全文获取类型
收费全文 | 583篇 |
免费 | 59篇 |
专业分类
642篇 |
出版年
2023年 | 3篇 |
2022年 | 8篇 |
2021年 | 13篇 |
2020年 | 3篇 |
2019年 | 8篇 |
2018年 | 7篇 |
2017年 | 4篇 |
2016年 | 19篇 |
2015年 | 29篇 |
2014年 | 27篇 |
2013年 | 31篇 |
2012年 | 40篇 |
2011年 | 47篇 |
2010年 | 24篇 |
2009年 | 21篇 |
2008年 | 31篇 |
2007年 | 31篇 |
2006年 | 26篇 |
2005年 | 32篇 |
2004年 | 23篇 |
2003年 | 25篇 |
2002年 | 27篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1999年 | 7篇 |
1998年 | 8篇 |
1997年 | 7篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 10篇 |
1992年 | 6篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 7篇 |
1986年 | 3篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 7篇 |
1977年 | 5篇 |
1976年 | 7篇 |
1975年 | 3篇 |
1974年 | 6篇 |
1973年 | 6篇 |
1968年 | 3篇 |
1965年 | 3篇 |
1964年 | 3篇 |
1961年 | 2篇 |
排序方式: 共有642条查询结果,搜索用时 0 毫秒
111.
Systematic analysis of genome-wide fitness data in yeast reveals novel gene function and drug action
Maureen E Hillenmeyer Elke Ericson Ronald W Davis Corey Nislow Daphne Koller Guri Giaever 《Genome biology》2010,11(3):R30
We systematically analyzed the relationships between gene fitness profiles (co-fitness) and drug inhibition profiles (co-inhibition)
from several hundred chemogenomic screens in yeast. Co-fitness predicted gene functions distinct from those derived from other
assays and identified conditionally dependent protein complexes. Co-inhibitory compounds were weakly correlated by structure
and therapeutic class. We developed an algorithm predicting protein targets of chemical compounds and verified its accuracy
with experimental testing. Fitness data provide a novel, systems-level perspective on the cell. 相似文献
112.
Keertan Dheda Virginia Davids Laura Lenders Teri Roberts Richard Meldau Daphne Ling Laurence Brunet Richard van Zyl Smit Jonathan Peter Clare Green Motasim Badri Leonardo Sechi Surendra Sharma Michael Hoelscher Rodney Dawson Andrew Whitelaw Jonathan Blackburn Madhukar Pai Alimuddin Zumla 《PloS one》2010,5(3)
Background
The accurate diagnosis of TB in HIV-infected patients, particularly with advanced immunosuppression, is difficult. Recent studies indicate that a lipoarabinomannan (LAM) assay (Clearview-TB®-ELISA) may have some utility for the diagnosis of TB in HIV-infected patients; however, the precise subgroup that may benefit from this technology requires clarification. The utility of LAM in sputum samples has, hitherto, not been evaluated.Methods
LAM was measured in sputum and urine samples obtained from 500 consecutively recruited ambulant patients, with suspected TB, from 2 primary care clinics in South Africa. Culture positivity for M. tuberculosis was used as the reference standard for TB diagnosis.Results
Of 440 evaluable patients 120/387 (31%) were HIV-infected. Urine-LAM positivity was associated with HIV positivity (p = 0.007) and test sensitivity, although low, was significantly higher in HIV-infected compared to uninfected patients (21% versus 6%; p<0.001), and also in HIV-infected participants with a CD4 <200 versus >200 cells/mm3 (37% versus 0%; p = 0.003). Urine-LAM remained highly specific in all 3 subgroups (95%–100%). 25% of smear-negative but culture-positive HIV-infected patients with a CD4 <200 cells/mm3 were positive for urine-LAM. Sputum-LAM had good sensitivity (86%) but poor specificity (15%) likely due to test cross-reactivity with several mouth-residing organisms including actinomycetes and nocardia species.Conclusions
These preliminary data indicate that in a high burden primary care setting the diagnostic usefulness of urine-LAM is limited, as a rule-in test, to a specific patient subgroup i.e. smear-negative HIV-infected TB patients with a CD4 count <200 cells/mm3, who would otherwise have required further investigation. However, even in this group sensitivity was modest. Future and adequately powered studies in a primary care setting should now specifically target patients with suspected TB who have advanced HIV infection. 相似文献113.
Dora Romaguera Lars ?ngquist Huaidong Du Marianne Uhre Jakobsen Nita G. Forouhi Jytte Halkj?r Edith J. M. Feskens Daphne L. van der A Giovanna Masala Annika Steffen Domenico Palli Nicholas J. Wareham Kim Overvad Anne Tj?nneland Heiner Boeing Elio Riboli Thorkild I. A. S?rensen 《PloS one》2010,5(7)
Background
Given the recognized health effects of visceral fat, the understanding of how diet can modulate changes in the phenotype “waist circumference for a given body mass index (WCBMI)”, a proxy measure of visceral adiposity, is deemed necessary. Hence, the objective of the present study was to assess the association between dietary factors and prospective changes in visceral adiposity as measured by changes in the phenotype WCBMI.Methods and Findings
We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WCBMI was defined as the residuals of waist circumference regressed on body mass index, and annual change in WCBMI (ΔWCBMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between energy, energy density (ED), macronutrients, alcohol, glycemic index (GI), glycemic load (GL), fibre and ΔWCBMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates. Men and women with higher ED and GI diets showed significant increases in their WCBMI, compared to those with lower ED and GI [1 kcal/g greater ED predicted a ΔWCBMI of 0.09 cm (95% CI 0.05 to 0.13) in men and 0.15 cm (95% CI 0.09 to 0.21) in women; 10 units greater GI predicted a ΔWCBMI of 0.07 cm (95% CI 0.03 to 0.12) in men and 0.06 cm (95% CI 0.03 to 0.10) in women]. Among women, lower fibre intake, higher GL, and higher alcohol consumption also predicted a higher ΔWCBMI.Conclusions
Results of this study suggest that a diet with low GI and ED may prevent visceral adiposity, defined as the prospective changes in WCBMI. Additional effects may be obtained among women of low alcohol, low GL, and high fibre intake. 相似文献114.
