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211.
Citrullination and the immune response to citrullinated proteins have been
fundamental for the early recognition of rheumatoid arthritis by serological tests
and a better understanding of its pathophysiology. In the first years after the
initial publications, the focus was on the antibodies directed to citrullinated
proteins. It is now realized that citrullinating enzymes and citrullinated proteins
may have important roles in the maintenance of the inflammatory processes in the
joints. There is also accumulating evidence for a direct role of citrullination in
tissue destruction in the rheumatoid synovium. Here we will discuss the development
and importance of anti-citrullinated protein antibodies in rheumatoid arthritis as
well as recent findings implicating citrullination in the pathophysiology of
rheumatoid arthritis.The first indication that patients with rheumatoid arthritis (RA) produce antibodies to
a specific autoantigen was published in 1964 by two Dutch scientists, Nienhuis and
Mandema. The exact nature of this antigen, the so-called perinuclear factor, remained
unclear for decades. In 1978, the target of seemingly unrelated RA-specific
autoantibodies (that is, keratin) was identified. Almost 15 years later, Guy
Serre’s group convincingly showed that both antigens were identical to the
cytokeratin filament-aggregating protein filaggrin (reviewed in [1]). Our own previously published results had shown that the newly made
precursor of filaggrin in cultured buccal mucosa cells (that is, profilaggrin) did not
react with RA antibodies [2]. This prompted us to consider the possibility that a post-translational
modification of filaggrin, absent on newly made profilaggrin, was required for the
formation of the antigenic target of these antibodies. Since 1994, we have tested
several likely modifications using synthetic peptides. Indeed, citrullination, the
enzymatic conversion of peptidylarginine into peptidylcitrulline, turned out to be
essential to make peptides reactive with RA autoantibodies. We subsequently developed an
enzyme-linked immunosorbent assay with citrullinated peptides and confirmed that the
anti-peptidylcitrulline activity was specific for RA [3]. Our further work was directed to the development of the CCP2 test, using
cyclic citrullinated peptides (CCPs) selected from random peptide libraries [4].The discovery of CCP/protein as the most prominent RA-specific antigen had great impact
on RA diagnostics and our understanding of RA pathophysiology. The following milestones
can be noted (see [5] also).1. After decades of intensive research by many groups, a specific diagnostic
test for RA had finally been developed. The CCP2 test has a specificity of more than
95%, is very sensitive (~75%), and is still considered the gold standard in RA
autoantibody testing. Since 2010, anti-citrullinated protein antibodies (ACPAs) have
been included in the new American College of Rheumatology/European League Against
Rheumatism classification criteria for RA.2. Recently, an international reference preparation for ACPAs was evaluated
by the International Committee for the Standardization of Autoantibodies in Rheumatic
and Related Diseases [6]. It is available for the scientific community via the Centers for Disease
Control and Prevention (Atlanta, GA, USA).3. A positive CCP2 test predicts the development of RA, often years before
clinical confirmation (reviewed in [5]). It appears that time to RA diagnosis is shorter in patients with high
anti-CCP2 titers at enrollment as compared with those with low titers [7].4. ACPA-positive RA is characterized by a more severe disease course. Early
treatment of ACPA-positive individuals appears to be very effective.5. ACPA-negative patients (about 25% of the total RA population) generally
display a much milder course of disease. About 35% of such ACPA-negative patients
produce anti-carbamylated protein antibodies. Interestingly, the chemical product of
carbamylation (that is, lysine converted to homocitrulline) is structurally very similar
to citrulline [8].6. Specific human leukocyte antigen (HLA) genes (DRB1 shared epitope (SE)
alleles) not only are the most important genetic risk factor for RA but also are
strongly associated with the production of ACPAs.7. The best known environmental risk factor for RA, cigarette smoking, is a
risk factor only for ACPA-positive and not for ACPA-negative RA [9]. There is increasing evidence that smoking acts as a trigger for
anti-citrulline immunity and does so mainly in the context of certain HLA genes and
