全文获取类型
收费全文 | 1650篇 |
免费 | 157篇 |
专业分类
1807篇 |
出版年
2023年 | 11篇 |
2022年 | 28篇 |
2021年 | 38篇 |
2020年 | 29篇 |
2019年 | 32篇 |
2018年 | 38篇 |
2017年 | 30篇 |
2016年 | 57篇 |
2015年 | 85篇 |
2014年 | 98篇 |
2013年 | 133篇 |
2012年 | 150篇 |
2011年 | 134篇 |
2010年 | 75篇 |
2009年 | 63篇 |
2008年 | 95篇 |
2007年 | 88篇 |
2006年 | 62篇 |
2005年 | 65篇 |
2004年 | 77篇 |
2003年 | 67篇 |
2002年 | 64篇 |
2001年 | 27篇 |
2000年 | 23篇 |
1999年 | 29篇 |
1998年 | 14篇 |
1997年 | 14篇 |
1996年 | 14篇 |
1995年 | 8篇 |
1993年 | 7篇 |
1992年 | 15篇 |
1991年 | 8篇 |
1990年 | 10篇 |
1989年 | 8篇 |
1988年 | 12篇 |
1987年 | 8篇 |
1986年 | 11篇 |
1985年 | 11篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1977年 | 6篇 |
1974年 | 4篇 |
1973年 | 3篇 |
1971年 | 3篇 |
1932年 | 3篇 |
1929年 | 3篇 |
1920年 | 2篇 |
排序方式: 共有1807条查询结果,搜索用时 0 毫秒
91.
Agnieszka A. Kendrick Michael J. Holliday Nancy G. Isern Fengli Zhang Carlo Camilloni Chi Huynh Michele Vendruscolo Geoffrey Armstrong Elan Z. Eisenmesser 《Protein science : a publication of the Protein Society》2014,23(4):464-480
Interleukin‐8 (CXCL8, IL‐8) is a proinflammatory chemokine important for the regulation of inflammatory and immune responses via its interaction with G‐protein coupled receptors, including CXC receptor 1 (CXCR1). CXCL8 exists as both a monomer and as a dimer at physiological concentrations, yet the molecular basis of CXCL8 interaction with its receptor as well as the importance of CXCL8 dimer formation remain poorly characterized. Although several biological studies have indicated that both the CXCL8 monomer and dimer are active, biophysical studies have reported conflicting results regarding the binding of CXCL8 to CXCR1. To clarify this problem, we expressed and purified a peptide (hCXCR1pep) corresponding to the N‐terminal region of human CXCR1 (hCXCR1) and utilized nuclear magnetic resonance (NMR) spectroscopy to interrogate the binding of wild‐type CXCL8 and a previously reported mutant (CXCL8M) that stabilizes the monomeric form. Our data reveal that the CXCL8 monomer engages hCXCR1pep with a slightly higher affinity than the CXCL8 dimer, but that the CXCL8 dimer does not dissociate upon binding hCXCR1pep. These investigations also showed that CXCL8 is dynamic on multiple timescales, which may help explain the versatility in this interleukin for engaging its target receptors. 相似文献
92.
Kristine Salmina 《Experimental cell research》2010,316(13):2099-695
We have previously documented that transient polyploidy is a potential cell survival strategy underlying the clonogenic re-growth of tumour cells after genotoxic treatment. In an attempt to better define this mechanism, we recently documented the key role of meiotic genes in regulating the DNA repair and return of the endopolyploid tumour cells (ETC) to diploidy through reduction divisions after irradiation. Here, we studied the role of the pluripotency and self-renewal stem cell genes NANOG, OCT4 and SOX2 in this polyploidy-dependent survival mechanism. In irradiation-resistant p53-mutated lymphoma cell-lines (Namalwa and WI-L2-NS) but not sensitive p53 wild-type counterparts (TK6), low background expression of OCT4 and NANOG was up-regulated by ionising radiation with protein accumulation evident in ETC as detected by OCT4/DNA flow cytometry and immunofluorescence (IF). IF analysis also showed that the ETC generate PML bodies that appear to concentrate OCT4, NANOG and SOX2 proteins, which extend into complex nuclear networks. These polyploid tumour cells resist apoptosis, overcome cellular senescence and undergo bi- and multi-polar divisions transmitting the up-regulated OCT4, NANOG and SOX2 self-renewal cassette to their descendents. Altogether, our observations indicate that irradiation-induced ETC up-regulate key components of germ-line cells, which potentially facilitate survival and propagation of the tumour cell population. 相似文献
93.
