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841.
Irina Kerkis Alvaro Rossan de Brandão Prieto da Silva Celine Pompeia Jan Tytgat Paulo L. de Sá Junior 《Cellular and molecular life sciences : CMLS》2017,74(4):647-661
Toxins have been shown to have many biological functions and to constitute a rich source of drugs and biotechnological tools. We focus on toxins that not only have a specific activity, but also contain residues responsible for transmembrane penetration, which can be considered bioportides—a class of cell-penetrating peptides that are also intrinsically bioactive. Bioportides are potential tools in pharmacology and biotechnology as they help deliver substances and nanoparticles to intracellular targets. Bioportides characterized so far are peptides derived from human proteins, such as cytochrome c (CYCS), calcitonin receptor (camptide), and endothelial nitric oxide synthase (nosangiotide). However, toxins are usually disregarded as potential bioportides. In this review, we discuss the inclusion of some toxins and molecules derived thereof as a new class of bioportides based on structure activity relationship, minimization, and biological activity studies. The comparative analysis of the amino acid residue composition of toxin-derived bioportides and their short molecular variants is an innovative analytical strategy which allows us to understand natural toxin multifunctionality in vivo and plan novel pharmacological and biotechnological products. Furthermore, we discuss how many bioportide toxins have a rigid structure with amphiphilic properties important for both cell penetration and bioactivity. 相似文献
842.
Trinidad Montero-Melendez Rachel A. E. Forfar Jennifer M. Cook Jeffrey C. Jerman Debra L. Taylor Mauro Perretti 《Cellular and molecular life sciences : CMLS》2017,74(7):1335-1345
The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases. 相似文献
843.
E. Giacomelli C. L. Mummery M. Bellin 《Cellular and molecular life sciences : CMLS》2017,74(20):3711-3739
Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions. 相似文献
844.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
845.
Functions and pathologies of BiP and its interaction partners 总被引:1,自引:1,他引:0
J. Dudek J. Benedix S. Cappel M. Greiner C. Jalal L. Müller R. Zimmermann 《Cellular and molecular life sciences : CMLS》2009,66(9):1556-1569
The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including
protein biogenesis, signal transduction, and calcium homeostasis. The central player in all these processes is the ER-lumenal
polypeptide chain binding protein BiP that acts as a molecular chaperone. BiP belongs to the heat shock protein 70 (Hsp70)
family and crucially depends on a number of interaction partners, including co-chaperones, nucleotide exchange factors, and
signaling molecules. In the course of the last five years, several diseases have been linked to BiP and its interaction partners,
such as a group of infectious diseases that are caused by Shigella toxin producing E. coli. Furthermore, the inherited diseases Marinesco-Sj?gren syndrome, autosomal dominant polycystic liver disease, Wolcott-Rallison
syndrome, and several cancer types can be considered BiP-related diseases. This review summarizes the physiological and pathophysiological
characteristics of BiP and its interaction partners.
Received 20 November 2008; received after revision 09 December 2008; accepted 12 December 2008 相似文献
846.
Ronda Bransteitter Courtney Prochnow Xiaojiang S. Chen 《Cellular and molecular life sciences : CMLS》2009,66(19):3137-3147
The apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of cytidine deaminases has emerged as an intensively
studied field as a result of their important biological functions. These enzymes are involved in lipid metabolism, antibody
diversification, and the inhibition of retrotransposons, retroviruses, and some DNA viruses. The APOBEC proteins function
in these roles by deaminating single-stranded (ss) DNA or RNA. There are two high-resolution crystal structures available
for the APOBEC family, Apo2 and the C-terminal catalytic domain (CD2) of Apo3G or Apo3G-CD2 [Holden et al. (Nature 456:121–124,
2008); Prochnow et al. (Nature 445:447–451, 2007)]. Additionally, the structure of Apo3G-CD2 has also been determined using
NMR [Chen et al. (Nature 452:116–119, 2008); Furukawa et al. (EMBO J 28:440–451, 2009); Harjes et al. (J Mol Biol, 2009)].
A detailed structural analysis of the APOBEC proteins and a comparison to other zinc-coordinating deaminases can facilitate
our understanding of how APOBEC proteins bind nucleic acids, recognize substrates, and form oligomers. Here, we review the
recent development of structural and functional studies that apply to Apo3G as well as the APOBEC deaminase family. 相似文献
847.
S. Kjellev 《Cellular and molecular life sciences : CMLS》2009,66(8):1350-1369
The trefoil factor family (TFF) comprises a group of small peptides which are highly expressed in tissues containing mucus-producing
cells – especially in the mucosa lining the gastrointestinal tract. The peptides seem crucial for epithelial restitution and
may work via other pathways than the conventional factors involved in restitution. In vitro studies have shown that the TFFs promote restitution using multiple mechanisms. The peptides also have other functionalities
including interactions with the immune system. Moreover, therapeutic effects of the TFFs have been shown in several animal
models of gastrointestinal damage. Still it is not clear which of their in vitro properties are involved in the in vivo mode of action. This review describes the TFF family with emphasis on their biological properties and involvement in mucosal
protection and repair.
Received 10 October 2008; received after revision 07 November 2008; accepted 10 November 2008 相似文献
848.
A. Shukla P. Chaurasia S. R. Bhaumik 《Cellular and molecular life sciences : CMLS》2009,66(8):1419-1433
Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore,
is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different
lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated
by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks
play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there
has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation
and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation
and roles in controlling gene expression and stability.
Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008 相似文献
849.
Dirk M. Walther Doron Rapaport Jan Tommassen 《Cellular and molecular life sciences : CMLS》2009,66(17):2789-2804
Membrane-embedded β-barrel proteins span the membrane via multiple amphipathic β-strands arranged in a cylindrical shape.
These proteins are found in the outer membranes of Gram-negative bacteria, mitochondria and chloroplasts. This situation is
thought to reflect the evolutionary origin of mitochondria and chloroplasts from Gram-negative bacterial endosymbionts. β-barrel
proteins fulfil a variety of functions; among them are pore-forming proteins that allow the flux of metabolites across the
membrane by passive diffusion, active transporters of siderophores, enzymes, structural proteins, and proteins that mediate
protein translocation across or insertion into membranes. The biogenesis process of these proteins combines evolutionary conservation
of the central elements with some noticeable differences in signals and machineries. This review summarizes our current knowledge
of the functions and biogenesis of this special family of proteins. 相似文献
850.
Berger W Steiner E Grusch M Elbling L Micksche M 《Cellular and molecular life sciences : CMLS》2009,66(1):43-61
The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular
ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional
proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several
short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated
in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses.
Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly
complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular
signal transduction and immune defence.
Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008 相似文献