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191.
Bins AD Wolkers MC van den Boom MD Haanen JB Schumacher TN 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(4):2126-2133
The factors that determine the immunogenicity of Ags encoded by viral vaccines or DNA vaccines in vivo are largely unknown. Depending on whether T cell induction occurs via direct presentation of vaccine-encoded epitopes or via one of the different proposed pathways for Ag cross-presentation, the effect of intracellular Ag stability on immunogenicity may possibly vary. However, the influence of Ag stability on CD8(+) T cell induction has not been addressed in clinically relevant vaccine models, nor has the accumulation of vaccine-encoded Ags been monitored in vivo. In this study, we describe the relationship between in vivo Ag stability and immunogenicity of DNA vaccine-encoded Ags. We show that in vivo accumulation of DNA vaccine-encoded Ags is required for the efficient induction of CD8(+) T cell responses. These data suggest that many of the currently used transgene designs in DNA vaccination trials may be suboptimal, and that one should either use pathogen-derived or tumor-associated Ags that are intrinsically stable, or should increase the stability of vaccine-encoded Ags by genetic engineering. 相似文献
192.
193.
Molecular and structural bases for the antigenicity of VP2 of infectious bursal disease virus 总被引:1,自引:0,他引:1 下载免费PDF全文
Letzel T Coulibaly F Rey FA Delmas B Jagt E van Loon AA Mundt E 《Journal of virology》2007,81(23):12827-12835
Infectious bursal disease virus (IBDV), a member of the family Birnaviridae, is responsible for a highly contagious and economically important disease causing immunosuppression in chickens. IBDV variants isolated in the United States exhibit antigenic drift affecting neutralizing epitopes in the capsid protein VP2. To understand antigenic determinants of the virus, we have used a reverse-genetics approach to introduce selected amino acid changes-individually or in combination-into the VP2 gene of the classical IBDV strain D78. We thus generated a total of 42 mutants with changes in 8 amino acids selected by sequence comparison and their locations on loops P(BC) and P(HI) at the tip of the VP2 spikes, as shown by the crystal structure of the virion. The antibody reactivities of the mutants generated were assessed using a panel of five monoclonal antibodies (MAbs). Our results show that a few amino acids of the projecting domain of VP2 control the reactivity pattern. Indeed, the binding of four out of the five MAbs analyzed here is affected by mutations in these loops. Furthermore, their importance is highlighted by the fact that some of the engineered mutants display identical reactivity patterns but have different growth phenotypes. Finally, this analysis shows that a new field strain isolated from a chicken flock in Belgium (Bel-IBDV) represents an IBDV variant with a hitherto unobserved antigenic profile, involving one change (P222S) in the P(BC) loop. Overall, our data provide important new insights for devising efficient vaccines that protect against circulating IBDV strains. 相似文献
194.
Toni Giorgino Davide Mattioni Amal Hassan Mario Milani Eloise Mastrangelo Alberto Barbiroli Adriaan Verhelle Jan Gettemans Maria Monica Barzago Luisa Diomede Matteo de Rosa 《生物化学与生物物理学报:疾病的分子基础》2019,1865(3):648-660
AGel amyloidosis, formerly known as familial amyloidosis of the Finnish-type, is caused by pathological aggregation of proteolytic fragments of plasma gelsolin. So far, four mutations in the gelsolin gene have been reported as responsible for the disease. Although D187N is the first identified variant and the best characterized, its structure has been hitherto elusive. Exploiting a recently-developed nanobody targeting gelsolin, we were able to stabilize the G2 domain of the D187N protein and obtained, for the first time, its high-resolution crystal structure. In the nanobody-stabilized conformation, the main effect of the D187N substitution is the impairment of the calcium binding capability, leading to a destabilization of the C-terminal tail of G2. However, molecular dynamics simulations show that in the absence of the nanobody, D187N-mutated G2 further misfolds, ultimately exposing its hydrophobic core and the furin cleavage site. The nanobody's protective effect is based on the enhancement of the thermodynamic stability of different G2 mutants (D187N, G167R and N184K). In particular, the nanobody reduces the flexibility of dynamic stretches, and most notably decreases the conformational entropy of the C-terminal tail, otherwise stabilized by the presence of the Ca2+ ion. A Caenorhabditis elegans-based assay was also applied to quantify the proteotoxic potential of the mutants and determine whether nanobody stabilization translates into a biologically relevant effect. Successful protection from G2 toxicity in vivo points to the use of C. elegans as a tool for investigating the mechanisms underlying AGel amyloidosis and rapidly screen new therapeutics. 相似文献
195.
