全文获取类型
收费全文 | 411篇 |
免费 | 33篇 |
出版年
2021年 | 2篇 |
2020年 | 5篇 |
2019年 | 7篇 |
2018年 | 4篇 |
2017年 | 7篇 |
2016年 | 10篇 |
2015年 | 19篇 |
2014年 | 17篇 |
2013年 | 31篇 |
2012年 | 30篇 |
2011年 | 18篇 |
2010年 | 15篇 |
2009年 | 9篇 |
2008年 | 25篇 |
2007年 | 13篇 |
2006年 | 13篇 |
2005年 | 12篇 |
2004年 | 18篇 |
2003年 | 14篇 |
2002年 | 12篇 |
2001年 | 14篇 |
2000年 | 8篇 |
1999年 | 11篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 11篇 |
1990年 | 7篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1986年 | 2篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 8篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 3篇 |
1975年 | 4篇 |
1974年 | 2篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1970年 | 2篇 |
1950年 | 1篇 |
排序方式: 共有444条查询结果,搜索用时 322 毫秒
101.
Teng YK Verburg RJ Verpoort KN Diepenhorst GM Bajema IM van Tol MJ Jol-van der Zijde EC Toes RE Huizinga TW van Laar JM 《Arthritis research & therapy》2007,9(5):R106
In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated
protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy
(HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized
in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against
rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was
measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial
biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with
clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy
were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median
of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to
388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were
differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies
as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative
therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity. 相似文献
102.
Sander A Huisman Wendy Bijman-Lagcher Jan NM IJzermans Ron Smits Ron WF de Bruin 《Cell cycle (Georgetown, Tex.)》2015,14(14):2333-2339
Irinotecan is a widely used topoisomerase-I-inhibitor with a very narrow therapeutic window because of its severe toxicity. In the current study we have examined the effects of fasting prior to irinotecan treatment on toxicity and anti-tumor activity. FabplCre;Apc15lox/+ mice, which spontaneously develop intestinal tumors, of 27 weeks of age were randomized into 3-day fasted and ad libitum fed groups, followed by treatment with a flat-fixed high dose of irinotecan or vehicle. Side-effects were recorded until 11 days after the start of the experiment. Tumor size, and markers for cell-cycle activity, proliferation, angiogenesis, and senescence were measured. Fasted mice were protected against the side-effects of irinotecan treatment. Ad libitum fed mice developed visible signs of discomfort including weight loss, lower activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia. Irinotecan reduced tumor size in fasted and ad libitum fed groups similarly compared to untreated controls (2.4 ± 0.67 mm and 2.4 ± 0.82 mm versus 3.0 ± 1.05 mm and 2.8 ± 1.08 mm respectively, P < 0.001). Immunohistochemical analysis showed reduced proliferation, a reduced number of vascular endothelial cells, and increased levels of senescence in tumors of both irinotecan treated groups. In conclusion, 3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients. 相似文献
103.
Robert P. de Vries Cornelis H. Smit Erwin de Bruin Alan Rigter Erik de Vries Lisette A. H. M. Cornelissen Dirk Eggink Nancy P. Y. Chung John P. Moore Rogier W. Sanders Cornelis H. Hokke Marion Koopmans Peter J. M. Rottier Cornelis A. M. de Haan 《Journal of virology》2012,86(21):11735-11744
Recombinant soluble trimeric influenza A virus (IAV) hemagglutinin (sHA3) has proven an effective vaccine antigen against IAV. Here, we investigate to what extent the glycosylation status of the sHA3 glycoprotein affects its immunogenicity. Different glycosylation forms of subtype H5 trimeric HA protein (sH53) were produced by expression in insect cells and different mammalian cells in the absence and presence of inhibitors of N-glycan-modifying enzymes or by enzymatic removal of the oligosaccharides. The following sH53 preparations were evaluated: (i) HA proteins carrying complex glycans produced in HEK293T cells; (ii) HA proteins carrying Man9GlcNAc2 moieties, expressed in HEK293T cells treated with kifunensine; (iii) HA proteins containing Man5GlcNAc2 moieties derived from HEK293S GnTI(−) cells; (iv) insect cell-produced HA proteins carrying paucimannosidic N-glycans; and (v) HEK293S GnTI(−) cell-produced HA proteins treated with endoglycosidase H, thus carrying side chains composed of only a single N-acetylglucosamine each. The different HA glycosylation states were confirmed by comparative electrophoretic analysis and by mass spectrometric analysis of released glycans. The immunogenicity of the HA preparations was studied in chickens and mice. The results demonstrate that HA proteins carrying terminal mannose moieties induce significantly lower hemagglutination inhibition antibody titers than HA proteins carrying complex glycans or single N-acetylglucosamine side chains. However, the glycosylation state of the HA proteins did not affect the breadth of the antibody response as measured by an HA1 antigen microarray. We conclude that the glycosylation state of recombinant antigens is a factor of significant importance when developing glycoprotein-based vaccines, such as recombinant HA proteins. 相似文献
104.
