全文获取类型
收费全文 | 3743篇 |
免费 | 245篇 |
专业分类
3988篇 |
出版年
2024年 | 3篇 |
2023年 | 30篇 |
2022年 | 68篇 |
2021年 | 101篇 |
2020年 | 52篇 |
2019年 | 84篇 |
2018年 | 105篇 |
2017年 | 87篇 |
2016年 | 134篇 |
2015年 | 223篇 |
2014年 | 224篇 |
2013年 | 260篇 |
2012年 | 399篇 |
2011年 | 304篇 |
2010年 | 189篇 |
2009年 | 185篇 |
2008年 | 238篇 |
2007年 | 240篇 |
2006年 | 202篇 |
2005年 | 185篇 |
2004年 | 148篇 |
2003年 | 124篇 |
2002年 | 129篇 |
2001年 | 20篇 |
2000年 | 11篇 |
1999年 | 29篇 |
1998年 | 18篇 |
1997年 | 16篇 |
1996年 | 6篇 |
1995年 | 19篇 |
1994年 | 11篇 |
1993年 | 15篇 |
1992年 | 16篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 9篇 |
1988年 | 7篇 |
1987年 | 10篇 |
1986年 | 8篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1974年 | 3篇 |
1972年 | 4篇 |
1967年 | 2篇 |
排序方式: 共有3988条查询结果,搜索用时 15 毫秒
41.
Bennati AM Castelli M Della Fazia MA Beccari T Caruso D Servillo G Roberti R 《Biochimica et biophysica acta》2006,1761(7):677-685
3Beta-hydroxysterol Delta(14)-reductase operates during the conversion of lanosterol to cholesterol in mammalian cells. Besides the endoplasmic reticulum 3beta-hydroxysterol Delta(14)-reductase (C14SR) encoded by TM7SF2 gene, the lamin B receptor (LBR) of the inner nuclear membrane possesses 3beta-hydroxysterol Delta(14)-reductase activity, based on its ability to complement C14SR-defective yeast strains. LBR was indicated as the primary 3beta-hydroxysterol Delta(14)-reductase in human cholesterol biosynthesis, since mutations in LBR gene were found in Greenberg skeletal dysplasia, characterized by accumulation of Delta(14)-unsaturated sterols. This study addresses the issue of C14SR and LBR role in cholesterol biosynthesis. Both human C14SR and LBR expressed in COS-1 cells exhibit 3beta-hydroxysterol Delta(14)-reductase activity in vitro. TM7SF2 mRNA and C14SR protein expression in HepG2 cells grown in delipidated serum (LPDS) plus lovastatin (sterol starvation) were 4- and 8-fold higher, respectively, than in LPDS plus 25-hydroxycholesterol (sterol feeding), resulting in 4-fold higher 3beta-hydroxysterol Delta(14)-reductase activity. No variations in LBR mRNA and protein levels were detected in the same conditions. The induction of TM7SF2 gene expression is turned-on by promoter activation in response to low cell sterol levels and is mediated by SREBP-2. The results suggest a primary role of C14SR in human cholesterol biosynthesis, whereas LBR role in the pathway remains unclear. 相似文献
42.
de Amicis F Lanzino M Kisslinger A Calì G Chieffi P Andò S Mancini FP Tramontano D 《Journal of cellular physiology》2006,209(1):74-80
Although prostate carcinoma is an aggressive cancer preferentially metastasizing to the bones, many prostate tumors remain localized and confined to the prostate indefinitely. Prediction of the behavior of anatomically localized and moderately differentiated prostate tumors remains difficult because of lack of prognostic markers. Cell motility is an important step in the progression of epithelial tumor toward invasive metastatic carcinomas and changes in the expression and function of adhesion molecules contribute to the acquisition of a more malignant phenotype. Proline-rich tyrosine kinase 2 (Pyk2) is implicated in regulating the organization of actin cytoskeleton, a process critical for cell migration, mitosis, and tumor metastasis. In this report, we investigated whether Pyk2 played a role in the acquisition of an aggressive phenotype in prostate cell. Data reported here demonstrate that loss of Pyk2 kinase function results in induction of cell motility and migration in EPN cells, a line of non-transformed epithelial cells derived from human normal prostate tissue. Changes in motility and migration of prostate cells were associated with changes in the expression of several proteins involved in cell adhesion and reorganization of actin cytoskeleton. Ablation of Pyk2 kinase activity caused a dramatic decrease of the expression of E-cadherin and IRS1 and an increase of the expression of alpha5-integrin. In addition, a massive reorganization of actin cytoskeleton was observed. Our data indicate that Pyk2 plays a central role in the mechanism that regulate cell-cell and cell-substrate interaction and lack of its kinase activity induces prostate cells to acquire a malignant, migrating phenotype. 相似文献
43.
