全文获取类型
收费全文 | 276篇 |
免费 | 6篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 2篇 |
理论与方法论 | 3篇 |
现状及发展 | 63篇 |
研究方法 | 51篇 |
综合类 | 164篇 |
自然研究 | 2篇 |
出版年
2021年 | 3篇 |
2020年 | 2篇 |
2019年 | 2篇 |
2018年 | 4篇 |
2017年 | 6篇 |
2016年 | 9篇 |
2015年 | 5篇 |
2014年 | 7篇 |
2013年 | 8篇 |
2012年 | 30篇 |
2011年 | 43篇 |
2010年 | 16篇 |
2009年 | 2篇 |
2008年 | 17篇 |
2007年 | 28篇 |
2006年 | 23篇 |
2005年 | 33篇 |
2004年 | 10篇 |
2003年 | 19篇 |
2002年 | 13篇 |
2001年 | 1篇 |
2000年 | 3篇 |
1999年 | 1篇 |
排序方式: 共有285条查询结果,搜索用时 15 毫秒
51.
Earth science: the rise and growth of Tibet 总被引:1,自引:0,他引:1
52.
Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the neuroparalytic syndrome of botulism. With a lethal dose of 1 ng kg(-1), they pose a biological hazard to humans and a serious potential bioweapon threat. BoNTs bind with high specificity at neuromuscular junctions and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. The molecular details of the toxin-cell recognition have been elusive. Here we report the structure of a BoNT in complex with its protein receptor: the receptor-binding domain of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of synaptotagmin II, determined at 2.15 A resolution. On binding, a helix is induced in the luminal domain which binds to a saddle-shaped crevice on a distal tip of BoNT/B. This crevice is adjacent to the non-overlapping ganglioside-binding site of BoNT/B. Synaptotagmin II interacts with BoNT/B with nanomolar affinity, at both neutral and acidic endosomal pH. Biochemical and neuronal ex vivo studies of structure-based mutations indicate high specificity and affinity of the interaction, and high selectivity of BoNT/B among synaptotagmin I and II isoforms. Synergistic binding of both synaptotagmin and ganglioside imposes geometric restrictions on the initiation of BoNT/B translocation after endocytosis. Our results provide the basis for the rational development of preventive vaccines or inhibitors against these neurotoxins. 相似文献
53.
Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births. Mouse and frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling might control neurulation by promoting the convergence of neural progenitors to the midline. Here we show a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a function for PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previously unrecognized mechanism that might underlie NTDs. 相似文献
54.
55.
Androutsellis-Theotokis A Leker RR Soldner F Hoeppner DJ Ravin R Poser SW Rueger MA Bae SK Kittappa R McKay RD 《Nature》2006,442(7104):823-826
56.
Fracture behavior and microstructure analysis of Al2O3–MgO–CaO castables for steel-ladle purging plugs 下载免费PDF全文
Three different castables based on the Al2O3–MgO–CaO system were prepared as steel-ladle purging plug refractories: corundum- based low-cement castable (C-LCC), corundum-spinel-based low-cement castable (C-S-LCC), and corundum-spinel no-cement castable (C-S-NCC) (hydratable alumina (ρ-Al2O3) bonded). The fracture behavior at room temperature was tested by the method of “wedge-splitting” on samples pre-fired at different temperatures; the specific fracture energy G′f and notched tensile strength σNT were obtained from these tests. In addition, the Young’s modulus E was measured by the method of resonance frequency of damping analysis (RFDA). The thermal stress resistance parameter R′′′′ calculated using the values of G′f, σNT, and E was used to evaluate the thermal shock resistance of the materials. According to the microstructure analysis results, the sintering effect and the bonding type of the matrix material were different among these three castables, which explains their different fracture behaviors. 相似文献
57.
Sven Herrmann Katharina T. Huber Vincent Moulton Andreas Spillner 《Journal of Classification》2012,29(3):321-340
A k-dissimilarity D on a finite set X, |X|????k, is a map from the set of size k subsets of X to the real numbers. Such maps naturally arise from edgeweighted trees T with leaf-set X: Given a subset Y of X of size k, D(Y ) is defined to be the total length of the smallest subtree of T with leaf-set Y . In case k?=?2, it is well-known that 2-dissimilarities arising in this way can be characterized by the so-called ??4-point condition??. However, in case k?>?2 Pachter and Speyer (2004) recently posed the following question: Given an arbitrary k-dissimilarity, how do we test whether this map comes from a tree? In this paper, we provide an answer to this question, showing that for k????3 a k-dissimilarity on a set X arises from a tree if and only if its restriction to every 2?k-element subset of X arises from some tree, and that 2?k is the least possible subset size to ensure that this is the case. As a corollary, we show that there exists a polynomial-time algorithm to determine when a k-dissimilarity arises from a tree. We also give a 6-point condition for determining when a 3-dissimilarity arises from a tree, that is similar to the aforementioned 4-point condition. 相似文献
58.
Knabl J Witschi R Hösl K Reinold H Zeilhofer UB Ahmadi S Brockhaus J Sergejeva M Hess A Brune K Fritschy JM Rudolph U Möhler H Zeilhofer HU 《Nature》2008,451(7176):330-334
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics. 相似文献
59.
给出了大气中二氧化碳浓度加倍引起的德国南部及邻近阿尔卑斯山区5年1月和 7月气温和降水率变化的模拟结果.模式采用在大气环流模式(ECHAM3)中嵌套的中尺度气候 和化学模式(MCCM).模拟结果显示:区域平均气温(地面上2 m处温度)的5年平均1月增 加0.8℃,7月增加4.7℃;区域降水率的5年逐月平均则显示1月无变化,7月减少40 %.讨论了气温、降水率以及降水频率等变化的空间分布,也给出了控制试验(1×CO2) 和敏感试验(2×CO2)中气温和降水率的年际变化模拟结果. 相似文献
60.
Melum E Franke A Schramm C Weismüller TJ Gotthardt DN Offner FA Juran BD Laerdahl JK Labi V Björnsson E Weersma RK Henckaerts L Teufel A Rust C Ellinghaus E Balschun T Boberg KM Ellinghaus D Bergquist A Sauer P Ryu E Hov JR Wedemeyer J Lindkvist B Wittig M Porte RJ Holm K Gieger C Wichmann HE Stokkers P Ponsioen CY Runz H Stiehl A Wijmenga C Sterneck M Vermeire S Beuers U Villunger A Schrumpf E Lazaridis KN Manns MP Schreiber S Karlsen TH 《Nature genetics》2011,43(1):17-19
Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively). 相似文献