certain other genetic risk factors.8. ACPAs and citrullinated antigens form immune complexes which stimulate the
inflammatory process. Continuous production of such immune complexes ultimately results
in the chronic inflammation, characteristic for RA (Figure 1).Open in a separate windowFigure 1Citrullination-related immunity and pathophysiology in rheumatoid
arthritis. In genetically susceptible individuals, an environmental factor
may initiate a primary inflammation, which can occur in various tissues, and
trigger the immune response to citrullinated proteins (left). The resulting
anti-citrullinated protein/peptide antibodies (ACPAs) are distributed through the
circulation and may form immune complexes with citrullinated proteins produced in
an inflamed synovium, thereby boosting the inflammatory process. This will be
associated with the infiltration and activation of neutrophils, macrophages, and
lymphocytes; cell death; extracellular DNA trap formation; the activation and
release of peptidylarginine deiminases (PADs); de novo citrullination;
and diversification of the ACPA response. Besides the common
inflammation-associated mediators of tissue destruction (not shown), ACPAs and
PADs can be directly involved in these processes. HLA, human leukocyte
antigen. 相似文献
212.
The interstitial cells of Cajal (ICC) have been reported to regulate gastrointestinal motility. We investigated the distribution and the morphological and morphometric characteristics of the immunohistochemical reaction against c-kit in the forestomachs of fetal, newborn and adult cows. The anti-c-kit reaction revealed different populations of ICC among age groups and organs. ICC were more numerous and smaller in fetuses. Larger ICC were identified in newborns, except for those in the rumen. During the earliest stages of development, ICC were abundant in the inner layer of the muscularis and were consistently associated with this layer. In all samples, ICC were found in the outer layer of the tunica muscularis. ICC were found between the two muscle layers in the omasum at all ages; however, they were identified only in the rumen of the adult. Our study demonstrated that ICC are present in the forestomach of bovines. 相似文献
213.
Valerie R Wiersma Marco de Bruyn Ce Shi Marloes JM Gooden Maartje CA Wouters Douwe F Samplonius Djoke Hendriks Hans W Nijman Yunwei Wei Jin Zhou Wijnand Helfrich Edwin Bremer 《MABS-AUSTIN》2015,7(2):321-330
The therapeutic effect of anti-cancer monoclonal antibodies stems from their capacity to opsonize targeted cancer cells with subsequent phagocytic removal, induction of antibody-dependent cell-mediated cytotoxicity (ADCC) or induction of complement-mediated cytotoxicity (CDC). The major immune effector cells involved in these processes are natural killer (NK) cells and granulocytes. The latter and most prevalent blood cell population contributes to phagocytosis, but is not effective in inducing ADCC. Here, we report that targeted delivery of the tumoricidal protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to granulocyte marker C-type lectin-like molecule-1 (CLL1), using fusion protein CLL1:TRAIL, equips granulocytes with high levels of TRAIL. Upon CLL1-selective binding of this fusion protein, granulocytes acquire additional TRAIL-mediated cytotoxic activity that, importantly, potentiates antibody-mediated cytotoxicity of clinically used therapeutic antibodies (e.g., rituximab, cetuximab). Thus, CLL1:TRAIL could be used as an adjuvant to optimize the clinical potential of anticancer antibody therapy by augmenting tumoricidal activity of granulocytes. 相似文献
214.
The Notch pathway contributes to self-renewal of tumor-initiating cell and inhibition of normal colonic epithelial cell differentiation. Deregulated expression of Notch1 and Jagged1 is observed in colorectal cancer. Hairy/enhancer of split (HES) family, the most characterized targets of Notch, involved in the development of many cancers. In this study, we explored the role of Hes1 in the tumorigenesis of colorectal cancer. Knocking down Hes1 induced CRC cell senescence and decreased the invasion ability, whereas over-expression of Hes1 increased STAT3 phosphorylation activity and up-regulated MMP14 protein level. We further explored the expression of Hes1 in human colorectal cancer and found high Hes1 mRNA expression is associated with poor prognosis in CRC patients. These findings suggest that Hes1 regulates the invasion ability through the STAT3-MMP14 pathway in CRC cells and high Hes1 expression is a predictor of poor prognosis of CRC. 相似文献
215.
