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71.
The construction of stable blood vessels is a fundamental challenge for tissue engineering in regenerative medicine. Although certain genes can be introduced into vascular cells to enhance their survival and proliferation, these manipulations may be oncogenic. We show here that a network of long-lasting blood vessels can be formed in mice by co-implantation of vascular endothelial cells and mesenchymal precursor cells, by-passing the need for risky genetic manipulations. These networks are stable and functional for one year in vivo. 相似文献
72.
Douma S Van Laar T Zevenhoven J Meuwissen R Van Garderen E Peeper DS 《Nature》2004,430(7003):1034-1039
Metastasis is a major factor in the malignancy of cancers, and is often responsible for the failure of cancer treatment. Anoikis (apoptosis resulting from loss of cell-matrix interactions) has been suggested to act as a physiological barrier to metastasis; resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumour formation in distant organs. In an attempt to identify metastasis-associated oncogenes, we designed an unbiased, genome-wide functional screen solely on the basis of anoikis suppression. Here, we report the identification of TrkB, a neurotrophic tyrosine kinase receptor, as a potent and specific suppressor of caspase-associated anoikis of non-malignant epithelial cells. By activating the phosphatidylinositol-3-OH kinase/protein kinase B pathway, TrkB induced the formation of large cellular aggregates that survive and proliferate in suspension. In mice, these cells formed rapidly growing tumours that infiltrated lymphatics and blood vessels to colonize distant organs. Consistent with the ability of TrkB to suppress anoikis, metastases--whether small vessel infiltrates or large tumour nodules--contained very few apoptotic cells. These observations demonstrate the potent oncogenic effects of TrkB and uncover a specific pro-survival function that may contribute to its metastatic capacity, providing a possible explanation for the aggressive nature of human tumours that overexpress TrkB. 相似文献
73.
74.
Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome 总被引:6,自引:0,他引:6
Windpassinger C Auer-Grumbach M Irobi J Patel H Petek E Hörl G Malli R Reed JA Dierick I Verpoorten N Warner TT Proukakis C Van den Bergh P Verellen C Van Maldergem L Merlini L De Jonghe P Timmerman V Crosby AH Wagner K 《Nature genetics》2004,36(3):271-276
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration. 相似文献
75.
Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis 总被引:11,自引:0,他引:11
Hellemans J Preobrazhenska O Willaert A Debeer P Verdonk PC Costa T Janssens K Menten B Van Roy N Vermeulen SJ Savarirayan R Van Hul W Vanhoenacker F Huylebroeck D De Paepe A Naeyaert JM Vandesompele J Speleman F Verschueren K Coucke PJ Mortier GR 《Nature genetics》2004,36(11):1213-1218
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells. 相似文献
76.
Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer 总被引:29,自引:0,他引:29
Suzuki H Watkins DN Jair KW Schuebel KE Markowitz SD Chen WD Pretlow TP Yang B Akiyama Y Van Engeland M Toyota M Tokino T Hinoda Y Imai K Herman JG Baylin SB 《Nature genetics》2004,36(4):417-422
Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer. 相似文献
77.
Ding H Wu X Boström H Kim I Wong N Tsoi B O'Rourke M Koh GY Soriano P Betsholtz C Hart TC Marazita ML Field LL Tam PP Nagy A 《Nature genetics》2004,36(10):1111-1116
PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers. Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated. 相似文献
78.
Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia 总被引:16,自引:0,他引:16
Hu Y Liu Y Pelletier S Buchdunger E Warmuth M Fabbro D Hallek M Van Etten RA Li S 《Nature genetics》2004,36(5):453-461
The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia. 相似文献
79.
Davila S Furu L Gharavi AG Tian X Onoe T Qian Q Li A Cai Y Kamath PS King BF Azurmendi PJ Tahvanainen P Kääriäinen H Höckerstedt K Devuyst O Pirson Y Martin RS Lifton RP Tahvanainen E Torres VE Somlo S 《Nature genetics》2004,36(6):575-577
Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease. 相似文献
80.