全文获取类型
收费全文 | 20217篇 |
免费 | 1675篇 |
国内免费 | 5篇 |
专业分类
21897篇 |
出版年
2023年 | 88篇 |
2022年 | 236篇 |
2021年 | 436篇 |
2020年 | 234篇 |
2019年 | 307篇 |
2018年 | 424篇 |
2017年 | 355篇 |
2016年 | 639篇 |
2015年 | 1034篇 |
2014年 | 1175篇 |
2013年 | 1414篇 |
2012年 | 1754篇 |
2011年 | 1666篇 |
2010年 | 1064篇 |
2009年 | 943篇 |
2008年 | 1273篇 |
2007年 | 1303篇 |
2006年 | 1111篇 |
2005年 | 1070篇 |
2004年 | 1039篇 |
2003年 | 945篇 |
2002年 | 901篇 |
2001年 | 208篇 |
2000年 | 151篇 |
1999年 | 159篇 |
1998年 | 236篇 |
1997年 | 153篇 |
1996年 | 142篇 |
1995年 | 128篇 |
1994年 | 114篇 |
1993年 | 102篇 |
1992年 | 85篇 |
1991年 | 68篇 |
1990年 | 68篇 |
1989年 | 63篇 |
1988年 | 55篇 |
1987年 | 65篇 |
1986年 | 48篇 |
1985年 | 51篇 |
1984年 | 47篇 |
1983年 | 64篇 |
1982年 | 42篇 |
1981年 | 33篇 |
1980年 | 38篇 |
1979年 | 30篇 |
1978年 | 45篇 |
1977年 | 35篇 |
1976年 | 33篇 |
1975年 | 25篇 |
1974年 | 27篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
71.
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels 总被引:13,自引:0,他引:13
Fischer C Jonckx B Mazzone M Zacchigna S Loges S Pattarini L Chorianopoulos E Liesenborghs L Koch M De Mol M Autiero M Wyns S Plaisance S Moons L van Rooijen N Giacca M Stassen JM Dewerchin M Collen D Carmeliet P 《Cell》2007,131(3):463-475
Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment. 相似文献
72.
Thireau J Poisson D Zhang BL Gillet L Le Pécheur M Andres C London J Babuty D 《Free radical biology & medicine》2008,45(4):396-403
Cu/Zn superoxide dismutase (SOD1) is implicated in various pathological conditions including Down's syndrome, neurodegenerative diseases, and afflictions of the autonomic nervous system (ANS). To assess the SOD1 contribution to ANS dysfunction, especially its influence on cardiac regulation, we studied the heart rate variability (HRV) and cardiac arrhythmias in conscious 12-month-old male and female transgenic mice for the human SOD1 gene (TghSOD1). TghSOD1 mice presented heart rate reduction as compared with control FVB/N individuals. All HRV parameters reflecting parasympathetic activity were increased in TghSOD1. Pharmacological studies confirmed that the parasympathetic tone was exacerbated and the sympathetic pathway was functional in TghSOD1 mice. A high frequency of atrioventricular block and premature ventricular contractions was observed in TghSOD1. By biochemical assays we found that SOD1 activities were multiplied by 9 and 4 respectively in the heart and brainstem of transgenic mice. A twofold decrease in cholinesterase activity was observed in the heart but not in the brainstem. We demonstrate that SOD1 overexpression induces an ANS dysfunction by an exacerbated vagal tone that may be related to impaired cardiac activity of the cholinesterases and may explain the high occurrence of arrhythmias. 相似文献
73.
74.
