全文获取类型
收费全文 | 888篇 |
免费 | 92篇 |
专业分类
980篇 |
出版年
2023年 | 6篇 |
2022年 | 26篇 |
2021年 | 27篇 |
2020年 | 20篇 |
2019年 | 28篇 |
2018年 | 28篇 |
2017年 | 19篇 |
2016年 | 26篇 |
2015年 | 70篇 |
2014年 | 46篇 |
2013年 | 72篇 |
2012年 | 86篇 |
2011年 | 72篇 |
2010年 | 25篇 |
2009年 | 42篇 |
2008年 | 49篇 |
2007年 | 45篇 |
2006年 | 54篇 |
2005年 | 43篇 |
2004年 | 43篇 |
2003年 | 35篇 |
2002年 | 30篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 9篇 |
1998年 | 7篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1966年 | 1篇 |
1956年 | 1篇 |
1935年 | 1篇 |
排序方式: 共有980条查询结果,搜索用时 15 毫秒
81.
Rahman NS Godderz LJ Stray SJ Capra JD Rodgers KK 《The Journal of biological chemistry》2006,281(18):12370-12380
Antibody and T cell receptor genes are assembled from gene segments by V(D)J recombination to produce an almost infinitely diverse repertoire of antigen specificities. Recombination is initiated by cleavage of conserved recombination signal sequences (RSS) by RAG1 and RAG2 during lymphocyte development. Recent evidence demonstrates that recombination can occur at noncanonical RSS sites within Ig genes or at other loci, outside the context of normal lymphocyte receptor gene rearrangement. We have characterized the ability of the RAG proteins to bind and cleave a cryptic RSS (cRSS) located within an Ig V(H) gene segment. The RAG proteins bound with sequence specificity to either the consensus RSS or the cRSS. The RAG proteins nick the cRSS on both the top and bottom strands, thereby bypassing the formation of the DNA hairpin intermediate observed in RAG cleavage of canonical RSS substrates. We propose that the RAG proteins may utilize an alternative mechanism for double-stranded DNA cleavage, depending on the substrate sequence. These results have implications for further diversification of the antigen receptor repertoire as well as the role of the RAG proteins in genomic instability. 相似文献
82.
Rodriguez AI Pereira-Flores K Hernández-Salinas R Boric MP Velarde V 《Biochemical and biophysical research communications》2006,345(2):652-659
The loss of endothelial function is the initiating factor in the development of diabetic vascular disease. Kinins control endothelial function by the activation of two receptors: the B2 which is constitutively expressed, and the B1 which is highly induced in pathological conditions. In the present study, we observed that the levels of B1-receptor mRNA and protein are induced in endothelial cells incubated in high glucose. An increase in B1-receptor was also observed in the endothelial layer of aortas, from 4-week diabetic rats. When cells were grown in high glucose, the B1 agonist des-Arg9-BK increased nitrite levels, whereas in normal glucose nitrite levels were unchanged. Nitrite increase was blocked by L-NAME and 1400W indicating the participation of the inducible Nitric Oxide Synthase (iNOS). iNOS protein levels were also increased in high glucose. These results demonstrate the participation of the B1 receptor in the signaling pathways mediated by kinins in high glucose. 相似文献
83.
Punkt K Schering S Löffler S Minin EA Samoilova VE Hasselblatt M Paulus W Müller-Werdan U Demus U Koehler G Boecker W Buchwalow IB 《Biochemical and biophysical research communications》2006,348(1):259-264
Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The neuronal NO synthase isoform (NOS1) was reported to be located exclusively in the sarcolemma. Its loss from the sarcolemma was associated with development of Duchenne muscular dystrophy (DMD). However, new studies evidence that all three NOS isoforms-NOS1, NOS2, and NOS3-are co-expressed in the sarcoplasm both in normal and in DMD skeletal muscles. To address this controversy, we assayed NOS expression in DMD myofibers in situ cytophotometrically and found NOS expression in DMD myofibers up-regulated. These results support the hypothesis that NO deficiency with consequent muscle degeneration in DMD results from NO scavenging by superoxides rather than from reduced NOS expression. 相似文献
84.
Gonzalez-Iglesias AE Kretschmannova K Tomic M Stojilkovic SS 《Biochemical and biophysical research communications》2006,346(3):845-850
Pituitary lactotrophs fire action potentials spontaneously and the associated voltage-gated calcium influx is sufficient to maintain high prolactin release. Here we studied the role of hyperpolarization-activated cation channels in pacemaking activity, calcium signaling, and prolactin secretion in these cells. A slowly developing and hyperpolarization-activated inward current was identified but only in a fraction of lactotrophs. The current was blocked by ZD7288, a relatively specific blocker of these channels. However, the pacemaking activity increased in ZD7288-treated cells independently of the presence of this current. This in turn facilitated voltage-gated calcium influx and transiently stimulated prolactin secretion. Sustained ZD7288 application in concentrations that are commonly used to block the hyperpolarization-activated cation channels inhibited hormone release at elevated intracellular calcium concentrations. Agonist and Bay K 8644-stimulated prolactin release was also inhibited by ZD7288, indicating that this compound attenuates the exocytotic pathway downstream of calcium influx. 相似文献
85.