Jelmer J. Nijp Arnaud J.A.M. Temme George A.K. van Voorn Lammert Kooistra Geerten M. Hengeveld Merel B. Soons Adriaan J. Teuling Jakob Wallinga 《Global Change Biology》2019,25(6):1905-1921
Prediction of ecosystem response to global environmental change is a pressing scientific challenge of major societal relevance. Many ecosystems display nonlinear responses to environmental change, and may even undergo practically irreversible ‘regime shifts’ that initiate ecosystem collapse. Recently, early warning signals based on spatiotemporal metrics have been proposed for the identification of impending regime shifts. The rapidly increasing availability of remotely sensed data provides excellent opportunities to apply such model‐based spatial early warning signals in the real world, to assess ecosystem resilience and identify impending regime shifts induced by global change. Such information would allow land‐managers and policy makers to interfere and avoid catastrophic shifts, but also to induce regime shifts that move ecosystems to a desired state. Here, we show that the application of spatial early warning signals in real‐world landscapes presents unique and unexpected challenges, and may result in misleading conclusions when employed without careful consideration of the spatial data and processes at hand. We identify key practical and theoretical issues and provide guidelines for applying spatial early warning signals in heterogeneous, real‐world landscapes based on literature review and examples from real‐world data. Major identified issues include (1) spatial heterogeneity in real‐world landscapes may enhance reversibility of regime shifts and boost landscape‐level resilience to environmental change (2) ecosystem states are often difficult to define, while these definitions have great impact on spatial early warning signals and (3) spatial environmental variability and socio‐economic factors may affect spatial patterns, spatial early warning signals and associated regime shift predictions. We propose a novel framework, shifting from an ecosystem perspective towards a landscape approach. The framework can be used to identify conditions under which resilience assessment with spatial remotely sensed data may be successful, to support well‐informed application of spatial early warning signals, and to improve predictions of ecosystem responses to global environmental change. 相似文献
196.
Projected changes in wind assistance under climate change for nocturnally migrating bird populations
Frank A. La Sorte Kyle G. Horton Cecilia Nilsson Adriaan M. Dokter 《Global Change Biology》2019,25(2):589-601
Current climate models and observations indicate that atmospheric circulation is being affected by global climate change. To assess how these changes may affect nocturnally migrating bird populations, we need to determine how current patterns of wind assistance at migration altitudes will be enhanced or reduced under future atmospheric conditions. Here, we use information compiled from 143 weather surveillance radars stations within the contiguous United States to estimate the daily altitude, density, and direction of nocturnal migration during the spring and autumn. We intersected this information with wind projections to estimate how wind assistance is expected to change during this century at current migration altitudes. The prevailing westerlies at midlatitudes are projected to increase in strength during spring migration and decrease in strength to a lesser degree during autumn migration. Southerly winds will increase in strength across the continent during both spring and autumn migration, with the strongest gains occurring in the center of the continent. Wind assistance is projected to increase across the central (0.44 m/s; 10.1%) and eastern portions of the continent (0.32 m/s; 9.6%) during spring migration, and wind assistance is projected to decrease within the central (0.32 m/s; 19.3%) and eastern portions of the continent (0.17 m/s; 6.6%) during autumn migration. Thus, across a broad portion of the continent where migration intensity is greatest, the efficiency of nocturnal migration is projected to increase in the spring and decrease in the autumn, potentially affecting time and energy expenditures for many migratory bird species. These findings highlight the importance of placing climate change projections within a relevant ecological context informed through empirical observations, and the need to consider the possibility that climate change may generate both positive and negative implications for natural systems. 相似文献
197.
Bouzo-Lorenzo Monica Stoddart Leigh A. Xia Lizi IJzerman Adriaan P. Heitman Laura H. Briddon Stephen J. Hill Stephen J. 《Purinergic signalling》2019,15(2):139-153
Purinergic Signalling - There is a growing interest in understanding the binding kinetics of compounds that bind to G protein-coupled receptors prior to progressing a lead compound into clinical... 相似文献
198.
Niels Grote Beverborg Niek Verweij IJsbrand T. Klip Haye H. van der Wal Adriaan A. Voors Dirk J. van Veldhuisen Ron T. Gansevoort Stephan J. L. Bakker Pim van der Harst Peter van der Meer 《PloS one》2015,10(4)
Background
Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population.Methods
We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001–2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants.Results
Mean age (± SD) was 53 ± 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8–9.9) IU/L in men and 7.9 (6.0–10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m²) this relation was linear (men) or absent (women) (P < 0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21), more significantly than other erythrocyte parameters.Conclusion
We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin. 相似文献199.
200.