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991.
Finberg KE Heeney MM Campagna DR Aydinok Y Pearson HA Hartman KR Mayo MM Samuel SM Strouse JJ Markianos K Andrews NC Fleming MD 《Nature genetics》2008,40(5):569-571
Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans. 相似文献
992.
Rosendahl J Witt H Szmola R Bhatia E Ozsvári B Landt O Schulz HU Gress TM Pfützer R Löhr M Kovacs P Blüher M Stumvoll M Choudhuri G Hegyi P te Morsche RH Drenth JP Truninger K Macek M Puhl G Witt U Schmidt H Büning C Ockenga J Kage A Groneberg DA Nickel R Berg T Wiedenmann B Bödeker H Keim V Mössner J Teich N Sahin-Tóth M 《Nature genetics》2008,40(1):78-82
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. 相似文献
993.
Saal LH Gruvberger-Saal SK Persson C Lövgren K Jumppanen M Staaf J Jönsson G Pires MM Maurer M Holm K Koujak S Subramaniyam S Vallon-Christersson J Olsson H Su T Memeo L Ludwig T Ethier SP Krogh M Szabolcs M Murty VV Isola J Hibshoosh H Parsons R Borg A 《Nature genetics》2008,40(1):102-107
Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair. 相似文献
994.
995.
The RNA-splicing endonuclease is an evolutionarily conserved enzyme responsible for the excision of introns from nuclear transfer
RNA (tRNA) and all archaeal RNAs. Since its first identification from yeast in the late 1970s, significant progress has been
made toward understanding the biochemical mechanisms of this enzyme. Four families of the splicing endonucleases possessing
the same active sites and overall architecture but with different subunit compositions have been identified. Two related consensus
structures of the precursor RNA splice sites and the critical elements required for intron excision have been established.
More recently, a glimpse was obtained of the structural mechanism by which the endonuclease recognizes the consensus RNA structures
and cleaves at the splice sites. This review summarizes these findings and discusses their implications in the evolution of
intron removal processes.
Received 24 August 2007; received after revision 24 November 2007; accepted 27 November 2007 相似文献
996.
Molecular mechanisms of spider silk 总被引:2,自引:0,他引:2
Hu X Vasanthavada K Kohler K McNary S Moore AM Vierra CA 《Cellular and molecular life sciences : CMLS》2006,63(17):1986-1999
Spiders spin high-performance silks through the expression and assembly of tissue-restricted fibroin proteins. Spider silks
are composite protein biopolymers that have complex microstructures. Retrieval of cDNAs and genomic DNAs encoding silk fibroins
has revealed an association between the protein sequences and structure-property relationships. However, before spider silks
can be subject to genetic engineering for commercial applications, the complete protein sequences and their functions, as
well as the details of the spinning mechanism, will require additional progress and collaborative efforts in the areas of
biochemistry, molecular biology and material science. Novel approaches to reveal additional molecular constituents embedded
in the spider fibers, as well as cloning strategies to manipulate the genes for expression, will continue to be important
aspects of spider biology research. Here we summarize the molecular characteristics of the different spider fibroins, the
mechanical properties and assembly process of spidroins and the advances in protein expression systems used for recombinant
silk production. We also highlight different technical approaches being used to elucidate the molecular constituents of silk
fibers.
Received 28 February 2006; received after revision 14 April 2006; accepted 22 May 2006
X. Hu and K. Vasanthavada contributed equally to this work. 相似文献
997.
Wu J Feng Y Xie D Li X Xiao W Tao D Qin J Hu J Gardner K Judge SI Li QQ Gong J 《Cellular and molecular life sciences : CMLS》2006,63(21):2538-2545
Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations
provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In
this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being
accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly,
this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine,
suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore,
cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these
cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed
by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation
in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin
B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or
indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.
Received 30 March 2006; received after revision 23 June 2006; accepted 24 August 2006
J. Wu and Y. Feng contributed equally to this work. 相似文献
998.
Briers Y Lavigne R Plessers P Hertveldt K Hanssens I Engelborghs Y Volckaert G 《Cellular and molecular life sciences : CMLS》2006,63(16):1899-1905
The kinetic, thermodynamic and structural stability of gp36C, the virion-associated peptidoglycan hydrolase domain of bacteriophage
ϕKMV, is analyzed. Recombinant gp36C is highly thermoresistant (k = 0.595 h−1 at 95°C), but not thermostable (Tm = 50.2°C, ΔHcal = 6.86 × 104 cal mol−1). However, aggregation influences kinetic stability in an unusual manner since aggregation is more pronounced at 55°C than
at higher temperatures. Furthermore, gp36C reversibly unfolds in a two-state endothermic transition, and circular dichroism
analysis shows that gp36C almost completely refolds after a 3-h heat treatment at 85°C. These properties are in agreement
with gp36C being part of the extensible tail which is ejected in an unfolded state during phage infection.
Received 24 April 2006; received after revision 26 May 2006; accepted 10 June 2006 相似文献
999.
Endomannosidase processes oligosaccharides of α1-antitrypsin and its naturally occurring genetic variants in the Golgi apparatus 总被引:3,自引:0,他引:3
Torossi T Fan JY Sauter-Etter K Roth J Ziak M 《Cellular and molecular life sciences : CMLS》2006,63(16):1923-1932
Endomannosidase provides an alternate glucose-trimming pathway in the Golgi apparatus. However, it is unknown if the action
of endomannosidase is dependent on the conformation of the substrate. We have investigated the processing by endomannosidase
of the α1-antitrypsin oligosaccharides and its disease-causing misfolded Z and Hong Kong variants. Oligosaccharides of wild-type
and misfolded α1-antitrypsin expressed in castanospermine-treated hepatocytes or glucosidase II-deficient Phar 2.7 cells were
selectively processed by endomannosidase and subsequently converted to complex type oligosaccharides as indicated by Endo
H resistance and PNGase F sensitivity. Overexpression of endomannosidase in castanospermine-treated hepatocytes resulted in
processing of all oligosaccharides of wild-type and variants of α1-antitrypsin. Thus, endomannosidase does not discriminate
the folding state of the substrate and provides a back-up mechanism for completion of N-glycosylation of endoplasmic reticulum-escaped glucosylated glycoproteins. For exported misfolded glycoproteins, this would
provide a pathway for the formation of mature oligosaccharides important for their proper trafficking and correct functioning.
Received 18 April 2006; received after revision 12 June 2006; accepted 15 June 2006 相似文献
1000.
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type 总被引:10,自引:0,他引:10
Lerner-Ellis JP Tirone JC Pawelek PD Doré C Atkinson JL Watkins D Morel CF Fujiwara TM Moras E Hosack AR Dunbar GV Antonicka H Forgetta V Dobson CM Leclerc D Gravel RA Shoubridge EA Coulton JW Lepage P Rommens JM Morgan K Rosenblatt DS 《Nature genetics》2006,38(1):93-100
Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. 相似文献