全文获取类型
收费全文 | 524篇 |
免费 | 51篇 |
出版年
2021年 | 5篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2017年 | 5篇 |
2016年 | 14篇 |
2015年 | 14篇 |
2014年 | 17篇 |
2013年 | 22篇 |
2012年 | 30篇 |
2011年 | 29篇 |
2010年 | 21篇 |
2009年 | 13篇 |
2008年 | 23篇 |
2007年 | 31篇 |
2006年 | 28篇 |
2005年 | 24篇 |
2004年 | 15篇 |
2003年 | 33篇 |
2002年 | 31篇 |
2001年 | 9篇 |
2000年 | 6篇 |
1999年 | 11篇 |
1998年 | 4篇 |
1997年 | 7篇 |
1996年 | 7篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 6篇 |
1987年 | 3篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1980年 | 5篇 |
1977年 | 3篇 |
1976年 | 6篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1970年 | 3篇 |
1968年 | 7篇 |
1967年 | 6篇 |
1963年 | 5篇 |
1958年 | 3篇 |
1935年 | 3篇 |
1928年 | 4篇 |
排序方式: 共有575条查询结果,搜索用时 31 毫秒
101.
Antje Willuweit Joachim Velden Robert Godemann Andre Manook Fritz Jetzek Hartmut Tintrup Gunther Kauselmann Branko Zevnik Gjermund Henriksen Alexander Drzezga Johannes Pohlner Michael Schoor John A. Kemp Heinz von der Kammer 《PloS one》2009,4(11)
Background
Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral β-amyloidosis, one of the characteristic hallmarks of Alzheimer''s disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.Methodology/Principal Findings
The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APPswe) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral β-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a γ-secretase inhibitor we show a dose dependent reduction of soluble amyloid β levels in the brain.Conclusions
ARTE10 mice develop a cerebral β-amyloidosis closely resembling the β-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD. 相似文献102.
103.
Bergemann S Brecht R Büttner F Guénard D Gust R Seitz G Stubbs MT Thoret S 《Bioorganic & medicinal chemistry》2003,11(7):1269-1281
Two new series of allocolchicinoids mimicking the structure of (-)-N-acetylcolchinol O-methyl ether (2, NCME) were synthesized and evaluated for their abilities to inhibit tubulin assembly. Possible antitumor properties resulting thereof were evaluated in vitro on the human MCF-7 breast cancer cell line. The first series of NCME-derivatives was brought about by extending the seven membered B-ring to novel semisynthetic variations with a nitrogen containing eight-membered B-ring similar, for example, to the artificial, potent steganacin aza-analogue 3. In the second series the seven-membered B-ring of NCME (2) was modified by annulation with a heterocyclic ring system. The racemic ketone 7a serving as key precursor involved in the syntheses of all the target NCME variants 9-13 and 15, 16 was easily transformed into the eight-membered B-ring lactams 9 and 10 via a Beckmann rearrangement of the corresponding E-oxime 8. The tetrazole annulated congener 11 was prepared via azidotrimethylsilane-mediated Schmidt rearrangement. Treatment of educt 7a with Bredereck's reagent led to the enamino ketone 14, which was easily converted into the pyrazole- or pyrimidine-annulated allocolchicinoids 15 and 16. Remarkably, all the allocolchicinoids 9-13 with an azocin-B-ring affected the tubulin/microtubule equilibrium only moderately. In contrast, the novel heterocycle annulated seven membered B-ring variants 15 and 16 proved to be highly potent tubulin-inhibitory, antimitotic agents. Interaction with tubulin occured at concentrations similar to those observed for colchicine (1) or the lead NCME (2). In all cases the antiproliferative effects correlated roughly with the inhibition of tubulin assembly. 相似文献
104.
Treatment of mouse spleen cells with a rabbit anti-mouse brain (RAMB) antiserum markedly suppressed antibody-dependent cell-mediated cytotoxicity (ADCC) on trinitrophenyl-coupled sheep erythrocyte targets. This inhibitory activity of RAMB antiserum was complement independent, absorbable with mouse brain tissue, and appeared to be separable from the anti-Thy-1 activity of this serum. Absorption studies indicated that various T- and B-lymphocyte cell lines as well as macrophage-like cell lines are not able to absorb the inhibitory activity of RAMB antiserum. In contrast, thymocytes and spleen cells, as well as the neural cell line, PC12, a chromocytoma derived from rat adrenal medulla, were capable of absorbing the inhibitory activity to some extent, suggesting that antigens characteristic for ADCC effector cells can be found on these cell populations. 相似文献
105.