Mie Agermose Gram Hanne-Dorthe Emborg Astrid Blicher Schelde Nikolaj Ulrik Friis Katrine Finderup Nielsen Ida Rask Moustsen-Helms Rebecca Legarth Janni Uyen Hoa Lam Manon Chaine Aisha Zahoor Malik Morten Rasmussen Jannik Fonager Raphael Niklaus Sieber Marc Stegger Steen Ethelberg Palle Valentiner-Branth Christian Holm Hansen 《PLoS medicine》2022,19(9)
BackgroundThe continued occurrence of more contagious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants and waning immunity over time require ongoing reevaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in 2 age groups (12 to 59 and 60 years or above) of 2 or 3 vaccine doses (BNT162b2 mRNA or mRNA-1273) by time since vaccination against SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) hospitalization in an Alpha-, Delta-, or Omicron-dominated period.Methods and findingsA Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha, Delta, or Omicron variant. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all previously uninfected residents in Denmark aged 12 years or above (18 years or above for the analysis of 3 doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021), and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated (1-hazard ratio∙100) using Cox proportional hazard regression models with underlying calendar time and adjustments for age, sex, comorbidity, and geographical region. Vaccination status was included as a time-varying exposure. In the oldest age group, VE against infection after 2 doses was 90.7% (95% CI: 88.2; 92.7) for the Alpha variant, 82.3% (95% CI: 75.5; 87.2) for the Delta variant, and 39.9% (95% CI: 26.3; 50.9) for the Omicron variant 14 to 30 days since vaccination. The VE waned over time and was 73.2% (Alpha, 95% CI: 57.1; 83.3), 50.0% (Delta, 95% CI: 46.7; 53.0), and 4.4% (Omicron, 95% CI: −0.1; 8.7) >120 days since vaccination. Higher estimates were observed after the third dose with VE estimates against infection of 86.1% (Delta, 95% CI: 83.3; 88.4) and 57.7% (Omicron, 95% CI: 55.9; 59.5) 14 to 30 days since vaccination. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 98.1% or above for the Alpha and Delta variants. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 95.5% or above for the Omicron variant. The main limitation of this study is the nonrandomized study design including potential differences between the unvaccinated (reference group) and vaccinated individuals.ConclusionsTwo vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha and Delta variants with protection, notably against infection, waning over time. Two vaccine doses provided only limited and short-lived protection against SARS-CoV-2 infection with Omicron. However, the protection against COVID-19 hospitalization following Omicron SARS-CoV-2 infection was higher. The third vaccine dose substantially increased the level and duration of protection against infection with the Omicron variant and provided a high level of sustained protection against COVID-19 hospitalization among the +60-year-olds.Mie Agermose Gram and colleagues estimate vaccine effectiveness against infection and COVID-19 hospitalization with the Alpha, Delta or Omicron variant in Denmark. 相似文献
75.
Razieh Karimi Aghcheh Zoltán Németh Lea Atanasova Erzsébet Fekete Melinda Paholcsek Erzsébet Sándor Benigno Aquino Irina S. Druzhinina Levente Karaffa Christian P. Kubicek 《PloS one》2014,9(11)
Trichoderma reesei is the industrial producer of cellulases and hemicellulases for biorefinery processes. Their expression is obligatorily dependent on the function of the protein methyltransferase LAE1. The Aspergillus nidulans orthologue of LAE1 - LaeA - is part of the VELVET protein complex consisting of LaeA, VeA and VelB that regulates secondary metabolism and sexual as well as asexual reproduction. Here we have therefore investigated the function of VEL1, the T. reesei orthologue of A. nidulans VeA. Deletion of the T. reesei vel1 locus causes a complete and light-independent loss of conidiation, and impairs formation of perithecia. Deletion of vel1 also alters hyphal morphology towards hyperbranching and formation of thicker filaments, and with consequently reduced growth rates. Growth on lactose as a sole carbon source, however, is even more strongly reduced and growth on cellulose as a sole carbon source eliminated. Consistent with these findings, deletion of vel1 completely impaired the expression of cellulases, xylanases and the cellulase regulator XYR1 on lactose as a cellulase inducing carbon source, but also in resting mycelia with sophorose as inducer. Our data show that in T. reesei VEL1 controls sexual and asexual development, and this effect is independent of light. VEL1 is also essential for cellulase gene expression, which is consistent with the assumption that their regulation by LAE1 occurs by the VELVET complex. 相似文献
76.
