全文获取类型
收费全文 | 1802篇 |
免费 | 166篇 |
出版年
2023年 | 8篇 |
2022年 | 14篇 |
2021年 | 26篇 |
2020年 | 26篇 |
2019年 | 27篇 |
2018年 | 52篇 |
2017年 | 38篇 |
2016年 | 53篇 |
2015年 | 89篇 |
2014年 | 72篇 |
2013年 | 140篇 |
2012年 | 144篇 |
2011年 | 110篇 |
2010年 | 89篇 |
2009年 | 61篇 |
2008年 | 93篇 |
2007年 | 121篇 |
2006年 | 86篇 |
2005年 | 86篇 |
2004年 | 71篇 |
2003年 | 72篇 |
2002年 | 64篇 |
2001年 | 37篇 |
2000年 | 31篇 |
1999年 | 33篇 |
1998年 | 17篇 |
1997年 | 19篇 |
1996年 | 9篇 |
1995年 | 11篇 |
1994年 | 14篇 |
1993年 | 13篇 |
1992年 | 19篇 |
1991年 | 21篇 |
1990年 | 18篇 |
1989年 | 20篇 |
1988年 | 14篇 |
1987年 | 10篇 |
1986年 | 13篇 |
1985年 | 14篇 |
1984年 | 10篇 |
1983年 | 15篇 |
1982年 | 6篇 |
1981年 | 7篇 |
1980年 | 6篇 |
1978年 | 5篇 |
1977年 | 9篇 |
1974年 | 5篇 |
1973年 | 8篇 |
1968年 | 8篇 |
1964年 | 5篇 |
排序方式: 共有1968条查询结果,搜索用时 73 毫秒
81.
Comparative proteome profiling and functional analysis of chronic myelogenous leukemia cell lines 总被引:1,自引:0,他引:1
Fontana S Alessandro R Barranca M Giordano M Corrado C Zanella-Cleon I Becchi M Kohn EC De Leo G 《Journal of proteome research》2007,6(11):4330-4342
The aim of the present study was the molecular profiling of different Ph+ chronic myelogenous leukemia (CML) cell lines (LAMA84, K562, and KCL22) by a proteomic approach. By employing two-dimensional gel electrophoresis combined with mass spectrometry analysis, we have identified 191 protein spots corresponding to 142 different proteins. Among these, 63% were cancer-related proteins and 74% were described for the first time in leukemia cells. Multivariate analysis highlighted significant differences in the global proteomic profile of the three CML cell lines. In particular, the detailed analysis of 35 differentially expressed proteins revealed that LAMA84 cells preferentially expressed proteins associated with an invasive behavior, while K562 and KCL22 cells preferentially expressed proteins involved in drug resistance. These data demonstrate that these CML cell lines, although representing the same pathological phenotype, show characteristics in their protein expression profile that suggest different phenotypic leukemia subclasses. These data contribute a new potential characterization of the CML phenotype and may help to understand interpatient variability in the progression of disease and in the efficacy of a treatment. 相似文献
82.
Giordano J Ge Y Gelfand Y Abrusán G Benson G Warburton PE 《PLoS computational biology》2007,3(7):e137
The constant bombardment of mammalian genomes by transposable elements (TEs) has resulted in TEs comprising at least 45% of the human genome. Because of their great age and abundance, TEs are important in comparative phylogenomics. However, estimates of TE age were previously based on divergence from derived consensus sequences or phylogenetic analysis, which can be unreliable, especially for older more diverged elements. Therefore, a novel genome-wide analysis of TE organization and fragmentation was performed to estimate TE age independently of sequence composition and divergence or the assumption of a constant molecular clock. Analysis of TEs in the human genome revealed approximately 600,000 examples where TEs have transposed into and fragmented other TEs, covering >40% of all TEs or approximately 542 Mbp of genomic sequence. The relative age of these TEs over evolutionary time is implicit in their organization, because newer TEs have necessarily transposed into older TEs that were already present. A matrix of the number of times that each TE has transposed into every other TE was constructed, and a novel objective function was developed that derived the chronological order and relative ages of human TEs spanning >100 million years. This method has been used to infer the relative ages across all four major TE classes, including the oldest, most diverged elements. Analysis of DNA transposons over the history of the human genome has revealed the early activity of some MER2 transposons, and the relatively recent activity of MER1 transposons during primate lineages. The TEs from six additional mammalian genomes were defragmented and analyzed. Pairwise comparison of the independent chronological orders of TEs in these mammalian genomes revealed species phylogeny, the fact that transposons shared between genomes are older than species-specific transposons, and a subset of TEs that were potentially active during periods of speciation. 相似文献
83.
