全文获取类型
收费全文 | 78907篇 |
免费 | 6553篇 |
国内免费 | 4801篇 |
专业分类
90261篇 |
出版年
2024年 | 138篇 |
2023年 | 901篇 |
2022年 | 2076篇 |
2021年 | 3602篇 |
2020年 | 2326篇 |
2019年 | 2838篇 |
2018年 | 2868篇 |
2017年 | 2029篇 |
2016年 | 2872篇 |
2015年 | 4586篇 |
2014年 | 5294篇 |
2013年 | 5965篇 |
2012年 | 6898篇 |
2011年 | 6353篇 |
2010年 | 3817篇 |
2009年 | 3372篇 |
2008年 | 4112篇 |
2007年 | 3652篇 |
2006年 | 3171篇 |
2005年 | 2679篇 |
2004年 | 2276篇 |
2003年 | 1972篇 |
2002年 | 1730篇 |
2001年 | 1559篇 |
2000年 | 1565篇 |
1999年 | 1447篇 |
1998年 | 847篇 |
1997年 | 797篇 |
1996年 | 808篇 |
1995年 | 736篇 |
1994年 | 687篇 |
1993年 | 530篇 |
1992年 | 818篇 |
1991年 | 657篇 |
1990年 | 601篇 |
1989年 | 531篇 |
1988年 | 421篇 |
1987年 | 362篇 |
1986年 | 336篇 |
1985年 | 299篇 |
1984年 | 221篇 |
1983年 | 199篇 |
1982年 | 112篇 |
1981年 | 118篇 |
1980年 | 86篇 |
1979年 | 147篇 |
1978年 | 84篇 |
1977年 | 95篇 |
1975年 | 111篇 |
1974年 | 116篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
21.
R B Widelitz T X Jiang C W Chen N S Stott H S Jung C M Chuong 《Development (Cambridge, England)》1999,126(12):2577-2587
How do vertebrate epithelial appendages form from the flat epithelia? Following the formation of feather placodes, the previously radially symmetrical primordia become anterior-posterior (A-P) asymmetrical and develop a proximo-distal (P-D) axis. Analysis of the molecular heterogeneity revealed a surprising parallel of molecular profiles in the A-P feather buds and the ventral-dorsal (V-D) Drosophila appendage imaginal discs. The functional significance was tested with an in vitro feather reconstitution model. Wnt-7a expression initiated all over the feather tract epithelium, intensifying as it became restricted first to the primordia domain, then to an accentuated ring pattern within the primordia border, and finally to the posterior bud. In contrast, sonic hedgehog expression was induced later as a dot within the primordia. RCAS was used to overexpress Wnt-7a in reconstituted feather explants derived from stage 29 dorsal skin to further test its function in feather formation. Control skin formed normal elongated, slender buds with A-P orientation, but Wnt-7a overexpression led to plateau-like skin appendages lacking an A-P axis. Feathers in the Wnt-7a overexpressing skin also had inhibited elongation of the P-D axes. This was not due to a lack of cell proliferation, which actually was increased although randomly distributed. While morphogenesis was perturbed, differentiation proceeded as indicated by the formation of barb ridges. Wnt-7a buds have reduced expression of anterior (Tenascin) bud markers. Middle (Notch-1) and posterior bud markers including Delta-1 and Serrate-1 were diffusely expressed. The results showed that ectopic Wnt-7a expression enhanced properties characteristic of the middle and posterior feather buds and suggest that P-D elongation of vertebrate skin appendages requires balanced interactions between the anterior and posterior buds. 相似文献
22.
Growth-related expression of a double-stranded RNA-dependent protein kinase in 3T3 cells 总被引:14,自引:0,他引:14
Cultured mouse 3T3-F442A and 3T3-C2 fibroblasts exhibit a transient double-stranded RNA (dsRNA)-dependent phosphorylation of a 67,000-dalton protein (67K) without prior treatment with interferon (IFN). This phosphoprotein is similar but not identical to the dsRNA-dependent eukaryotic initiation factor-2 (eIF-2) alpha protein kinase (dsI), which regulates protein synthesis in rabbit reticulocytes. We have studied the relationship between cell growth and phosphorylation of the 67K protein (designated 3T3-dsRNA-dependent eIF-2 alpha kinase). A low level of dsRNA-dependent phosphorylation of 3T3-dsI was detectable in extracts prepared from cells not treated with IFN and grown at a low cell density. The phosphorylation of dsI and the phosphorylation of a 38K protein identified as the alpha-subunit (38K) of 3T3-eIF-2 (eIF-2 alpha) occurred concomitantly; the levels of these phosphorylations confluent and thereafter decreased markedly. Treatment of cells with IFN at all stages of growth resulted in an increase in phosphorylation of dsI. 3T3-F442A and 3T3-C2 fibroblasts were found to produce and secrete IFN at levels sufficient to induce an elevated dsI activity. 相似文献
23.
