twiss Yussanne Ma Bianca Olver Amy Lloyd Jayaram Vijayakrishnan Mobshra Qureshi Peter Broderick Tom van Wezel Hans Morreau Sari Tuupanen Lauri A. Aaltonen M. Eva Alonso Miguel Manzanares Angela Gavilán Tapio Visakorpi José Luis Gómez-Skarmeta Richard S. Houlston 《PLoS genetics》2010,6(9)
86.
Hanno Jaakson Katri Ling Jaak Samarütel Aire Ilves Tanel Kaart Olav Kärt 《Acta veterinaria Scandinavica》2010,52(1):4
Background
Insulin secretion and tissue sensitivity to insulin is considered to be one of the factors controlling lipid metabolism post partum. The objective of this study was to compare glucose-induced blood insulin and metabolite responses in Estonian Holstein (EH, n = 14) and Estonian Red (ER, n = 14) cows. 相似文献87.
Strang-Karlsson S Kajantie E Pesonen AK Räikkönen K Hovi P Lahti J Heinonen K Järvenpää AL Eriksson JG Andersson S Paavonen EJ 《Chronobiology international》2010,27(9-10):1829-1842
The authors explored morningness-eveningness propensity in adults born prematurely at very low birth weight (VLBW; 1500g) and in controls born at term. At age 21 to 29 yrs, 184 participants completed the Morningness-Eveningness Questionnaire (MEQ). Compared with controls, VLBW adults scored higher in morningness propensity (group difference: 2.8 scores, 95% confidence interval: 0.1 to 5.5; p?=?.042). This finding was confined to those VLBW adults whose birth weight was not small for gestational age, and remained similar when adjusting for age, sex, and working conditions. The finding is potentially important, since morningness is associated with beneficial health outcomes. 相似文献
88.
89.
Juha Taavela Outi Koskinen Heini Huhtala Marja-Leena L?hdeaho Alina Popp Kaija Laurila Pekka Collin Katri Kaukinen Kalle Kurppa Markku M?ki 《PloS one》2013,8(10)
Background
Assessment of the gluten-induced small-intestinal mucosal injury remains the cornerstone of celiac disease diagnosis. Usually the injury is evaluated using grouped classifications (e.g. Marsh groups), but this is often too imprecise and ignores minor but significant changes in the mucosa. Consequently, there is a need for validated continuous variables in everyday practice and in academic and pharmacological research.Methods
We studied the performance of our standard operating procedure (SOP) on 93 selected biopsy specimens from adult celiac disease patients and non-celiac disease controls. The specimens, which comprised different grades of gluten-induced mucosal injury, were evaluated by morphometric measurements. Specimens with tangential cutting resulting from poorly oriented biopsies were included. Two accredited evaluators performed the measurements in blinded fashion. The intraobserver and interobserver variations for villus height and crypt depth ratio (VH:CrD) and densities of intraepithelial lymphocytes (IELs) were analyzed by the Bland-Altman method and intraclass correlation.Results
Unevaluable biopsies according to our SOP were correctly identified. The intraobserver analysis of VH:CrD showed a mean difference of 0.087 with limits of agreement from −0.398 to 0.224; the standard deviation (SD) was 0.159. The mean difference in interobserver analysis was 0.070, limits of agreement −0.516 to 0.375, and SD 0.227. The intraclass correlation coefficient in intraobserver variation was 0.983 and that in interobserver variation 0.978. CD3+ IEL density countings in the paraffin-embedded and frozen biopsies showed SDs of 17.1% and 16.5%; the intraclass correlation coefficients were 0.961 and 0.956, respectively.Conclusions
Using our SOP, quantitative, reliable and reproducible morphometric results can be obtained on duodenal biopsy specimens with different grades of gluten-induced injury. Clinically significant changes were defined according to the error margins (2SD) of the analyses in VH:CrD as 0.4 and in CD3+-stained IELs as 30%. 相似文献90.
Katri Raikkonen Eero Kajantie Anu-Katriina Pesonen Kati Heinonen Hanna Alastalo Jukka T. Leskinen Kai Nyman Markus Henriksson Jari Lahti Marius Lahti Riikka Pyh?l? Soile Tuovinen Clive Osmond David J. P. Barker Johan G. Eriksson 《PloS one》2013,8(1)