44.
Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells 总被引:1,自引:0,他引:1
Meng A Luberto C Meier P Bai A Yang X Hannun YA Zhou D 《Experimental cell research》2004,292(2):385-392
Tricyclodecan-9-yl-xanthogenate (D609) is a selective tumor cytotoxic agent. However, the mechanisms of action of D609 against tumor cells have not been well established. Using U937 human monocytic leukemia cells, we examined the ability of D609 to inhibit sphingomyelin synthase (SMS), since inhibition of SMS may contribute to D609-induced tumor cell cytotoxicity via modulating the cellular levels of ceramide and diacylglycerol (DAG). The results showed that D609 is capable of inducing U937 cell death by apoptosis in a dose- and time-dependent manner. The induction of U937 cell apoptosis was associated with an inhibition of SMS activity and a significant increase in the intracellular level of ceramide and decrease in that of sphingomyelin (SM) and DAG, which resulted in an elevation of the ratio between ceramide and DAG favoring the induction of apoptosis. In addition, incubation of U937 cells with C(6)-ceramide and/or H7 (a selective PKC inhibitor) reduced U937 cell viability; whereas pretreatment of the cells with a PKC activator, PMA or 1-oleoyl-2-acetylglycerol (OAG), attenuated D609-induced U937 cell apoptosis. These results suggest that SMS is a potential target of D609 and inhibition of SMS may contribute to D609-induced tumor cell death via modulation of the cellular levels of ceramide and DAG. 相似文献
45.
Lambertucci C Cristalli G Dal Ben D Kachare DD Bolcato C Klotz KN Spalluto G Volpini R 《Purinergic signalling》2007,3(4):339-346
A new series of 2,6,9-trisubstituted adenines (5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A1, A2A and A3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N
6 position of 9-propyladenine significantly increased binding affinity at the human A1 and A3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending
on the receptor subtype and/or on the substituent present in the N
6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human
A2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct
receptor selectivity profiles. 相似文献
46.
Long term bed rest with and without vibration exercise countermeasures: effects on human muscle protein dysregulation 总被引:1,自引:0,他引:1
Moriggi M Vasso M Fania C Capitanio D Bonifacio G Salanova M Blottner D Rittweger J Felsenberg D Cerretelli P Gelfi C 《Proteomics》2010,10(21):3756-3774
The present investigation, the first in the field, was aimed at analyzing differentially, on individual samples, the effects of 55 days of horizontal bed rest, a model for microgravity, on myosin heavy and myosin light chain isoforms distribution (by SDS) and on the proteome (by 2-D DIGE and MS) in the vastus lateralis (VL), a mixed type II/I (~50:50%) head of the quadriceps and in the calf soleus (SOL), a predominantly slow (~35:65%) twitch muscle. Two separate studies were performed on six subjects without (BR) and six with resistive vibration exercise (RVE) countermeasures, respectively. Both VL and SOL underwent in BR decrements of ~15% in cross-sectional area and of ~22% in maximal torque that were prevented by RVE. Myosin heavy chain distribution showed increased type I and decreased type IIA in BR both in VL and in SOL, the opposite with RVE. A substantial downregulation of proteins involved in aerobic metabolism characterized both in SOL and VL in BR. RVE reversed the pattern more in VL than in SOL, whereas proteins involved in anaerobic glycolysis were upregulated. Proteins from the Z-disk region and from costamers were differently dysregulated during bed rest (both BR and RVE), particularly in VL. 相似文献
47.