Peng Wang Ronghua Luo Min Zhang Yaqing Wang Tianzhang Song Tingting Tao Zhongyu Li Lin Jin Hongyi Zheng Wenwen Chen Mengqian Zhao Yongtang Zheng Jianhua Qin 《Cell death & disease》2020,11(12)
COVID-19, caused by SARS-CoV-2, is an acute and rapidly developing pandemic, which leads to a global health crisis. SARS-CoV-2 primarily attacks human alveoli and causes severe lung infection and damage. To better understand the molecular basis of this disease, we sought to characterize the responses of alveolar epithelium and its adjacent microvascular endothelium to viral infection under a co-culture system. SARS-CoV-2 infection caused massive virus replication and dramatic organelles remodeling in alveolar epithelial cells, alone. While, viral infection affected endothelial cells in an indirect manner, which was mediated by infected alveolar epithelium. Proteomics analysis and TEM examinations showed viral infection caused global proteomic modulations and marked ultrastructural changes in both epithelial cells and endothelial cells under the co-culture system. In particular, viral infection elicited global protein changes and structural reorganizations across many sub-cellular compartments in epithelial cells. Among the affected organelles, mitochondrion seems to be a primary target organelle. Besides, according to EM and proteomic results, we identified Daurisoline, a potent autophagy inhibitor, could inhibit virus replication effectively in host cells. Collectively, our study revealed an unrecognized cross-talk between epithelium and endothelium, which contributed to alveolar–capillary injury during SARS-CoV-2 infection. These new findings will expand our understanding of COVID-19 and may also be helpful for targeted drug development.Subject terms: Mechanisms of disease, Viral infection 相似文献
24.
Vinyl chloride (VC) is used as an example to demonstrate how biological information can be incorporated into quantitative risk assessment. The information included is the pharmacokinetics of VC in animals and humans and the data-generated hypothesis that VC primarily affects the initiation stage of the multistage carcinogenesis. The emphasis in this paper is on the improvement of risk assessment methodology rather than the risk assessment of VC per se.Sufficient data are available to construct physiologically-based pharmacokinetic models for both animals and humans. These models are used to calculate the metabolized dose corresponding to exposure scenarios in animals and in humans.On the basis of the data on liver angiosarcomas and carcinomas in rats, the cancer risk per unit of metabolized dose is comparable, irrespective of routes (oral or inhalation) of exposure. The tumor response from an intermittent/partial lifetime exposure is shown to be consistent with that from a lifetime exposure when VC is assumed to affect the first (initiation) stage of the multistage carcinogenic process. Furthermore, the risk estimates calculated on the basis of animal data are shown to be consistent with the human experience. 相似文献
25.
26.
Semiparametric Regression in Size-Biased Sampling 总被引:1,自引:0,他引:1
Ying Qing Chen 《Biometrics》2010,66(1):149-158
Summary . Size-biased sampling arises when a positive-valued outcome variable is sampled with selection probability proportional to its size. In this article, we propose a semiparametric linear regression model to analyze size-biased outcomes. In our proposed model, the regression parameters of covariates are of major interest, while the distribution of random errors is unspecified. Under the proposed model, we discover that regression parameters are invariant regardless of size-biased sampling. Following this invariance property, we develop a simple estimation procedure for inferences. Our proposed methods are evaluated in simulation studies and applied to two real data analyses. 相似文献
27.
Y Y Shiau K C Chen 《Proceedings of the National Science Council, Republic of China. Part B, Life sciences》1986,10(1):57-63
A synchronized system of EMG and jaw motion tracking device was used to observe some chewing parameters of jaw elevator muscles in 15 patients with temporomandibular joint and muscle pain dysfunction syndrome (TMJ) and 15 normal subjects. Duration of tooth contact (DTC), duration of muscle contraction before tooth contact (DMC), total duration of muscle contraction (DTM) and velocity of jaw movement during peanut chewing were observed. Symptoms of the TMJ patients included pain and tenderness at joints and muscles, and limitation and clicking at joints during jaw movements. It was found that the TMJ patients needed more numerous breaking off strokes before trituration at the occlusal level. There was a longer DMC in the earlier trituration period and TMJ patients had longer DMC than in normals. No difference was found between right and left side chewing or between temporalis and masseter muscles. DTM in the TMJ group was only slightly longer than in normals and the difference between early and late chewing periods was statistically not significant. DTC was only slightly shorter in the TMJ group while the difference between early and late chewing periods in both groups was significant. The average and maximum closing velocities were significantly lower in the TMJ group in both right and left chewing. The difference in the opening phase was not as significant. It was concluded that DMC and jaw closing velocity are more sensitive parameters than DTM and DTC on the diagnosis of TMJ dysfunction with or without occlusal interference. DTM and DTC are parameters more closely related to the influence of occlusal factors.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
28.
