全文获取类型
收费全文 | 28691篇 |
免费 | 2480篇 |
国内免费 | 1388篇 |
专业分类
32559篇 |
出版年
2024年 | 62篇 |
2023年 | 272篇 |
2022年 | 681篇 |
2021年 | 1053篇 |
2020年 | 710篇 |
2019年 | 898篇 |
2018年 | 991篇 |
2017年 | 754篇 |
2016年 | 1164篇 |
2015年 | 1852篇 |
2014年 | 2101篇 |
2013年 | 2166篇 |
2012年 | 2657篇 |
2011年 | 2549篇 |
2010年 | 1495篇 |
2009年 | 1389篇 |
2008年 | 1719篇 |
2007年 | 1590篇 |
2006年 | 1432篇 |
2005年 | 1246篇 |
2004年 | 1188篇 |
2003年 | 1030篇 |
2002年 | 832篇 |
2001年 | 409篇 |
2000年 | 322篇 |
1999年 | 323篇 |
1998年 | 256篇 |
1997年 | 196篇 |
1996年 | 189篇 |
1995年 | 151篇 |
1994年 | 132篇 |
1993年 | 94篇 |
1992年 | 110篇 |
1991年 | 83篇 |
1990年 | 97篇 |
1989年 | 69篇 |
1988年 | 53篇 |
1987年 | 54篇 |
1986年 | 31篇 |
1985年 | 37篇 |
1984年 | 41篇 |
1983年 | 15篇 |
1982年 | 13篇 |
1981年 | 13篇 |
1980年 | 9篇 |
1979年 | 3篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1975年 | 3篇 |
1974年 | 3篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
151.
Antimicrobial peptides (AMPs) have been proposed as a promising new class of antimicrobials despite warnings that therapeutic use could drive the evolution of pathogens resistant to our own immunity peptides. Using experimental evolution, we demonstrate that Staphylococcus aureus rapidly evolved resistance to pexiganan, a drug-candidate for diabetic leg ulcer infections. Evolved resistance was costly in terms of impaired growth rate, but costs-of-resistance were completely ameliorated by compensatory adaptation. Crucially, we show that, in some populations, experimentally evolved resistance to pexiganan provided S. aureus with cross-resistance to human-neutrophil-defensin-1, a key component of the innate immune response to infection. This unintended consequence of therapeutic use could drastically undermine our innate immune system's ability to control and clear microbial infections. Our results therefore highlight grave potential risks of AMP therapies, with implications for their development. 相似文献
152.
153.
iQPR技术处理污水是一项新型尖端的技术,此技术可以成功降低污水乃至受到污染的地下水中的各种污染指标。但是,iQPR技术处理污水尤其是地下水是否存在潜在的生物安全性问题有待于进一步研究。因此,为评估iQPR技术对生物安全性的影响,本研究首先分析了三种不同iQPR法处理水的水质成分;其次系统研究了iQPR水对SD鼠在个体水平、组织水平和病理形态学损伤的研究。研究表明:iQPR处理的水质成分较对照组普通饮用水好,在个体组织水平检测未见异常,尽管其中一组iQPR处理水造成了SD鼠的脾小体增大,但是可能的原因是水处理环节存在微生物污染现象,因此,初步认定此技术未造成SD大鼠的个体损伤。本研究为揭示iQPR处理的水对生物体的安全性评价提供一个理论依据。 相似文献
154.
Katarzyna Kazmierczak Michelle Jones Olga M. Hernandez Danuta Szczesna-Cordary 《Journal of molecular biology》2009,387(3):706-103
To study the regulation of cardiac muscle contraction by the myosin essential light chain (ELC) and the physiological significance of its N-terminal extension, we generated transgenic (Tg) mice by partially replacing the endogenous mouse ventricular ELC with either the human ventricular ELC wild type (Tg-WT) or its 43-amino-acid N-terminal truncation mutant (Tg-Δ43) in the murine hearts. The mutant protein is similar in sequence to the short ELC variant present in skeletal muscle, and the ELC protein distribution in Tg-Δ43 ventricles resembles that of fast skeletal muscle. Cardiac muscle preparations from Tg-Δ43 mice demonstrate reduced force per cross-sectional area of muscle, which is likely caused by a reduced number of force-generating myosin cross-bridges and/or by decreased force per cross-bridge. As the mice grow older, the contractile force per cross-sectional area further decreases in Tg-Δ43 mice and the mutant hearts develop a phenotype of nonpathologic hypertrophy while still maintaining normal cardiac performance. The myocardium of older Tg-Δ43 mice also exhibits reduced myosin content. Our results suggest that the role of the N-terminal ELC extension is to maintain the integrity of myosin and to modulate force generation by decreasing myosin neck region compliance and promoting strong cross-bridge formation and/or by enhancing myosin attachment to actin. 相似文献
155.
156.
