全文获取类型
收费全文 | 1592篇 |
免费 | 187篇 |
专业分类
1779篇 |
出版年
2022年 | 12篇 |
2021年 | 19篇 |
2020年 | 13篇 |
2019年 | 13篇 |
2018年 | 19篇 |
2017年 | 24篇 |
2016年 | 29篇 |
2015年 | 72篇 |
2014年 | 39篇 |
2013年 | 80篇 |
2012年 | 87篇 |
2011年 | 98篇 |
2010年 | 61篇 |
2009年 | 46篇 |
2008年 | 77篇 |
2007年 | 66篇 |
2006年 | 75篇 |
2005年 | 64篇 |
2004年 | 60篇 |
2003年 | 62篇 |
2002年 | 79篇 |
2001年 | 53篇 |
2000年 | 62篇 |
1999年 | 60篇 |
1998年 | 38篇 |
1997年 | 34篇 |
1996年 | 22篇 |
1995年 | 30篇 |
1994年 | 28篇 |
1993年 | 28篇 |
1992年 | 32篇 |
1991年 | 39篇 |
1990年 | 29篇 |
1989年 | 19篇 |
1988年 | 23篇 |
1987年 | 11篇 |
1986年 | 12篇 |
1985年 | 25篇 |
1984年 | 10篇 |
1983年 | 9篇 |
1982年 | 8篇 |
1981年 | 7篇 |
1979年 | 11篇 |
1978年 | 11篇 |
1977年 | 9篇 |
1976年 | 8篇 |
1975年 | 10篇 |
1974年 | 7篇 |
1973年 | 9篇 |
1968年 | 6篇 |
排序方式: 共有1779条查询结果,搜索用时 0 毫秒
81.
Genetic heterogeneity in tuberous sclerosis 总被引:8,自引:0,他引:8
L A Janssen L A Sandkuyl E C Merkens J A Maat-Kievit J R Sampson P Fleury R C Hennekam G C Grosveld D Lindhout D J Halley 《Genomics》1990,8(2):237-242
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by widespread hamartosis. Preliminary evidence of linkage between the TSC locus and markers on chromosome 9q34 was established, but subsequently disputed. More recently, a putative TSC locus on chromosome 11 has been suggested and genetic heterogeneity seems likely. Here we describe an approach combining multipoint linkage analysis and heterogeneity tests that has enabled us to obtain significant evidence for locus heterogeneity after studying a relatively small number of families. Our results support a model with two different loci independently causing the disease. One locus (TSC1) maps in the vicinity of the Abelson oncogene at 9q34 and a second locus (TSC2) maps in the region of the anonymous DNA marker Lam L7 and the dopamine D2 receptor gene at 11q23. 相似文献
82.
Barbara H. Janssen Nicoline B. M. Voet Christine I. Nabuurs Hermien E. Kan Jacky W. J. de Rooy Alexander C. Geurts George W. Padberg Baziel G. M. van Engelen Arend Heerschap 《PloS one》2014,9(1)
Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34–76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D 31P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle’s length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase with distal fat infiltration and altered energy metabolite levels. Fat replacement then relatively rapidly spreads over the whole muscle. 相似文献
83.
Koen M J Janssen Menke J de Smit Elisabeth Brouwer Fenne A C de Kok Jan Kraan Josje Altenburg Marije K Verheul Leendert A Trouw Arie Jan van Winkelhoff Arjan Vissink Johanna Westra 《Arthritis research & therapy》2015,17(1)
IntroductionRheumatoid arthritis–associated autoantibodies (RA-AAB) can be present in serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.MethodsThe presence of RA-AAB (immunoglobulin A [IgA] and IgG anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), IgM and IgA rheumatoid factor (RF), IgG anti-carbamylated protein antibodies and IgG and IgA anti-citrullinated peptide antibodies against fibrinogen, vimentin and enolase) were determined in sera of non-RA patients with periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group. Association of the diseases with RA-AAB seropositivity was assessed with a logistic regression model, adjusted for age, sex and smoking.ResultsLogistic regression analysis revealed that IgG anti-CCP seropositivity was associated with BR and RA, whereas the association with PD was borderline significant. IgA anti-CCP seropositivity was associated with CF and RA. IgM RF seropositivity was associated with RA, whereas the association with BR was borderline significant. IgA RF seropositivity was associated with CF and RA. Apart from an influence of smoking on IgA RF in patients with RA, there was no influence of age, sex or smoking on the association of RA-AAB seropositivity with the diseases. Anti-CarP levels were increased only in patients with RA. The same held for IgG reactivity against all investigated citrullinated peptides.ConclusionAlthough overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates. 相似文献
84.
