全文获取类型
收费全文 | 44146篇 |
免费 | 240篇 |
国内免费 | 538篇 |
专业分类
系统科学 | 1213篇 |
丛书文集 | 75篇 |
教育与普及 | 277篇 |
理论与方法论 | 508篇 |
现状及发展 | 29132篇 |
研究方法 | 44篇 |
综合类 | 11488篇 |
自然研究 | 2187篇 |
出版年
2013年 | 800篇 |
2012年 | 411篇 |
2011年 | 2370篇 |
2009年 | 591篇 |
2008年 | 597篇 |
2007年 | 638篇 |
2006年 | 756篇 |
2005年 | 925篇 |
2004年 | 2048篇 |
2003年 | 1668篇 |
2002年 | 1313篇 |
2001年 | 893篇 |
2000年 | 421篇 |
1999年 | 678篇 |
1998年 | 638篇 |
1997年 | 770篇 |
1996年 | 528篇 |
1995年 | 395篇 |
1994年 | 679篇 |
1993年 | 687篇 |
1992年 | 651篇 |
1991年 | 580篇 |
1990年 | 635篇 |
1989年 | 470篇 |
1988年 | 449篇 |
1987年 | 443篇 |
1986年 | 539篇 |
1985年 | 648篇 |
1984年 | 613篇 |
1983年 | 529篇 |
1982年 | 705篇 |
1981年 | 751篇 |
1980年 | 811篇 |
1979年 | 1046篇 |
1978年 | 998篇 |
1977年 | 1006篇 |
1976年 | 910篇 |
1975年 | 873篇 |
1974年 | 599篇 |
1973年 | 940篇 |
1972年 | 1014篇 |
1971年 | 949篇 |
1970年 | 911篇 |
1969年 | 901篇 |
1968年 | 868篇 |
1967年 | 725篇 |
1966年 | 581篇 |
1965年 | 508篇 |
1964年 | 455篇 |
1963年 | 414篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Arachiche A Badirou I Dachary-Prigent J Garcin I Geldwerth-Feniger D Kerbiriou-Nabias D 《Cellular and molecular life sciences : CMLS》2008,65(23):3861-3871
Rapid Ca2+-dependent phospholipid (PL) reorganization (scrambling) at the plasma membrane is a mechanism common to hematopoietic cells
exposing procoagulant phosphatidylserine (PS). The aim of this research was to determine whether activation of the extracellular
signal-regulated kinase (ERK) pathway was required for PL scrambling, based on a single report analyzing both responses induced
by Ca2+ ionophores in megakaryoblastic HEL cells. Ca2+ ionophore-stimulated ERK phosphorylation was induced in platelets without external Ca2+, whereas exogenous Ca2+ entry was crucial for ERK activation in Jurkat T cells. In both cells, membrane scrambling only occurred following Ca2+ entry and was not blocked by inhibiting ERK phosphorylation. Furthermore, ERK proteins are strongly phosphorylated in transformed
B lymphoblastic cell lines, which do not expose PS in their resting state. Overall, the data demonstrated that ERK activation
and membrane scrambling are independent mechanisms.
A. Arachiche, I. Badirou: These authors contributed equally to this work.
Received 18 June 2008; received after revision 24 September 2008; accepted 1 October 2008 相似文献
992.
Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various
subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different
sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases
β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen
vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal
consisting of the amino acids E5P6 in gal-T1 and D2P3 in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008 相似文献
993.
Olfactory receptors typically exhibit poor plasma membrane localization and functionality when heterologously expressed in
most cell types. It has therefore proven difficult to effectively study olfactory receptor pharmacology and signaling mechanisms
using traditional cell culture systems. Over the past few years, a variety of distinct proteins have been reported to interact
with olfactory receptors and facilitate olfactory receptor trafficking to the plasma membrane in heterologous cells. Advances
in this area have shed significant light on the fundamental factors governing the cell-specific control of olfactory receptor
trafficking. 相似文献
994.
A. F. Vanin L. M. Bevers A. Slama-Schwok E. E. van Faassen 《Cellular and molecular life sciences : CMLS》2008,65(24):4066-4069
Announcement
Announcement 相似文献995.
Taylor DM Maxwell MM Luthi-Carter R Kazantsev AG 《Cellular and molecular life sciences : CMLS》2008,65(24):4000-4018
Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are
key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The
desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven
mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer,
cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets
for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance
to human disease.