115.
116.
117.
de Beer VJ Bender SB Taverne YJ Gao F Duncker DJ Laughlin MH Merkus D 《American journal of physiology. Heart and circulatory physiology》2011,300(5):H1950-H1959
We previously demonstrated that endothelin (ET)-mediated coronary vasoconstriction wanes with increasing exercise intensity via a nitric oxide- and prostacyclin-dependent mechanism (Ref. 23). Therefore, we hypothesized that the waning of ET coronary vasoconstriction during exercise is the result of decreased production of ET and/or decreased ET receptor sensitivity. We investigated coronary ET receptor sensitivity using intravenous infusion of ET and coronary ET production using intravenous infusion of the ET precursor Big ET, at rest and during continuous treadmill exercise at 3 km/h in 16 chronically instrumented swine. In the systemic vasculature, Big ET and ET induced similar changes in hemodynamic parameters at rest and during continuous exercise at 3 km/h, indicating that exercise does not alter ET production or receptor sensitivity in the systemic vasculature. In the coronary vasculature, infusion of ET resulted in similar dose-dependent decreases in coronary blood flow and coronary venous oxygen tension and saturation at rest and during exercise. In contrast, administration of Big ET resulted in dose-dependent decreases in coronary blood flow, as well as coronary venous oxygen tension and saturation at rest. These effects of Big ET were significantly reduced during exercise. Altogether, our data indicate that continuous exercise at 3 km/h attenuates ET-mediated coronary vasoconstriction through reduced production of ET from Big ET rather than through reduced ET sensitivity of the coronary vasculature. The decreased ET production during exercise likely contributes to metabolic coronary vasodilation. 相似文献
118.
van Gent M Griffin BD Berkhoff EG van Leeuwen D Boer IG Buisson M Hartgers FC Burmeister WP Wiertz EJ Ressing ME 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(3):1694-1702
Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV(-) and EBV(+) human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses. 相似文献
119.
Anne D. van Diepeningen Dani?l J. P. Engelmoer Carole H. Sellem Daphne H. E. W. Huberts S. Marijke Slakhorst Annie Sainsard-Chanet Bas J. Zwaan Rolf F. Hoekstra Alfons J. M. Debets 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1646)
Autophagy is a well-conserved catabolic process, involving the degradation of a cell''s own components through the lysosomal/vacuolar machinery. Autophagy is typically induced by nutrient starvation and has a role in nutrient recycling, cellular differentiation, degradation and programmed cell death. Another common response in eukaryotes is the extension of lifespan through dietary restriction (DR). We studied a link between DR and autophagy in the filamentous fungus Podospora anserina, a multicellular model organism for ageing studies and mitochondrial deterioration. While both carbon and nitrogen restriction extends lifespan in P. anserina, the size of the effect varied with the amount and type of restricted nutrient. Natural genetic variation for the DR response exists. Whereas a switch to carbon restriction up to halfway through the lifetime resulted in extreme lifespan extension for wild-type P. anserina, all autophagy-deficient strains had a shorter time window in which ageing could be delayed by DR. Under nitrogen limitation, only PaAtg1 and PaAtg8 mediate the effect of lifespan extension; the other autophagy-deficient mutants PaPspA and PaUth1 had a similar response as wild-type. Our results thus show that the ageing process impinges on the DR response and that this at least in part involves the genetic regulation of autophagy. 相似文献
120.
Flowering plants have evolved various strategies for avoiding self-pollen to drive genetic diversity. These strategies include spatially separated sexual organs (herkogamy), timing differences between male pollen release and female pistil receptivity (dichogamy), and self-pollen rejection. Within the Brassicaceae, these outcrossing systems are the evolutionary default state, and many species display these traits, including Arabidopsis lyrata. In contrast to A. lyrata, closely related Arabidopsis thaliana has lost these self-pollen traits and thus represents an excellent system to test genes for reconstructing these evolutionary traits. We previously demonstrated that the ARC1 E3 ligase is required for self-incompatibility in two diverse Brassicaceae species, Brassica napus and A. lyrata, and is frequently deleted in self-compatible species, including A. thaliana. In this study, we examined ARC1’s requirement for reconstituting self-incompatibility in A. thaliana and uncovered an important role for ARC1 in promoting a strong and stable pollen rejection response when expressed with two other A. lyrata self-incompatibility factors. Furthermore, we discovered that ARC1 promoted an approach herkogamous phenotype in A. thaliana flowers. Thus, ARC1’s expression resulted in two different A. lyrata traits for self-pollen avoidance and highlights the key role that ARC1 plays in the evolution and retention of outcrossing systems. 相似文献