Frank Lennartz Karen Bayer Nadine Czerwonka Yinghui Lu Kristine Kehr Manuela Hirz Torsten Steinmetzer Wolfgang Garten Christiane Herden 《Cellular microbiology》2016,18(3):340-354
Borna disease virus (BDV) is a non‐segmented negative‐stranded RNA virus that maintains a strictly neurotropic and persistent infection in affected end hosts. The primary target cells for BDV infection are brain cells, e.g. neurons and astrocytes. The exact mechanism of how infection is propagated between these cells and especially the role of the viral glycoprotein (GP) for cell–cell transmission, however, are still incompletely understood. Here, we use different cell culture systems, including rat primary astrocytes and mixed cultures of rat brain cells, to show that BDV primarily spreads through cell–cell contacts. We employ a highly stable and efficient peptidomimetic inhibitor to inhibit the furin‐mediated processing of GP and demonstrate that cleaved and fusion‐active GP is strictly necessary for the cell‐to‐cell spread of BDV. Together, our quantitative observations clarify the role of Borna disease virus‐glycoprotein for viral dissemination and highlight the regulation of GP expression as a potential mechanism to limit viral spread and maintain persistence. These findings furthermore indicate that targeting host cell proteases might be a promising approach to inhibit viral GP activation and spread of infection. 相似文献
94.
Stephen?M.?ShusterEmail author Mark?P.?Miller Brian?K.?Lang Nathan?Zorich Lynn?Huynh Paul?Keim 《Conservation Genetics》2005,6(3):355-368
The endangered Socorro Isopod, Thermosphaeroma thermophilum, is endemic to a single thermal spring in Socorro, NM. This species is cannibalistic, with males more cannibalistic than females, and with females and juveniles more vulnerable than males as prey. In 1990, the New Mexico Department of Game and Fish, created the Socorro Isopod Propagation Facility (SIPF) near the natural habitat, Sedillo Spring (SS), to increase total population size and to examine the effects of habitat heterogeneity on population growth. We report the genetic and morphological effects of this experiment, using the natural population as a control. Captive subpopulations experienced bottlenecks of known intensity and duration, as well as different intensities of cannibalism. Using 57 AFLP markers, we show that in 6 years (1990–1996), captive subpopulations diverged significantly from the natural population. Also during this 6-year period, body lengths of captive isopods diverged nearly 2-fold from the natural population, evidently because cannibalism and thus selection favoring large size was more intense in captive subpopulations than in nature. This hypothesis is supported by the fact that cannibalism and the apparent response to selection on body size became variable among captive subpopulations when physical structure was added to three of the four SIPF pools in April 1997. As expected if cannibalism was the source of selection for large body size, by August 1998 (15 months = 7–8 generations), the rate at which body size increased became inversely proportional to the amount of physical structure within pools. Although we are unable to separate the specific effects of population subdivision and cannibalism, our results show that these conditions in combination caused rapid changes in genetic variation and the external morphology of these captive subpopulations. Our results have important implications for future attempts to manage and propagate endangered species. 相似文献
95.