Received 25 June 2008; received after revision 20 August 2008; accepted 29 August 2008 相似文献
996.
It is generally thought that microtubule-associated motors insure long-range movements of the secretory vesicles from the center of the cell to its periphery, while myosins insure short-range movements at the cell periphery. However, several of the myosins that have been reported during the last decade to be involved in the exocytic pathway are not processive, meaning that they do not have the ability to move cargos along actin polymers. We will review here the possible mechanisms by which these myosins could contribute to the traffic of secretory proteins from the Golgi complex to the plasma membrane. 相似文献
997.
Zinc binding to peptide analogs of the structural zinc site in alcohol dehydrogenase: Implications for an entatic state 总被引:1,自引:0,他引:1
Bergman T Zhang K Palmberg C Jörnvall H Auld DS 《Cellular and molecular life sciences : CMLS》2008,65(24):4019-4027
Zinc binding to the peptide replica and analogs to residues 93–115 of horse liver alcohol dehydrogenase (ADH) was examined
by competition of the peptides and the chromophoric chelator 4-(2- pyridylazo)resorcinol for zinc and X-ray absorption fine
structure analysis of the zinc ligands. In the enzyme, zinc is coordinated by four Cys residues. In the peptide replica, zinc
is bound to three Cys and one His residue. A four-Cys zinc coordination is observed only when His is removed, leading to increased
zinc stability. ADH crystal structures reveal that the ε-amino group of the conserved residue Lys323 is within H-bond distance
of the backbone amide oxygens of residues 103, 105 and 108, likely stabilizing the zinc coordination in the enzyme. The peptide
data thus indicate structural strain and increased energy in the zinc-binding site in the protein, characteristic of an entatic
state, implying a functional nature for this zinc site.
Received 3 July 2008; received after revision 11 August 2008; accepted 1 September 2008 相似文献
998.
Cardiolipin, the heart of mitochondrial metabolism 总被引:5,自引:0,他引:5
Cardiolipin is a unique phospholipid, which is almost exclusively localized in the mitochondrial inner membrane where it is
synthesized from phosphatidylglycerol and cytidinediphosphate-diacylglycerol. After primary synthesis, the mature acyl chain
composition of cardiolipin is achieved by at least two remodeling mechanisms. In the mitochondrial membrane cardiolipin plays
an important role in energy metabolism, mainly by providing stability for the individual enzymes and enzyme complexes involved
in energy production. Moreover, cardiolipin is involved in different stages of the mitochondrial apoptotic process and in
mitochondrial membrane dynamics. Cardiolipin alterations have been described in various pathological conditions. Patients
suffering from Barth syndrome have an altered cardiolipin homeostasis caused by a primary deficiency in cardiolipin remodeling.
Alterations in cardiolipin content or composition have also been reported in more frequent diseases such as diabetes and heart
failure. In this review we provide an overview of cardiolipin metabolism, function and its role in different pathological
states.
Received 16 January 2008; received after revision 26 February 2008; accepted 26 March 2008 相似文献
999.
Galat A 《Cellular and molecular life sciences : CMLS》2008,65(21):3481-3493
Extracellular domains of some cellular receptors expressed in the organisms at different levels of development belong to three-fingered
protein (TFP) fold. The Homo sapiens genome encodes at least 45 genes containing from one to three TFP domains (TFPDs), namely diverse paralogues of the Ly6 gene,
CD59 and the receptors of activins, bone morphogenetic proteins, Mullerian inhibiting substance and transforming growth factor-β.
C4.4a and urokinase/plasminogen activatory receptor contain two and three TFPD repeats, respectively. These diverse proteins
have a low overall sequence similarity with each other and their hydrophobicity levels vary to a considerable degree. It is
suggested that sequence differentiation within the TFPD led to distinct groups of proteins whose attributes were optimized
to fit both the physicochemical properties specific to their functional microenvironment and selective targeting of their
highly diversified extracellular cofactors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 7 August 2008; accepted 29 August 2008 相似文献
1000.
Loos RJ Lindgren CM Li S Wheeler E Zhao JH Prokopenko I Inouye M Freathy RM Attwood AP Beckmann JS Berndt SI;Prostate Lung Colorectal Ovarian 《Nature genetics》2008,40(6):768-775
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits. 相似文献