Jessica Perugini Laura Bordoni Wiebe Venema Samantha Acciarini Saverio Cinti Rosita Gabbianelli Antonio Giordano 《Journal of cellular physiology》2019,234(3):2031-2036
In the mammalian adipose organ cold exposure not only activates typical brown adipose tissue, but also induces browning, that is the formation of thermogenic multilocular adipocytes in white, or predominantly white, adipose depots such as subcutaneous fat. Unlike typical brown adipocytes, newly formed thermogenic adipocytes have been reported not to express the gene zinc finger of the cerebellum 1 (Zic1). Here, a time course approach enabled us to document a significant increase in Zic1 messenger RNA in inguinal subcutaneous fat from acutely (24 hr) cold-exposed mice, which was paralleled by an increase in multilocular and paucilocular uncoupling protein 1-positive adipocytes and in parenchymal noradrenergic innervation. This transient, depot-specific molecular signature was associated not to Zic1 promoter demethylation, but to chromatin remodeling through an H3K9me3 histone modification. These findings challenge the notion that Zic1 is exclusively expressed by typical brown adipocytes and suggest its involvement in brown adipocyte precursor differentiation and/or white-to-brown adipocyte transdifferentiation. 相似文献
84.
Balasubramanian Chandramouli Sara Del Galdo Giordano Mancini Vincenzo Barone 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(2):472-480
Background
The mechanism of how the hydrophilic threefold channel (C3) of ferritin nanocages facilitates diffusion of diverse metal ions into the internal cavity remains poorly explored.Methods
Computational modeling and free energy estimations were carried out on R. catesbeiana H´ ferritin. Transit features and associated energetics for Fe2+, Mg2+, Zn2+ ions through the C3 channel have been examined.Results
We highlight that iron conduction requires the involvement of two Fe2+ ions in the channel. In such doubly occupied configuration, as observed in X-ray structures, Fe2+ is displaced from the internal site (stabilized by D127) at lower energetic cost. Moreover, comparison of Fe2+, Mg2+ and Zn2+ transit features shows that E130 geometric constriction provides not only an electrostatic anchor to the incoming ions but also differentially influence their diffusion kinetics.Conclusions
Overall, the study provides insights into Fe2+ entry mechanism and characteristic features of metal-protein interactions that influence the metal ions passage. The dynamics data suggest that E130 may act as a metal selectivity gate. This implicates an ion-specific entry mechanism through the channel with the distinct diffusion kinetics being the discriminating factor.General Significance
Ferritin nanocages not only act as biological iron reservoirs but also have gained importance in material science as template scaffolds for synthesizing metal nanoparticles. This study provides mechanistic understanding on the conduction of different metal ions through the channel. 相似文献85.
Serena Ricci Federica Pinto Adelaide Auletta Antonio Giordano Alfonso Giovane Giuliana Settembre Mariarosaria Boccellino Silvia Boffo Angelina Di Carlo Marina Di Domenico 《Journal of cellular biochemistry》2019,120(5):6813-6819
The most prevalent malignancy in the oral cavity is represented by oral squamous cell carcinoma, an aggressive disease mostly detected in low-income communities. This neoplasia is mostly diffused in older men particularly exposed to risk factors such as tobacco, alcohol, and a diet rich in fatty foods and poor in vegetables. In oral squamous cell carcinoma, a wide range of matrix-cleaving proteinases are involved in extracellular matrix remodeling of cancer microenvironment. In particular, matrix metalloproteinases (MMPs) represent the major and most investigated protagonists. Owing to their strong involvement in malignant pathologies, MMPs are considered the most promising new biomarkers in cancer diagnosis and prognosis. The interest in studying MMPs in oral cancer biology is also owing to their prominent role in epithelial-to-mesenchymal transition (EMT). EMT is an intricate process involving different complex pathways. EMT-related proteins are attractive diagnostic biomarkers that characterize the activation of biological events that promote cancer's aggressive expansion. Different antioncogenic natural compounds have been investigated to counteract oral carcinogenesis, with the scope of obtaining better clinical results and lower morbidity. In particular, we describe the role of different nutraceuticals used for the regulation of MMP-related invasion and proliferation of oral cancer cells. 相似文献
86.