在人工气候室内比较研究了灰飞虱和褐飞虱在汕优63和秀水11上的种内和种间密度效应对其主要生物学参数的影响,结果表明两种稻飞虱均存在显著的种内竞争,主要表现为随着密度增加,若虫发育历期延长、若虫羽化率下降、雌成虫寿命缩短、每雌产卵量下降。种内密度效应与稻飞虱种类和寄主品种有显著互作关系,灰飞虱种内竞争较褐飞虱明显,二者在适宜寄主上种内竞争更为明显。同时,两种稻飞虱存在着显著的种间密度效应,主要表现为异种存在时的促进作用,即异种共存时若虫历期缩短、若虫羽化率提高、雌虫寿命延长、每雌产卵量增加。种间密度效应也与稻飞虱种类和寄主品种有显著互作关系,两种共存对灰飞虱的有利作用显著大于对褐飞虱的有利作用,在欠适宜寄主上种间互利效应更为明显。最后,本文对稻飞虱种内和种间密度效应的机制和进化意义进行了讨论。 相似文献
157.
Jeon SB Jin F Kim JI Kim SH Suk K Chae SC Jun JE Park WH Kim IK 《Biochemical and biophysical research communications》2006,343(1):27-33
Agonist and depolarization-induced vascular smooth muscle contractions involve the activation of Rho-kinase pathway. However, there are no reports addressing the question whether this pathway is involved in NaF-induced vascular contractions. We hypothesized that Rho-kinase plays a role in vascular contraction evoked by sodium fluoride in rat aortae. In both physiological salt solution and calcium-free solution with 2 mM EGTA, cumulative addition of NaF increased vascular tension in concentration-dependent manners. Effects of Rho-kinase inhibitor (Y27632) on phosphorylation of myosin light chain (MLC20) and myosin targeting subunit (MYPT1(Thr696)) of myosin light chain phosphatase as well as NaF-induced contractions were determined using isolated tissue and the Western blot experiments. Y27632 inhibited NaF-induced contractions in a concentration-dependent manner. NaF increased phosphorylation of MLC20 and MYPT1(Thr696), which were also inhibited by Y27632. However, MLCK inhibitor (ML-7) or PKC inhibitor (Ro31-8220) did not inhibit the NaF-induced contraction. These results indicate that activation of Rho-kinase and the subsequent phosphorylation of MYPT1(Thr696) play important roles in NaF-induced contraction of rat aortae. 相似文献
158.
During development, axons must integrate directional information encoded by multiple guidance cues and their receptors. Axon guidance receptors, such as UNC-40 (DCC) and SAX-3 (Robo), can function individually or combinatorially with other guidance receptors to regulate downstream effectors. However, little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. Here, we show that UNC-40, SAX-3 and the SYD-1 RhoGAP-like protein function interdependently to regulate the MIG-2 (Rac) GTPase in the HSN axon of C. elegans. We find that SYD-1 mediates an UNC-6 (netrin) independent UNC-40 activity to promote ventral axon guidance. Genetic analysis suggests that SYD-1 function in axon guidance requires both UNC-40 and SAX-3 activity. Moreover, the cytoplasmic domains of UNC-40 and SAX-3 bind to SYD-1 and SYD-1 binds to and negatively regulates the MIG-2 (Rac) GTPase. We also find that the function of SYD-1 in axon guidance is mediated by its phylogenetically conserved C isoform, indicating that the role of SYD-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. Our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector, providing a potential means for the integration of guidance signals. 相似文献
159.
Local and global cerebral blood flow and glucose utilization in the α-galactosidase A knockout mouse model of Fabry disease 总被引:2,自引:0,他引:2
Yoshiaki Itoh Takanori Esaki Michelle Cook Pankaj Qasba † Kazuaki Shimoji § Joseph Alroy ‡ Roscoe O. Brady † Louis Sokoloff David F. Moore† 《Journal of neurochemistry》2001,79(6):1217-1224
Fabry disease is an X-linked lysosomal disorder characterized by deficient alpha-galactosidase A activity and intracellular accumulations of glycosphingolipids, mainly globotriaosylceramide (Gb3). Clinically, patients occasionally present CNS dysfunction. To examine the pathophysiology underlying brain dysfunction, we examined glucose utilization (CMR(glc)) and cerebral blood flow (CBF) globally and locally in 18 brain structures in the alpha-galactosidase A gene knockout mouse. Global CMR(glc) was statistically significantly reduced by 22% in Fabry mice (p < 0.01). All 18 structures showed decreases in local CMR(glc) ranging from 14% to 33%. The decreases in all structures of the diencephalon, caudate-putamen, brain stem, and cerebellar cortex were statistically significant (p < 0.05). Global cerebral blood flow (CBF) and local CBF measured in the same 18 structures were lower in Fabry mice than in control mice, but none statistically significantly. Histological examination of brain revealed no cerebral infarcts but abundant Gb3 deposits in the walls of the cerebral vessels with neuronal deposits localized to the medulla oblongata. These results indicate an impairment in cerebral energy metabolism in the Fabry mice, but one not necessarily due to circulatory insufficiency. 相似文献
160.
Jang Hye Jin Choi Ji Yeon Kim Kangjoon Yong Seung Hyun Kim Yeon Wook Kim Song Yee Kim Eun Young Jung Ji Ye Kang Young Ae Park Moo Suk Kim Young Sam Cho Young-Jae Lee Sang Hoon 《Respiratory research》2021,22(1):1-9
IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism. Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3. IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process. IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis. 相似文献