Benjamin E. Steinberg Kassidy K. Huynh Alexandre Brodovitch Sabrina Jabs Tobias Stauber Thomas J. Jentsch Sergio Grinstein 《The Journal of cell biology》2010,189(7):1171-1186
The profound luminal acidification essential for the degradative function of lysosomes requires a counter-ion flux to dissipate an opposing voltage that would prohibit proton accumulation. It has generally been assumed that a parallel anion influx is the main or only counter-ion transport that enables acidification. Indeed, defective anion conductance has been suggested as the mechanism underlying attenuated lysosome acidification in cells deficient in CFTR or ClC-7. To assess the individual contribution of counter-ions to acidification, we devised means of reversibly and separately permeabilizing the plasma and lysosomal membranes to dialyze the cytosol and lysosome lumen in intact cells, while ratiometrically monitoring lysosomal pH. Replacement of cytosolic Cl− with impermeant anions did not significantly alter proton pumping, while the presence of permeant cations in the lysosomal lumen supported acidification. Accordingly, the lysosomes were found to acidify to the same pH in both CFTR- and ClC-7–deficient cells. We conclude that cations, in addition to chloride, can support lysosomal acidification and defects in lysosomal anion conductance cannot explain the impaired microbicidal capacity of CF phagocytes. 相似文献
96.
Allisan Aquilina-Beck Kristine Ilagan Qin Liu Jennifer O Liang 《BMC developmental biology》2007,7(1):126
Background
Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish. 相似文献97.
The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery. 相似文献
98.
99.
Objective
The aim of the study is to evaluate the long-term near-transfer effects of computerized working memory (WM) training on standard WM tasks in children with Attention-Deficit/Hyperactivity Disorder (ADHD).Method
Sixty-seven children aged 10–12 years in Vestfold/Telemark counties (Norway) diagnosed with F90.0 Hyperkinetic disorder (ICD-10) were randomly assigned to training or control group. The training group participated in a 25-day training program at school, while the control group received treatment-as-usual. Participants were tested one week before intervention, immediately after and eight months later. Based on a component analysis, six measures of WM were grouped into composites representing Visual, Auditory and Manipulation WM.Results
The training group had significant long-term differential gains compared to the control group on all outcome measures. Performance gains for the training group were significantly higher in the visual domain than in the auditory domain. The differential gain in Manipulation WM persisted after controlling for an increase in simple storage capacity.Conclusion
Systematic training resulted in a long-term positive gain in performance on similar tasks, indicating the viability of training interventions for children with ADHD. The results provide evidence for both domain-general and domain-specific models. Far-transfer effects were not investigated in this article.Trial Registration: Controlled-Trials.com ISRCTN19133620 相似文献100.
High light stress induced not only a sustained form of xanthophyll cycle-dependent energy dissipation but also sustained thylakoid protein phosphorylation. The effect of protein phosphatase inhibitors (fluoride and molybdate ions) on recovery from a 1-h exposure to a high PFD was examined in leaf discs of Parthenocissus quinquefolia (Virginia creeper). Inhibition of protein dephosphorylation induced zeaxanthin retention and sustained energy dissipation (NPQ) upon return to low PFD for recovery, but had no significant effects on pigment and Chl fluorescence characteristics under high light exposure. In addition, whole plants of Monstera deliciosa and spinach grown at low to moderate PFDs were transferred to high PFDs, and thylakoid protein phosphorylation pattern (assessed with anti-phosphothreonine antibody) as well as pigment and Chl fluorescence characteristics were examined over several days. A correlation was obtained between dark-sustained D1/D2 phosphorylation and dark-sustained zeaxanthin retention and maintenance of PS II in a state primed for energy dissipation in both species. The degree of these dark-sustained phenomena was more pronounced in M. deliciosa compared with spinach. Moreover, M. deliciosa but not spinach plants showed unusual phosphorylation patterns of Lhcb proteins with pronounced dark-sustained Lhcb phosphorylation even under low PFD growth conditions. Subsequent to the transfer to a high PFD, dark-sustained Lhcb protein phosphorylation was further enhanced. Thus, phosphorylation patterns of D1/D2 and Lhcb proteins differed from each other as well as among plant species. The results presented here suggest an association between dark-sustained D1/D2 phosphorylation and sustained retention of zeaxanthin and energy dissipation (NPQ) in light-stressed, and particularly photoinhibited, leaves. Functional implications of these observations are discussed.This revised version was published online in October 2005 with corrections to the Cover Date. 相似文献