86.
K Smyth K Garcia Z Sun W Tuo Z Xiao 《Biochemical and biophysical research communications》2012,424(3):635-640
Cytotoxic T lymphocytes (CTLs) play a critical role in controlling intracellular pathogens and cancer cells, and induction of memory CTLs holds promise for developing effective vaccines against critical virus infections. However, generating memory CTLs remains a major challenge for conventional vector-based, prime-boost vaccinations. Thus, it is imperative that we explore nonconventional alternatives, such as boosting without vectors. We show here that repetitive intravenous boosting with peptide and adjuvant generates memory CD8 T cells of sufficient quality and quantity to protect against infection in mice. The resulting memory CTLs possess a unique and long-lasting effector memory phenotype, characterized by decreased interferon-γ but increased granzyme B production. These results are observed in both transgenic and endogenous models. Overall, our findings have important implications for future vaccine development, as they suggest that intravenous peptide boosting with adjuvant following priming can induce long-term functional memory CTLs. 相似文献
87.
Stucker KM Pagan I Cifuente JO Kaelber JT Lillie TD Hafenstein S Holmes EC Parrish CR 《Journal of virology》2012,86(3):1514-1521
The adaptation of viruses to new hosts is a poorly understood process likely involving a variety of viral structures and functions that allow efficient replication and spread. Canine parvovirus (CPV) emerged in the late 1970s as a host-range variant of a virus related to feline panleukopenia virus (FPV). Within a few years of its emergence in dogs, there was a worldwide replacement of the initial virus strain (CPV type 2) by a variant (CPV type 2a) characterized by four amino acid differences in the capsid protein. However, the evolutionary processes that underlie the acquisition of these four mutations, as well as their effects on viral fitness, both singly and in combination, are still uncertain. Using a comprehensive experimental analysis of multiple intermediate mutational combinations, we show that these four capsid mutations act in concert to alter antigenicity, cell receptor binding, and relative in vitro growth in feline cells. Hence, host adaptation involved complex interactions among both surface-exposed and buried capsid mutations that together altered cell infection and immune escape properties of the viruses. Notably, most intermediate viral genotypes containing different combinations of the four key amino acids possessed markedly lower fitness than the wild-type viruses. 相似文献
88.
Saraiva DG Fournier GF Martins TF Leal KP Vieira FN Câmara EM Costa CG Onofrio VC Barros-Battesti DM Guglielmone AA Labruna MB 《Experimental & applied acarology》2012,58(2):159-166
From June 2005 to November 2010, 43 small mammals encompassing 6 species of Didelphimorphia, 8 species of Rodentia, and 1 species of Lagomorpha were found parasitized by ticks in the state of Minas Gerais, southeastern Brazil. Nine tick species, in total 186 specimens, were identified as follows: Amblyomma cajennense (larvae and nymphs) on opossums and rodents; Amblyomma ovale (nymphs) on rodents; Amblyomma parvum (nymphs) on rodents; Amblyomma coelebs (nymphs) on opossums; Amblyomma dubitatum (nymph) on opossums; Ixodes amarali (females, nymphs, and larvae) on opossums and rodents; Ixodes loricatus (male, females, nymph) on opossums; Ixodes schulzei (female) on rodents; and Haemaphysalis leporispalustris (female) on rabbits. Most of the tick-host associations found in the present study have never been recorded in the literature; those include three new host records for I. amarali, four for A. cajennense, one for A. dubitatum, two for A. ovale, and one for A. coelebs. In addition, we provide the first record of A. coelebs in the state of Minas Gerais. 相似文献
89.
Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current
The expression of GABA(A) receptors and the efficacy of GABAergic neurotransmission are subject to adaptive compensatory regulation as a result of changes in neuronal activity. Here, we show that activation of L-type voltage-gated Ca(2+) channels (VGCCs) leads to Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of S383 within the β3 subunit of the GABA(A) receptor. Consequently, this results in rapid insertion of GABA(A) receptors at the cell surface and enhanced tonic current. Furthermore, we demonstrate that acute changes in neuronal activity leads to the rapid modulation of cell surface numbers of GABA(A) receptors and tonic current, which are critically dependent on Ca(2+) influx through L-type VGCCs and CaMKII phosphorylation of β3S383. These data provide a mechanistic link between activity-dependent changes in Ca(2+) influx through L-type channels and the rapid modulation of GABA(A) receptor cell surface numbers and tonic current, suggesting a homeostatic pathway involved in regulating neuronal intrinsic excitability in response to changes in activity. 相似文献
90.