全文获取类型
收费全文 | 10159篇 |
免费 | 1100篇 |
出版年
2023年 | 80篇 |
2022年 | 58篇 |
2021年 | 343篇 |
2020年 | 203篇 |
2019年 | 253篇 |
2018年 | 293篇 |
2017年 | 250篇 |
2016年 | 388篇 |
2015年 | 612篇 |
2014年 | 597篇 |
2013年 | 775篇 |
2012年 | 865篇 |
2011年 | 797篇 |
2010年 | 520篇 |
2009年 | 402篇 |
2008年 | 563篇 |
2007年 | 499篇 |
2006年 | 454篇 |
2005年 | 385篇 |
2004年 | 359篇 |
2003年 | 327篇 |
2002年 | 296篇 |
2001年 | 121篇 |
2000年 | 91篇 |
1999年 | 97篇 |
1998年 | 96篇 |
1997年 | 73篇 |
1996年 | 53篇 |
1995年 | 57篇 |
1994年 | 52篇 |
1993年 | 58篇 |
1992年 | 61篇 |
1991年 | 56篇 |
1990年 | 72篇 |
1989年 | 52篇 |
1988年 | 60篇 |
1987年 | 65篇 |
1986年 | 76篇 |
1985年 | 57篇 |
1984年 | 60篇 |
1983年 | 55篇 |
1982年 | 50篇 |
1981年 | 37篇 |
1980年 | 36篇 |
1979年 | 54篇 |
1978年 | 42篇 |
1977年 | 36篇 |
1976年 | 38篇 |
1974年 | 28篇 |
1972年 | 24篇 |
排序方式: 共有10000条查询结果,搜索用时 203 毫秒
991.
Paris D Bachmeier C Patel N Quadros A Volmar CH Laporte V Ganey J Beaulieu-Abdelahad D Ait-Ghezala G Crawford F Mullan MJ 《Molecular medicine (Cambridge, Mass.)》2011,17(3-4):149-162
Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro, whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB. 相似文献
992.
Gambarino S Costa C Astegiano S Piasentin EA Segoloni GP Cavallo R Bergallo M 《Molecular biotechnology》2011,49(2):151-158
Polyomavirus BK latently persist in different sites, including the renourinary tract, and may reactivate causing nephropathy
in renal transplant recipients or hemorrhagic cystitis in bone marrow recipients. Based on the sequence of the VP1 gene, four
genotypes have been described, corresponding to the four serologically differentiated subtypes I–IV, with different prevalence
and geographic distribution. In this study, the development and clinical validation of four different Real-Time PCR assays
for the detection and discrimination of BKV genotypes as a substitute of DNA sequencing are described. 379 BK VP1 sequences,
belonging to the main four genotypes, were aligned and “hot spots” of mutation specific for all the strains or isolates were
identified. Specific primers and probes for the detection and discrimination of each genotype by four Real-Time PCR assays
were designed and technically validated. Subsequently, the four Real-Time PCR assays were used to test 20 BK-positive urine
specimens from renal transplant patients, and evidenced a prevalence of BK genotype I, as previously reported in Europe. Results
were confirmed by sequencing. The availability of a rapid and simple genotyping method could be useful for the evaluation
of BK genotypes prevalence and studies on the impact of the infecting genotype on viral biological behavior, pathogenic role,
and immune evasion strategies. 相似文献
993.
As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment. 相似文献
994.
Dominance of warm‐season grasses modulates tallgrass prairie ecosystem structure and function. Reintroduction of these grasses is a widespread practice to conserve soil and restore prairie ecosystems degraded from human land use changes. Seed sources for reintroduction of dominant prairie grass species include local (non‐cultivar) and selected (cultivar) populations. The primary objective of this study was to quantify whether intraspecific variation in developing root systems exists between population sources (non‐cultivar and cultivar) of two dominant grasses (Sorghastrum nutans and Schizachyrium scoparium) widely used in restoration. Non‐cultivar and cultivar grass seedlings of both species were isolated in an experimental prairie restoration at the Konza Prairie Biological Station. We measured above‐ and belowground net primary production (ANPP and BNPP, respectively), root architecture, and root tissue quality, as well as soil moisture and plant available inorganic nitrogen (N) in soil associated with each species and source at the end of the first growing season. Cultivars had greater root length, surface area, and volume than non‐cultivars. Available inorganic N and soil moisture were present in lower amounts in soil proximal to roots of cultivars than non‐cultivars. Additionally, soil NO3–N was negatively correlated with root volume in S. nutans cultivars. While cultivars had greater BNPP than non‐cultivars, this was not reflected aboveground root structure, as ANPP was similar between cultivars and non‐cultivars. Intraspecific variation in belowground root structure and function exists between cultivar and non‐cultivar sources of the dominant prairie grasses during initial reestablishment of tallgrass prairie. Population source selection should be considered in setting restoration goals and objectives. 相似文献
995.