The 231-residue capsid (CA) protein of human immunodeficiency virus type 1 (HIV-1) spontaneously self-assembles into tubes with a hexagonal lattice that is believed to mimic the surface lattice of conical capsid cores within intact virions. We report the results of solid-state nuclear magnetic resonance (NMR) measurements on HIV-1 CA tubes that provide new information regarding changes in molecular structure that accompany CA self-assembly, local dynamics within CA tubes, and possible mechanisms for the generation of lattice curvature. This information is contained in site-specific assignments of signals in two- and three-dimensional solid-state NMR spectra, conformation-dependent 15N and 13C NMR chemical shifts, detection of highly dynamic residues under solution NMR conditions, measurements of local variations in transverse spin relaxation rates of amide 1H nuclei, and quantitative measurements of site-specific 15N–15N dipole–dipole couplings. Our data show that most of the CA sequence is conformationally ordered and relatively rigid in tubular assemblies and that structures of the N-terminal domain (NTD) and the C-terminal domain (CTD) observed in solution are largely retained. However, specific segments, including the N-terminal β-hairpin, the cyclophilin A binding loop, the inter-domain linker, segments involved in intermolecular NTD–CTD interactions, and the C-terminal tail, have substantial static or dynamical disorder in tubular assemblies. Other segments, including the 310-helical segment in CTD, undergo clear conformational changes. Structural variations associated with curvature of the CA lattice appear to be localized in the inter-domain linker and intermolecular NTD–CTD interface, while structural variations within NTD hexamers, around local 3-fold symmetry axes, and in CTD–CTD dimerization interfaces are less significant. 相似文献
29.
We have established a series of 20 colorectal cancer cell lines and performed cytogenetic and RFLP analyses to show that the
recurrent genetic abnormalities of chromosomes 1, 5, 17 and 18 associated with multistep tumorigenesis in colorectal cancer,
and frequently detected as recurrent abnormalities in primary tumours, are also retained in long-term established cell lines.
Earlier studies by us and other investigators showed that allelic losses of chromosomes 1 and 17 in primary colorectal cancers
predicted poorer survival for the patients (P = 0.03). We utilized the cell lines to identify specific chromosomal sites or gene(s) on chromosomes 1 and 17 which confer
more aggressive phenotype. Cytogenetic deletions of chromosome 1p were detected in 14 out of the 20 (70%) cell lines, whereas
allelic deletions for 1p using polymorphic markers were detected in 13 out of 18 (72%) informative cell lines for at least
one polymorphic marker. We have performed Northern blotting, immunohistochemical staining (p53 mRNA, protein) and RFLP analysis
using several probes including p53 and nm23. RFLP analysis using a total of seven polymorphic markers located on 17p and 17q
arms showed allelic losses aroundthe p53 locus in 16 out of the 20 cell lines (80%), four of which were losses of thep53 locus itself. In addition, seven cell lines (out of nine informative cases) also showed losses of thenm23 gene, four with concurrent losses of thep53 locus, while the remaining three were homozygous. In addition, five out of seven cell lines withnm23 deletions were derived from hepatic metastatic tumours, and one cell line was obtained from recurrent tumour. A comparison
between allelic deletions of 1p and functional loss ofnm23 gene revealed a close association between these two events in cell lines derived from hepatic metastasis. Following immunohistochemical
staining, nine out of the twenty cell lines showed high levels (25–80%) of mutant p53, four showed intermediate levels (>20%),
and seven had undetectable levels of the protein. Of these seven, four showed complete absence of mRNA. Of the remaining three
cell lines one showed aberrant mRNA due to germline rearrangement of thep53 gene, whereas in two cell lines normal levels of mRNA were present. Nineteen of the 20 cell lines had normal germline configurations
for thep53 gene, while one showed a rearrangement. These data suggest that functional loss ofp53 andnm23 genes accomplished by a variety of mechanisms may be associated with poor prognosis and survival. In addition, concurrent
deletions of chromosome regions 17p, 17q and 1p were closely associated with high-stage hepatic metastatic disease. These
cell lines with well-characterized genetic alterations and known clinical history provide an invaluable source of material
for various biological and clinical studies relating to multistep colorectal tumorigenesis. 相似文献
30.
Yitao Luo Chengqiang Zhang Li Ma Yuxiao Zhang Zhengyuan Liu Li Chen Rui Wang Yujing Luan Yulan Rao 《Journal of lipid research》2022,63(6):100228
7-dehydrocholesterol (7-DHC) and cholesterol (CHOL) are biomarkers of Smith-Lemli-Opitz Syndrome (SLOS), a congenital autosomal recessive disorder characterized by elevated 7-DHC level in patients. Hair samples have been shown to have great diagnostic and research value, which has long been neglected in the SLOS field. In this study, we sought to investigate the feasibility of using hair for SLOS diagnosis. In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), hair samples were completely pulverized and extracted by micro-pulverized extraction in alkaline solution or in n-hexane. After microwave-assisted derivatization with N,O-Bis(trimethylsilyl)trifluoroacetamide, the analytes were measured by GC-MS. We found that the limits of determination for 7-DHC and CHOL were 10 ng/mg and 8 ng/mg, respectively. In addition, good linearity was obtained in the range of 50–4000 ng/mg and 30–6000 ng/mg for 7-DHC and CHOL, respectively, which fully meets the requirement for SLOS diagnosis and related research. Finally, by applying the proposed method to real hair samples collected from 14 healthy infants and two suspected SLOS patients, we confirmed the feasibility of hair analysis as a diagnostic tool for SLOS. In conclusion, we present an optimized and validated analytical method for the simultaneous determination of two SLOS biomarkers using human hair. 相似文献