216.
Dimitrios Makrygiannakis Shankar Revu Marianne Engström Erik af Klint Anthony P Nicholas Ger JM Pruijn Anca I Catrina 《Arthritis research & therapy》2012,14(1):R20-9
Introduction
Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. As a result, the present study examined the possibility that effective antirheumatic treatment will decrease the level of synovial citrullination.Methods
Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intraarticular glucocorticoid injection, and eight healthy volunteers. Synovial inflammation was assessed with double-blind semiquantitative analysis of lining thickness, cell infiltration, and vascularity by using a 4-point scale. Expression of citrullinated proteins (CPs) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically with double-blind semiquantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB), mononuclear cells (MCs), and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed with immunohistochemistry for expression of CP as well as PAD2 and PAD4 enzymes.Results
The presence of synovial CP was almost exclusive in RA compared with healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination, as demonstrated by the decrease in the level of citrullination and PAD expression after incubation of SFMC and synovial explants with dexamethasone.Conclusion
Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids. 相似文献217.
Jayne E Rattray Marc Strous Huub JM Op den Camp Stefan Schouten Mike SM Jetten Jaap S Sinninghe Damsté 《Biology direct》2009,4(1):8-16
Background
The fatty acids of anaerobic ammonium oxidizing (anammox) bacteria contain linearly concatenated cyclobutane moieties, so far unique to biology. These moieties are under high ring strain and are synthesised by a presently unknown biosynthetic pathway. 相似文献218.
Oscar González-Recio Daniel Gianola Guilherme JM Rosa Kent A Weigel Andreas Kranis 《遗传、选种与进化》2009,41(1):3
Accuracy of prediction of yet-to-be observed phenotypes for food conversion rate (FCR) in broilers was studied in a genome-assisted selection context. Data consisted of FCR measured on the progeny of 394 sires with SNP information. A Bayesian regression model (Bayes A) and a semi-parametric approach (Reproducing kernel Hilbert Spaces regression, RKHS) using all available SNPs (p = 3481) were compared with a standard linear model in which future performance was predicted using pedigree indexes in the absence of genomic data. The RKHS regression was also tested on several sets of pre-selected SNPs (p = 400) using alternative measures of the information gain provided by the SNPs. All analyses were performed using 333 genotyped sires as training set, and predictions were made on 61 birds as testing set, which were sons of sires in the training set. Accuracy of prediction was measured as the Spearman correlation () between observed and predicted phenotype, with its confidence interval assessed through a bootstrap approach. A large improvement of genome-assisted prediction (up to an almost 4-fold increase in accuracy) was found relative to pedigree index. Bayes A and RKHS regression were equally accurate ( = 0.27) when all 3481 SNPs were included in the model. However, RKHS with 400 pre-selected informative SNPs was more accurate than Bayes A with all SNPs. 相似文献
219.
Background
In black-background-adapted Xenopus laevis, the intermediate pituitary melanotrope cells are hyperactive, producing large amounts of their major secretory cargo proopiomelanocortin (POMC, representing ~80% of all newly synthesised proteins), whereas in white-adapted frogs these cells are only basally active. Here we explored in the hyperactive and basally active melanotrope cells the capacity for posttranslational POMC processing events in the secretory pathway. 相似文献220.
Alexandre C Motta Joost LM Vissers Renée Gras Betty CAM Van Esch Antoon JM Van Oosterhout Martijn C Nawijn 《Respiratory research》2009,10(1):1-8