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641.
Kozyrev SV Abelson AK Wojcik J Zaghlool A Linga Reddy MV Sanchez E Gunnarsson I Svenungsson E Sturfelt G Jönsen A Truedsson L Pons-Estel BA Witte T D'Alfonso S Barizzone N Barrizzone N Danieli MG Gutierrez C Suarez A Junker P Laustrup H González-Escribano MF Martin J Abderrahim H Alarcón-Riquelme ME 《Nature genetics》2008,40(2):211-216
642.
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes 总被引:1,自引:0,他引:1
Zeggini E Scott LJ Saxena R Voight BF Marchini JL Hu T de Bakker PI Abecasis GR Almgren P Andersen G Ardlie K Boström KB Bergman RN Bonnycastle LL Borch-Johnsen K Burtt NP Chen H Chines PS Daly MJ Deodhar P Ding CJ Doney AS Duren WL Elliott KS Erdos MR Frayling TM Freathy RM Gianniny L Grallert H Grarup N Groves CJ Guiducci C Hansen T Herder C Hitman GA Hughes TE Isomaa B Jackson AU Jørgensen T Kong A Kubalanza K Kuruvilla FG Kuusisto J Langenberg C Lango H Lauritzen T Li Y Lindgren CM 《Nature genetics》2008,40(5):638-645
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D. 相似文献
643.
Haigis KM Kendall KR Wang Y Cheung A Haigis MC Glickman JN Niwa-Kawakita M Sweet-Cordero A Sebolt-Leopold J Shannon KM Settleman J Giovannini M Jacks T 《Nature genetics》2008,40(5):600-608
Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways. 相似文献
644.
van Es MA van Vught PW Blauw HM Franke L Saris CG Van den Bosch L de Jong SW de Jong V Baas F van't Slot R Lemmens R Schelhaas HJ Birve A Sleegers K Van Broeckhoven C Schymick JC Traynor BJ Wokke JH Wijmenga C Robberecht W Andersen PM Veldink JH Ophoff RA van den Berg LH 《Nature genetics》2008,40(1):29-31
We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies. 相似文献
645.
Vitart V Rudan I Hayward C Gray NK Floyd J Palmer CN Knott SA Kolcic I Polasek O Graessler J Wilson JF Marinaki A Riches PL Shu X Janicijevic B Smolej-Narancic N Gorgoni B Morgan J Campbell S Biloglav Z Barac-Lauc L Pericic M Klaric IM Zgaga L Skaric-Juric T Wild SH Richardson WA Hohenstein P Kimber CH Tenesa A Donnelly LA Fairbanks LD Aringer M McKeigue PM Ralston SH Morris AD Rudan P Hastie ND Campbell H Wright AF 《Nature genetics》2008,40(4):437-442
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes. 相似文献
646.
Gereben B Zeöld A Dentice M Salvatore D Bianco AC 《Cellular and molecular life sciences : CMLS》2008,65(4):570-590
The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting
the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control
thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is secreted by the thyroid gland.
These pathways ensure regulation of the availability of the biologically active molecule T3, which occurs in a time-and tissue-specific
fashion. In addition, because cells and plasma are in equilibrium and deiodination affects central thyroid hormone regulation,
these local deiodinase-mediated events can also affect systemic thyroid hormone economy, such as in the case of non-thyroidal
illness. Heightened interest in the field has been generated following the discovery that the deiodinases can be a component
in both the Sonic hedgehog signaling pathway and the TGR-5 signaling cascade, a G-protein-coupled receptor for bile acids.
These new mechanisms involved in deiodinase regulation indicate that local thyroid hormone activation and inactivation play
a much broader role than previously thought.
Received 29 August 2007; received after revision 11 October 2007; accepted 16 October 2007 相似文献
647.
Specific protein-protein interactions are essential for cellular functions. Experimentally determined three-dimensional structures
of protein-protein complexes offer the possibility to characterize binding interfaces in terms of size, shape and packing
density. Comparison with crystal-packing interfaces representing nonspecific protein-protein contacts gives insight into how
specific binding differs from nonspecific low-affinity binding. An overview is given on empirical structural rules for specific
protein-protein recognition derived from known complex structures. Although single parameters such as interface size, shape
or surface complementary show clear trends for different interface types, each parameter alone is insufficient to fully distinguish
between specific versus crystal-packing contacts. A combination of interface parameters is, however, well suited to characterize a specific interface.
This knowledge provides us with the essential ingredients that make up a specific protein recognition site. It is also of
great value for the prediction of protein binding sites and for the evaluation of predicted complex structures.
Received 1 October 2007; received after revision 9 November 2007; accepted 9 November 2007 相似文献
648.
Cohausz O Blenn C Malanga M Althaus FR 《Cellular and molecular life sciences : CMLS》2008,65(4):644-655
Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor
(AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR
molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we
determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG),
the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2
and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems
to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.
Received 7 November 2007; received after revision 19 December 2007; accepted 21 December 2007
O. Cohausz, C. Blenn: These two authors contributed equally to this work. 相似文献
649.
Oddi S Fezza F Pasquariello N De Simone C Rapino C Dainese E Finazzi-Agrò A Maccarrone M 《Cellular and molecular life sciences : CMLS》2008,65(5):840-850
Anandamide is a lipid messenger that carries out a wide variety of biological functions. It has been suggested that anandamide
accumulation involves binding to a saturable cellular component. To identify the structure(s) involved in this process, we
analyzed the intracellular distribution of both biotinylated and radiolabeled anandamide, providing direct evidence that lipid
droplets, also known as adiposomes, constitute a dynamic reservoir for the sequestration of anandamide. In addition, confocal
microscopy and biochemical studies revealed that the anandamide-hydrolase is also spatially associated with lipid droplets,
and that cells with a larger adiposome compartment have an enhanced catabolism of anandamide. Overall, these findings suggest
that adiposomes may have a critical role in accumulating anandamide, possibly by connecting plasma membrane to internal organelles
along the metabolic route of this endocannabinoid.
S. Oddi, F. Fezza: These authors contributed equally to the study. 相似文献
650.
Navarro S Aleu J Jiménez M Boix E Cuchillo CM Nogués MV 《Cellular and molecular life sciences : CMLS》2008,65(2):324-337
Human eosinophil cationic protein (ECP)/ ribonuclease 3 (RNase 3) is a protein secreted from the secondary granules of activated
eosinophils. Specific properties of ECP contribute to its cytotoxic activities associated with defense mechanisms. In this
work the ECP cytotoxic activity on eukaryotic cell lines is analyzed. The ECP effects begin with its binding and aggregation
to the cell surface, altering the cell membrane permeability and modifying the cell ionic equilibrium. No internalization
of the protein is observed. These signals induce cell-specific morphological and biochemical changes such as chromatin condensation,
reversion of membrane asymmetry, reactive oxygen species production and activation of caspase-3-like activity and, eventually,
cell death. However, the ribonuclease activity component of ECP is not involved in this process as no RNA degradation is observed.
In summary, the cytotoxic effect of ECP is attained through a mechanism different from that of other cytotoxic RNases and
may be related with the ECP accumulation associated with the inflammatory processes, in which eosinophils are present.
Received 26 October 2007; accepted 23 November 2007 相似文献