87.
Giordano D De Stefano ME Citro G Modica A Giorgi M 《Biochimica et biophysica acta》2001,1539(1-2):16-27
We have produced a polyclonal antibody that specifically recognizes cGMP-binding cGMP-specific phosphodiesterase (PDE5). The antibody was raised in rabbit using as immunogen a fusion protein, in which glutathione S-transferase was coupled to a 171 amino acid polypeptide of the N-terminal region of bovine PDE5. The antibody is able to immunoprecipitate PDE5 activity from mouse tissues and neuroblastoma extracts while it has no effect on all other PDE isoforms present in the extracts. PDE5 activity recovered in the immunoprecipitates retains its sensitivity to specific inhibitors such as zaprinast (IC(50)=0.6 microM) and sildenafil (IC(50)=3.5 nM). Bands of the expected molecular mass were revealed when solubilized immunoprecipitates were analysed in Western blots. The antibody selectively stained cerebellar Purkinje neurones, which are known to express high levels of PDE5 mRNA. Western blot analysis of mouse tissues revealed the highest expression signal in mouse lung, followed by heart and cerebellum, while a lower signal was evident in brain, kidney and a very low signal was present in the liver. In the hybrid neuroblastoma-glioma NG108-15 cells the antibody revealed a high PDE5 induction after dibutyryl-cAMP treatment. 相似文献
88.
Galimi F Cottone E Vigna E Arena N Boccaccio C Giordano S Naldini L Comoglio PM 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(2):1241-1247
Hepatocyte growth factor (HGF) is a potent paracrine mediator of stromal/epithelial interactions, which is secreted as a matrix-associated inactive precursor (pro-HGF) and locally activated by tightly controlled urokinase cleavage. It induces proliferation and motility in epithelial and endothelial cells, and plays a role in physiological and pathological processes involving invasive cell growth, such as angiogenesis and parenchymal regeneration. We now report that HGF induces directional migration and cytokine secretion in human monocytes. Monocyte activation by endotoxin and IL-1beta results in the up-regulation of the HGF receptor expression and in the induction of cell-associated pro-HGF convertase activity, thus enhancing cell responsiveness to the factor. Furthermore, we provide evidence for the secretion of biologically active HGF by activated monocytes, implying an autocrine stimulation. Altogether, these data indicate that monocyte function is modulated by HGF in a paracrine/autocrine manner, and provide a new link between stromal environment and mononuclear phagocytes. 相似文献
89.
Giordano M Oefner PJ Underhill PA Cavalli Sforza LL Tosi R Richiardi PM 《Genomics》1999,56(3):247-253
Genetic association analysis of candidate regions where evidence of linkage has accumulated is becoming a key issue in the study of complex diseases. A high density of markers, at least one per centimorgan, is required to improve the chances of observing linkage disequilibrium with disease alleles. A recently available single nucleotide polymorphism (SNP) map designed to cover the whole genome provides an average density of one marker per 2 cM. In the present study we show that the number of markers can be approximately doubled in a selected region, thus reaching a density suitable for association studies, by applying a completely automated technique for polymorphism detection, denaturing high-performance liquid chromatography (DHPLC). A systematic search for SNPs was performed in the region 5ptel-q13, where weak but convergent evidence for linkage with multiple sclerosis has accumulated. Screening for polymorphisms was performed on 124 sequence tagged sites (STSs) in the 3'UTR ends of expressed sequence tags totaling about 30,000 bp. Thirty SNPs in 28 STSs were found with less than 10% overlap with the markers already detected in the same region. The data confirm the validity of the approach using DHPLC on expressed gene sequences tagged by a set of standard commercially available primers. 相似文献
90.
Trimethylamine N-oxide reductase (TorA) is an anaerobically synthesized molybdoenzyme. It is translocated across the cytoplasmic membrane in a folded conformation via the Tat pathway of Escherichia coli. The requirement for phospholipids for the export of this enzyme was analyzed in the pgsA and pss mutants lacking anionic phospholipids and phosphatidylethanolamine, respectively. Anaerobic growth did not influence phospholipid composition of the pgsA and pss mutants. Interestingly, both pgsA and pss mutations severely retarded the translocation of TorA into the periplasm. Therefore, translocation of proteins through the Tat pathway is dependent on the anionic phospholipids and on lipid polymorphism. 相似文献