HSV‐1 Glycoproteins Are Delivered to Virus Assembly Sites Through Dynamin‐Dependent Endocytosis 下载免费PDF全文
Anna Albecka Romain F. Laine Anne F.J. Janssen Clemens F. Kaminski Colin M. Crump 《Traffic (Copenhagen, Denmark)》2016,17(1):21-39
Herpes simplex virus‐1 (HSV‐1) is a large enveloped DNA virus that belongs to the family of Herpesviridae. It has been recently shown that the cytoplasmic membranes that wrap the newly assembled capsids are endocytic compartments derived from the plasma membrane. Here, we show that dynamin‐dependent endocytosis plays a major role in this process. Dominant‐negative dynamin and clathrin adaptor AP180 significantly decrease virus production. Moreover, inhibitors targeting dynamin and clathrin lead to a decreased transport of glycoproteins to cytoplasmic capsids, confirming that glycoproteins are delivered to assembly sites via endocytosis. We also show that certain combinations of glycoproteins colocalize with each other and with the components of clathrin‐dependent and ‐independent endocytosis pathways. Importantly, we demonstrate that the uptake of neutralizing antibodies that bind to glycoproteins when they become exposed on the cell surface during virus particle assembly leads to the production of non‐infectious HSV‐1. Our results demonstrate that transport of viral glycoproteins to the plasma membrane prior to endocytosis is the major route by which these proteins are localized to the cytoplasmic virus assembly compartments. This highlights the importance of endocytosis as a major protein‐sorting event during HSV‐1 envelopment. 相似文献
85.
Tran DT Vermeeren V Grieten L Wenmackers S Wagner P Pollet J Janssen KP Michiels L Lammertyn J 《Biosensors & bioelectronics》2011,26(6):2987-2993
Like antibodies, aptamers are highly valuable as bioreceptor molecules for protein biomarkers because of their excellent selectivity, specificity and stability. The integration of aptamers with semiconducting materials offers great potential for the development of reliable aptasensors. In this paper we present an aptamer-based impedimetric biosensor using a nanocrystalline diamond (NCD) film as a working electrode for the direct and label-free detection of human immunoglobulin E (IgE). Amino (NH(2))-terminated IgE aptamers were covalently attached to carboxyl (COOH)-modified NCD surfaces using carbodiimide chemistry. Electrochemical impedance spectroscopy (EIS) was applied to measure the changes in interfacial electrical properties that arise when the aptamer-functionalized diamond surface was exposed to IgE solutions. During incubation, the formation of aptamer-IgE complexes caused a significant change in the capacitance of the double-layer, in good correspondence with the IgE concentration. The linear dynamic range of IgE detection was from 0.03 μg/mL to 42.8 μg/mL. The detection limit of the aptasensor reached physiologically relevant concentrations (0.03 μg/mL). The NCD-based aptasensor was demonstrated to be highly selective even in the presence of a large excess of IgG. In addition, the aptasensor provided reproducible signals during six regeneration cycles. The impedimetric aptasensor was successfully tested on human serum samples, which opens up the potential of using EIS for direct and label-free detection of IgE levels in blood serum. 相似文献
86.
G Schieren O Janssen G M H?nsch 《Journal of immunology (Baltimore, Md. : 1950)》1992,148(10):3183-3188
C8 binding protein (C8bp) is a 65-kDa membrane glycoprotein that inhibits complement-mediated lysis by homologous C5b-9. C8bp was first identified on human erythrocytes, but could also be detected on peripheral blood cells, platelets, glomerular cells and synovial fibroblasts. Lack of C8bp as seen in patients with paroxysmal nocturnal hemoglobinuria type III results in enhanced susceptibility of the cells toward C5b-9. We studied C8bp expression on the promonocytic cell line U937. In addition to the membrane-bound C8bp, a cytoplasmic form of C8bp could also be identified by immunofluorescence, blotting, and precipitation. Stimulation of the cells with IL-1 beta, endotoxin, IFN-gamma, or phorbol ester increased C8bp surface expression. Because cycloheximide did not inhibit enhanced surface expression, it was most probably mobilized from cytoplasmic reservoirs. Thus, resistance of nuclear cells to complement attack seems to be based on two events: 1) the removal of the C5b-9 complex from the membrane; and 2) expression of regulatory surface proteins such as C8bp, which inhibit C5b-9-mediated lysis. We propose that the C8bp mobilization by cytokines might provide an additional protection against complement attack by its known interference with the C5b-9 assembly. 相似文献
87.