Caroline Truntzer Catherine Mercier Jacques Estève Christian Gautier Pascal Roy 《BMC bioinformatics》2007,8(1):90
Background
With the advance of microarray technology, several methods for gene classification and prognosis have been already designed. However, under various denominations, some of these methods have similar approaches. This study evaluates the influence of gene expression variance structure on the performance of methods that describe the relationship between gene expression levels and a given phenotype through projection of data onto discriminant axes. 相似文献77.
Effects of grass species and grass growth on atmospheric nitrogen deposition to a bog ecosystem surrounded by intensive agricultural land use 下载免费PDF全文
Miriam Hurkuck Christian Brümmer Karsten Mohr Oliver Spott Reinhard Well Heinz Flessa Werner L. Kutsch 《Ecology and evolution》2015,5(13):2556-2571
We applied a 15N dilution technique called “Integrated Total Nitrogen Input” (ITNI) to quantify annual atmospheric N input into a peatland surrounded by intensive agricultural practices over a 2-year period. Grass species and grass growth effects on atmospheric N deposition were investigated using Lolium multiflorum and Eriophorum vaginatum and different levels of added N resulting in increased biomass production. Plant biomass production was positively correlated with atmospheric N uptake (up to 102.7 mg N pot−1) when using Lolium multiflorum. In contrast, atmospheric N deposition to Eriophorum vaginatum did not show a clear dependency to produced biomass and ranged from 81.9 to 138.2 mg N pot−1. Both species revealed a relationship between atmospheric N input and total biomass N contents. Airborne N deposition varied from about 24 to 55 kg N ha−1 yr−1. Partitioning of airborne N within the monitor system differed such that most of the deposited N was found in roots of Eriophorum vaginatum while the highest share was allocated in aboveground biomass of Lolium multiflorum. Compared to other approaches determining atmospheric N deposition, ITNI showed highest airborne N input and an up to fivefold exceedance of the ecosystem-specific critical load of 5–10 kg N ha−1 yr−1. 相似文献
78.
79.
Veron P Leborgne C Monteilhet V Boutin S Martin S Moullier P Masurier C 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(12):6418-6424
A major impediment to the use of adeno-associated virus (AAV)-mediated gene delivery to muscle in clinical applications is the pre-existing immune responses against the vector. Pre-existing humoral response to different AAV serotypes is now well documented. In contrast, cellular responses to AAV capsid have not been analyzed in a systematic manner, despite the risk of T cell reactivation upon gene transfer. AAV1 has been widely used in humans to target muscle. In this study, we analyzed PBMCs and sera of healthy donors for the presence of AAV1 capsid-specific T cell responses and AAV1 neutralizing factors. Approximately 30% of donors presented AAV1 capsid-specific T cells, mainly effector memory CD8(+) cells. IFN-γ-producing cells were also observed among effector memory CD4(+) cells for two of these donors. Moreover, to our knowledge, this study shows for the first time on a large cohort that there was no correlation between AAV1-specific T cell and humoral responses. Indeed, most donors presenting specific Ig and neutralizing factors were negative for cellular response (and vice versa). These new data raise the question of prescreening patients not only for the humoral response, but also for the cellular response. Clearly, a better understanding of the natural immunology of AAV serotypes will allow us to improve AAV gene therapy and make it an efficient treatment for genetic disease. 相似文献
80.
Nora Wender Jan Hegermann Bettina Brunner Brigitte Nuscher Tim Bartels Armin Giese Klaus Beyer Stefan Eimer Konstanze F Winklhofer Christian Haass 《The EMBO journal》2010,29(20):3571-3589
Aggregation of α‐synuclein (αS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of αS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that αS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, αS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age‐dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous αS. In contrast, siRNA‐mediated downregulation of αS results in elongated mitochondria in cell culture. αS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, αS prevents fusion of differently labelled mitochondrial populations. Thus, αS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of αS is rescued by coexpression of PINK1, parkin or DJ‐1 but not the PD‐associated mutations PINK1 G309D and parkin Δ1–79 or by DJ‐1 C106A. 相似文献