Ichi S Boshnjaku V Shen YW Mania-Farnell B Ahlgren S Sapru S Mansukhani N McLone DG Tomita T Mayanil CS 《Molecular biology of the cell》2011,22(4):503-512
Pax3 plays a role in regulating Hes1 and Neurog2 activity and thereby stem cell maintenance and neurogenesis. A mechanism for Pax3 regulation of these two opposing events, during caudal neural tube development, is examined in this study. Pax3 acetylation on C-terminal lysine residues K437 and K475 may be critical for proper regulation of Hes1 and Neurog2. Removal of these lysine residues increased Hes1 but decreased Neurog2 promoter activity. SIRT1 deacetylase may be a key component in regulating Pax3 acetylation. Chromatin immunoprecipitation assays showed that SIRT1 is associated with Hes1 and Neurog2 promoters during murine embryonic caudal neural tube development at E9.5, but not at E12.5. Overexpression of SIRT1 decreased Pax3 acetylation, Neurog2 and Brn3a positive staining. Conversely, siRNA-mediated silencing of SIRT1 increased these factors. These studies suggest that Pax3 acetylation results in decreased Hes1 and increased Neurog2 activity, thereby promoting sensory neuron differentiation. 相似文献
996.
Keng CT Akerström S Leung CS Poon LL Peiris JS Mirazimi A Tan YJ 《Microbes and infection / Institut Pasteur》2011,13(2):179-188
The severe acute respiratory syndrome coronavirus (SARS-CoV) 8b protein, which is not expressed by other known coronaviruses, can down-regulate the envelope (E) protein via a proteasome-dependent pathway. Here, we showed that the down-regulation of E is not dependent on the lysine residues on 8b and the reduction of polyubiquitination of E mutants is not correlated with their down-regulation by 8b, suggesting an ubiquitin-independent proteasome pathway is involved. A time-course study revealed that 8b was expressed at late-stages of SARS-CoV infection. By using Vero E6 cells stably expressing green fluorescence protein-tagged 8b, ectopic expression of 8b was shown to significantly reduce the production of progeny virus and down-regulate E expression. Taken together, these results suggest that 8b negatively modulates virus replication by down-regulating E via an ubiquitin-independent proteasome pathway. 相似文献
997.
998.
Khouri C Dittrich A Sackett SD Denecke B Trautwein C Schaper F 《Biological chemistry》2011,392(12):1123-1134
Inflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target gene Tfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response. 相似文献
999.
The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function 总被引:1,自引:0,他引:1
Podosomes and invadopodia are actin-based dynamic protrusions of the plasma membrane of metazoan cells that represent sites of attachment to - and degradation of - the extracellular matrix. The key proteins in these structures include the actin regulators cortactin and neural Wiskott-Aldrich syndrome protein (N-WASP), the adaptor proteins Tyr kinase substrate with four SH3 domains (TKS4) and Tyr kinase substrate with five SH3 domains (TKS5), and the metalloprotease membrane type 1 matrix metalloprotease (MT1MMP; also known as MMP14). Many cell types can produce these structures, including invasive cancer cells, vascular smooth muscle and endothelial cells, and immune cells such as macrophages and dendritic cells. Recently, progress has been made in our understanding of the regulatory and functional aspects of podosome and invadopodium biology and their role in human disease. 相似文献
1000.
Berthoumieux S Brilli M de Jong H Kahn D Cinquemani E 《Bioinformatics (Oxford, England)》2011,27(13):i186-i195
MOTIVATION: High-throughput measurement techniques for metabolism and gene expression provide a wealth of information for the identification of metabolic network models. Yet, missing observations scattered over the dataset restrict the number of effectively available datapoints and make classical regression techniques inaccurate or inapplicable. Thorough exploitation of the data by identification techniques that explicitly cope with missing observations is therefore of major importance. RESULTS: We develop a maximum-likelihood approach for the estimation of unknown parameters of metabolic network models that relies on the integration of statistical priors to compensate for the missing data. In the context of the linlog metabolic modeling framework, we implement the identification method by an Expectation-Maximization (EM) algorithm and by a simpler direct numerical optimization method. We evaluate performance of our methods by comparison to existing approaches, and show that our EM method provides the best results over a variety of simulated scenarios. We then apply the EM algorithm to a real problem, the identification of a model for the Escherichia coli central carbon metabolism, based on challenging experimental data from the literature. This leads to promising results and allows us to highlight critical identification issues. 相似文献