Chronic Helicobacter pylori Infection Does Not Significantly Alter the Microbiota of the Murine Stomach 总被引:1,自引:0,他引:1 下载免费PDF全文
Mai Ping Tan Maria Kaparakis Maja Galic John Pedersen Martin Pearse Odilia L. C. Wijburg Peter H. Janssen Richard A. Strugnell 《Applied microbiology》2007,73(3):1010-1013
We examined the impact of Helicobacter pylori infection on the murine gastric microbiota by culture and terminal-restriction fragment length polymorphism and found that neither acute nor chronic H. pylori infection substantially affected the gastric microbial composition. Interestingly, the total H. pylori burden detected by real-time PCR was significantly higher than that revealed by viable counts, suggesting that the antigenic load sustaining H. pylori-induced gastritis could be considerably higher than previously believed. 相似文献
88.
Jan M. Baert Nico Eisenhauer Colin R. Janssen Frederik De Laender 《Ecology letters》2018,21(8):1191-1199
Understanding how biodiversity (B) affects ecosystem functioning (EF) is essential for assessing the consequences of ongoing biodiversity changes. An increasing number of studies, however, show that environmental conditions affect the shape of BEF relationships. Here, we first use a game‐theoretic community model to reveal that a unimodal response of the BEF slope can be expected along environmental stress gradients, but also how the ecological mechanisms underlying this response may vary depending on how stress affects species interactions. Next, we analysed a global dataset of 44 experiments that crossed biodiversity with environmental conditions. Confirming our main model prediction, the effect of biodiversity on ecosystem functioning tends to be greater at intermediate levels of environmental stress, but varies among studies corresponding to differences in stress‐effects on species interactions. Together, these results suggest that increases in stress from ongoing global environmental changes may amplify the consequences of biodiversity changes. 相似文献
89.
At two sites, one with a 4-year-old (4-Y) secondary vegetation and the other with a 20-year-old (20-Y) vegetation, the influence of burning slashed vegetation on crop performance was studied during three seasons. In the first season after clearing, also the influence on weed growth was studied. At both sites, burning significantly decreased the number of weed seedlings. The lowest number of seedlings was found on the burnt plots of the 20-Y site. Burning increased yield and nutrient uptake significantly in the first and second season after clearing. In the third season after burning, only at the 4-Y site a significantly higher yield and nutrient uptake were found. At the 20-Y site the effect had disappeared. Calculations of efficiency of utilization of absorbed N, P and K indicated that P was the least available nutrient, also after burning. At both sites three consecutive crops absorbed approximately 40% of P applied in ash, while the cumulative recovery of K was at least 36% at the 4-Y site and at least 59% at the 20-Y site. On non-burnt plots, yields were not lower in the third season than in the first season after clearing, thus indicating that the inherent soil fertility did not decrease. Hence, yield decline on the burnt plots could be ascribed to ash depletion. It was concluded that in the local shifting cultivation system, the combination of ash depletion and infestation of weeds are the main reasons for abandoning the fields. 相似文献
90.
Heather A. Rupp Thomas W. James Ellen D. Ketterson Dale R. Sengelaub Erick Janssen Julia R. Heiman 《Evolution and human behavior》2009,30(1):1-10
Women's preference for masculine faces varies with hormonal state, sociosexuality, and relationship status, but the underlying mechanisms are poorly understood. We hypothesized that hormones and psychosexual factors (sociosexuality, sexual inhibition/excitation) mediate the perception and evaluation of male faces thereby influencing women's preferences. We used functional magnetic resonance imaging to measure brain activity in 12 women as they evaluated pictures of male faces (half 30% masculinized, half 30% feminized). Participants were heterosexual women, age 23–28 years, who were not in a committed relationship and not using hormonal contraception. Women were tested during both the follicular and luteal phase of their menstrual cycle. We found five brain regions related to face and risk processing that responded more to the masculinized than to the feminized faces, including the superior temporal gyrus, precentral gyrus, posterior cingulate cortex, inferior parietal lobule, and anterior cingulate cortex. Increased activation in the anterior cingulate cortex, specifically, may indicate that women perceive masculinized faces to be both more risky and more attractive. We did not see any areas that were more strongly activated by feminized faces. Levels of activation were influenced by hormonal and psychosexual factors. The patterns of hormonally and psychosexually mediated neural activation observed may offer insight into the cognitive processes underlying women's partner preferences. 相似文献