全文获取类型
收费全文 | 314篇 |
免费 | 17篇 |
专业分类
331篇 |
出版年
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 14篇 |
2014年 | 16篇 |
2013年 | 23篇 |
2012年 | 15篇 |
2011年 | 15篇 |
2010年 | 24篇 |
2009年 | 27篇 |
2008年 | 13篇 |
2007年 | 13篇 |
2006年 | 11篇 |
2005年 | 13篇 |
2004年 | 13篇 |
2003年 | 3篇 |
2002年 | 4篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 9篇 |
1997年 | 10篇 |
1996年 | 4篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 7篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 16篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有331条查询结果,搜索用时 15 毫秒
231.
Rohola Hosseini Gerda EM Lamers Zlatan Hodzic Annemarie H Meijer Marcel JM Schaaf Herman P Spaink 《Autophagy》2014,10(10):1844-1857
High-resolution imaging of autophagy has been used intensively in cell culture studies, but so far it has been difficult to visualize this process in detail in whole animal models. In this study we present a versatile method for high-resolution imaging of microbial infection in zebrafish larvae by injecting pathogens into the tail fin. This allows visualization of autophagic compartments by light and electron microscopy, which makes it possible to correlate images acquired by the 2 techniques. Using this method we have studied the autophagy response against Mycobacterium marinum infection. We show that mycobacteria during the progress of infection are frequently associated with GFP-Lc3-positive vesicles, and that 2 types of GFP-Lc3-positive vesicles were observed. The majority of these vesicles were approximately 1 μm in size and in close vicinity of bacteria, and a smaller number of GFP-Lc3-positive vesicles was larger in size and were observed to contain bacteria. Quantitative data showed that these larger vesicles occurred significantly more in leukocytes than in other cell types, and that approximately 70% of these vesicles were positive for a lysosomal marker. Using electron microscopy, it was found that approximately 5% of intracellular bacteria were present in autophagic vacuoles and that the remaining intracellular bacteria were present in phagosomes, lysosomes, free inside the cytoplasm or occurred as large aggregates. Based on correlation of light and electron microscopy images, it was shown that GFP-Lc3-positive vesicles displayed autophagic morphology. This study provides a new approach for injection of pathogens into the tail fin, which allows combined light and electron microscopy imaging in vivo and opens new research directions for studying autophagy process related to infectious diseases. 相似文献
232.
233.
Marco van der Toorn Dirk-Jan Slebos Harold G de Bruin Renee Gras Delaram Rezayat Lucie Jorge Koen Sandra Antoon JM van Oosterhout 《Respiratory research》2013,14(1):45
Background
Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation.Methods
BALB/c mice were exposed to CS, water filtered CS (WF-CS) or air for 5 days. Levels of total particulate matter (TPM) and aldehydes in CS and WF-CS were measured. Six hours after the last exposure, inflammatory cells and cytokine levels were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Furthermore, Beas-2b bronchial epithelial cells were exposed to CS extract (CSE) or WF-CS extract (WF-CSE) in the absence or presence of the aldehyde acrolein and IL-8 production was measured after 24 hrs.Results
Compared to CS, in WF-CS strongly decreased (CS; 271.1 ± 41.5 μM, WF-CS; 58.5 ± 8.2 μM) levels of aldehydes were present whereas levels of TPM were only slightly reduced (CS; 20.78 ± 0.59 mg, WF-CS; 16.38 ± 0.36 mg). The numbers of mononuclear cells in BALF (p<0.01) and lung tissue (p<0.01) were significantly increased in the CS- and WF-CS-exposed mice compared to air control mice. Interestingly, the numbers of neutrophils (p<0.001) in BALF and neutrophils and eosinophils (p<0.05) in lung tissue were significantly increased in the CS-exposed but not in WF-CS-exposed mice as compared to air control mice. Levels of the neutrophil and eosinophil chemoattractants KC, MCP-1, MIP-1α and IL-5 were all significantly increased in lung tissue from CS-exposed mice compared to both WF-CS-exposed and air control mice. Interestingly, depletion of aldehydes in WF-CS extract significantly reduced IL-8 production in Beas-2b as compared to CSE, which could be restored by the aldehyde acrolein.Conclusion
Aldehydes present in CS play a critical role in inflammatory cytokine production and neutrophilic- but not mononuclear airway inflammation. 相似文献234.
235.
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
236.
237.
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238.
Marianne Eijkemans Monique Mommers Jos M. Th. Draaisma Carel Thijs Martin H. Prins 《PloS one》2012,7(12)
Introduction
This review aims to give an overview of available published evidence concerning the association between physical activity and asthma in children, adolescents and adults.Methods
We included all original articles in which both physical activity and asthma were assessed in case-control, cross-sectional or longitudinal (cohort) studies. Excluded were studies concerning physical fitness, studies in athletes, therapeutic or rehabilitation intervention studies such as physical training or exercise in asthma patients. Methodological quality of the included articles was assessed according to the Newcastle-Ottawa Scale (NOS).Results
A literature search was performed until June 2011 and resulted in 6,951 publications derived from PubMed and 1,978 publications from EMBASE. In total, 39 studies met the inclusion criteria: 5 longitudinal studies (total number of subjects n = 85,117) with physical activity at baseline as exposure, and asthma incidence as outcome. Thirty-four cross-sectional studies (n = 661,222) were included. Pooling of the longitudinal studies showed that subjects with higher physical activity levels had lower incidence of asthma (odds ratio 0.88 (95% CI: 0.77–1.01)). When restricting pooling to the 4 prospective studies with moderate to good study quality (defined as NOS≥5) the pooled odds ratio only changed slightly (0.87 (95% CI: 0.77–0.99)). In the cross-sectional studies, due to large clinical variability and heterogeneity, further statistical analysis was not possible.Conclusions
The available evidence indicates that physical activity is a possible protective factor against asthma development. The heterogeneity suggests that possible relevant effects remain hidden in critical age periods, sex differences, or extremes of levels of physical activity (e.g. sedentary). Future longitudinal studies should address these issues. 相似文献239.
240.
Jörg Barke Ryan F Seipke Sabine Grüschow Darren Heavens Nizar Drou Mervyn J Bibb Rebecca JM Goss Douglas W Yu Matthew I Hutchings 《BMC biology》2010,8(1):109