105.
Williamson L Raess NA Caldelari R Zakher A de Bruin A Posthaus H Bolli R Hunziker T Suter MM Müller EJ 《The EMBO journal》2006,25(14):3298-3309
The autoimmune disease pemphigus vulgaris (PV) manifests as loss of keratinocyte cohesion triggered by autoantibody binding to desmoglein (Dsg)3, an intercellular adhesion molecule of mucous membranes, epidermis, and epidermal stem cells. Here we describe a so far unknown signaling cascade activated by PV antibodies. It extends from a transient enhanced turn over of cell surface-exposed, nonkeratin-anchored Dsg3 and associated plakoglobin (PG), through to depletion of nuclear PG, and as one of the consequences, abrogation of PG-mediated c-Myc suppression. In PV patients (6/6), this results in pathogenic c-Myc overexpression in all targeted tissues, including the stem cell compartments. In summary, these results show that PV antibodies act via PG to abolish the c-Myc suppression required for both maintenance of epidermal stem cells in their niche and controlled differentiation along the epidermal lineage. Besides a completely novel insight into PV pathogenesis, these data identify PG as a potent modulator of epithelial homeostasis via its role as a key suppressor of c-Myc. 相似文献
106.
Vanesa Esteban Silvia Heringer-Walther Anja Sterner-Kock Ron de Bruin Sandra van den Engel Yong Wang Sergio Mezzano Jesus Egido Heinz-Peter Schultheiss Marta Ruiz-Ortega Thomas Walther 《PloS one》2009,4(4)
Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1–7) by interacting with the G protein-coupled receptor Mas may also have important biological activities.In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1–7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-κB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1–7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1–7)-mediated NF-κB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-κB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney. 相似文献
107.
108.
Cai J Robinson J Belshaw S Everett K Fradera X van Zeeland M van Berkom L van Rijnsbergen P Popplestone L Baugh M Dempster M Bruin J Hamilton W Kinghorn E Westwood P Kerr J Rankovic Z Arbuckle W Bennett DJ Jones PS Long C Martin I Uitdehaag JC Meulemans T 《Bioorganic & medicinal chemistry letters》2010,20(23):6890-6894
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position. 相似文献
109.
Steens SC Bosma GP Steup-Beekman GM le Cessie S Huizinga TW van Buchem MA 《Arthritis research & therapy》2006,8(2):R38-7
The pathogenetic role of anticardiolipin antibodies (aCLs) in patients with neuropsychiatric systemic lupus erythematosus
(NPSLE) without cerebral infarcts remains elusive. Magnetization transfer imaging (MTI) has proved to be a sensitive tool
for detecting diffuse microscopic brain damage in NPSLE patients. In this study we examined the correlation between grey and
white matter magnetization transfer ratio (MTR) parameters and the presence of IgM and IgG aCLs and lupus anticoagulant in
18 patients with systemic lupus erythematosus and a history of NPSLE but without cerebral infarcts on conventional magnetic
resonance imaging. Lower grey matter mean MTR (P < 0.05), white matter mean MTR (P < 0.05), white matter peak location (P < 0.05) and grey matter peak location (trend toward statistical significance) were observed in IgM aCL-positive patients
than in IgM aCL-negative patients. No significant differences were found in MTR histogram parameters with respect to IgG aCL
and lupus anticoagulant status, nor with respect to anti-dsDNA or anti-ENA (extractable nuclear antigen) status. This is the
first report of an association between the presence of aCLs and cerebral damage in grey and white matter in NPSLE. Our findings
suggest that aCLs are associated with diffuse brain involvement in NPSLE patients. 相似文献
110.
Normal values are given for height velocity in a Dutch population. A construction of velocity curves is given and a comparison is made with other studies. 相似文献