106.
Characterization of an electrogenic ATP and chloride-dependent proton translocating pump from rat renal medulla 总被引:5,自引:0,他引:5
To study acidification mechanisms in the distal nephron, microsomes were prepared from rat renal medulla by differential centrifugation. Microsomes were enriched in the enzyme marker gamma-glutamyl transferase and contained an ATP-dependent proton pump, as evidenced by ATP-dependent, 3,3',4',5-tetrachlorosalicylanilide-reversible quenching of acridine orange fluorescence. Acidification was vanadate-insensitive, but was completely inhibited by micromolar N-ethylmaleimide. Maximal acidification was achieved in the presence of halide (Cl-, Br-) only and was not attainable with potassium-valinomycin diffusion potentials without halide ion. Microsomal ATPase activity was neither chloride- nor N-ethylmaleimide-sensitive. A chloride conductance was observed only with vesicles which had undergone ATP-dependent acidification. An ATP-dependent, N-ethylmaleimide-inhibitable, 3,3',4',5-tetrachlorosalicylanilide-reversible, and chloride-attenuated quench of bis(1,3-dibutylbarbituric acid-(5] pentamethinoxonol fluorescence was seen, consistent with net transfer of positive charge into the vesicles. Nonetheless, positive intravesicular potentials increased the ATP-dependent initial acidification rate, perhaps by increasing availability of chloride ion to the transport site. Our results are consistent with an electrogenic, ATP-dependent proton pump regulated by a voltage-sensitive chloride site. 相似文献
107.
108.
109.
Philipp Küchler Gunther Zimmermann Michael Winzker Petra Janning Herbert Waldmann Slava Ziegler 《Bioorganic & medicinal chemistry》2018,26(8):1426-1434
Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod rhodopsin-sensitive cGMP 3′,5′-cyclic phosphodiesterase subunit delta (PDEδ) is a prenyl binding protein that is essential for the shuttling of small GTPases between different membrane compartments and, thus, for their proper functioning. Although the prenylome comprises up to 2% of the mammalian proteome, only few prenylated proteins are known to interact with PDEδ. A proteome-wide approach was employed to map the PDEδ interactome among the prenylome and revealed RAB23, CDC42 and CNP as novel PDEδ interacting proteins. Moreover, PDEδ associates with the lamin A mutant progerin in a prenyl-dependent manner. These findings shed new light on the role of PDEδ in binding (and regulating) prenylated proteins in cells. 相似文献
110.
Jorunn Sletten Miguel Julve Francesc Lloret Isabel Castro Gunther Seitz Klaus Mann 《Inorganica chimica acta》1996,250(1-2):219-225
The first crystal and molecular structure of a transition metal complex containing 1,2-dithiocroconate (1,2-dtcr, dianion of 1,2-dimercaptocylopent-1-ene-3,4,5-trione), [Cu(bpca)(H2O)]2[Cu(1,2-dtcr)2]·2H2O (where bpca is the bis(2-pyrdidylcarbonyl)amide anion), has been determined by single crystal X-ray diffraction methods. The compound crystallizesin the monoclinic syste, space group P21/c, with a = 11.661(3), b = 20.255(6), c = 8.265(3) Å, ß = 107.26(2)° and Z = 2. The structure is formally built of [Cu(1,2-dtcr)2]2− and [Cu(bpca)(H2O)]+ ions and water of hydration. The copper atom of the anion is situated at a crystallographic inversion centre, bonded to four sulfur atoms in a planar, approximately square arrangement. In the cation the copper equatorial plane is formed by the three nitrogen atoms of the bpca ligand and a water oxygen atom. In addition there is a very weak axial bond to one of the sulfur atoms of a 1,2-dtcr ligand in the anion. Through these latter weak bonds each anion is connected to, and sandwiched between, two cations, resulting in neutral, trinuclear, centrosymmetric formula units. The triple-decker molecules are arranged in stacks along the crystallographic a-axis creating close contacts between the terminal copper atoms and bpca groups of the neighbouring molecules. This intermolecular interaction is, however, too weak to define the structure as a chain compound. The distance between adjacent copper atoms within the trinuclear unit is 4.189(1) Å, while the shortest intra-stack metal-metal separation between terminal copper atoms is 5.281(1) Å. Variable-temperature magnetic susceptibility measurements in the temperature r.2–140 K reveal that a Curie law is followed; with three non-interacting copper(II) ions in the formula unit. 相似文献