The paper couples the results obtained by applying the expert and the rapid Macrophyte Quality Indices set up to assess the
ecological status of the Italian transitional environments according to the requirements by the Water Framework Directive
(2000/60/CE). The indices were validated by comparing the composition of the macrophyte assemblages and the values of some
bio-physico-chemical parameters of the water column of 20 stations of the Venice lagoon sampled monthly for one year between
2003 and 2005. In 5 stations out of the 20, the ones which fall within the 5 classes of ecological status suggested by the
Water Framework Directive, sedimentation rates, sediment grain-size, and nutrient and pollutant (metals, Polychloro-Dibenzo-Dioxins/Furans,
Polycyclic Aromatic Hydrocarbons, Pesticides and Polychlorinated Biphenils) concentrations in surface sediments were also
determined. Results showed strong relationships between the trends of these environmental parameters and the composition and
structure of macrophyte associations, as well as with the Macrophyte Quality Index assessment. Chlorophyceae showed a trend
opposite to Rhodophyceae whose presence was concentrated in oxygenated and transparent environments. Chlorophyceae and the
species characterised by low scores prevailed in turbid areas where nutrient and pollutant concentrations were high. Results
allowed the identification of the conditions of the “reference sites” (confinement areas and sites with high water renewal)
and the integration of the dichotomic key used for the application of the R-MaQI.
Handling editor: S. M. Thomaz 相似文献
48.
Francesca Borgo Aristodemo Carpen Chiara Ferrario Stefania Iametti Maria Grazia Fortina 《Journal of industrial microbiology & biotechnology》2013,40(5):489-494
Through the analysis of the recently available genome shotgun sequence of Enterococcus italicus DSM 15952T type strain (Accession PRJNA61487, ID 61487), we found the presence of a gene encoding a bifunctional enzyme, termed γ-GCS-GS or GshF, involved in glutathione production and not influenced by feedback inhibition. The gshF gene exhibited high nucleotide and amino acid sequence similarity to other reported sequences from the Enterococcus genus and was constitutively expressed both in osmotic shock or in common cultural conditions. Several experimental studies concerning the culture medium, physiological stress, cell extract obtainment, and scaling-up showed that in selected conditions E. italicus was able to accumulate up to 250 μM of intracellular glutathione, which represented the main thiol group present into the cells. This is the first report regarding the production of glutathione by E. italicus, a species that could be used as a safe adjunct culture for glutathione-enriched dairy foods. 相似文献
49.
50.
Marazziti D Baroni S Pirone A Giannaccini G Betti L Schmid L Vatteroni E Palego L Borsini F Bordi F Piano I Gargini C Castagna M Catena-Dell'osso M Lucacchini A 《Neurochemical research》2012,37(5):920-927
The aim of this study was to investigate the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in postmortem human prefrontal cortex, striatum and hippocampus. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by the pharmacological characterization, where possible, and by autoradiographic, immunohistochemical and immunofluorescence evaluations. A specific and saturable [(125)I]SB-258585 binding was detected in striatum only, with a pharmacological characterization consistent with that of a 5-HT(6) receptor. The autoradiography showed the presence of a specific [(125)I]SB-258585 binding distributed homogeneously in caudate, putamen and accumbens. The immunohistochemistry, carried out in the striatum only, coupled with the immunofluorescence with glial fibrillary acidic protein (GFAP) and parvalbumin (PV) showed the co-localization of 5-HT(6) receptor with PV, while indicating that this receptor subtype was expressed in neurons and not in astrocytes. Taken together, the present findings showed the presence of a higher density of 5-HT(6) receptors, as labeled by [(125)I]SB-258585, in striatum than in hippocampus and prefrontal cortex, and specifically within the neuronal body. In addition, they would suggest that striatum is one of the major potential CNS targets linked to 5-HT(6) receptor modulation. 相似文献