全文获取类型
收费全文 | 357篇 |
免费 | 37篇 |
出版年
2022年 | 2篇 |
2021年 | 2篇 |
2020年 | 10篇 |
2019年 | 7篇 |
2018年 | 11篇 |
2017年 | 7篇 |
2016年 | 13篇 |
2015年 | 23篇 |
2014年 | 20篇 |
2013年 | 27篇 |
2012年 | 15篇 |
2011年 | 16篇 |
2010年 | 15篇 |
2009年 | 9篇 |
2008年 | 13篇 |
2007年 | 19篇 |
2006年 | 16篇 |
2005年 | 15篇 |
2004年 | 15篇 |
2003年 | 10篇 |
2002年 | 12篇 |
2001年 | 4篇 |
2000年 | 11篇 |
1999年 | 4篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 4篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 7篇 |
1987年 | 11篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1977年 | 2篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1970年 | 4篇 |
1967年 | 3篇 |
1966年 | 2篇 |
1940年 | 1篇 |
排序方式: 共有394条查询结果,搜索用时 15 毫秒
51.
Zanuy M Ramos-Montoya A Villacañas O Canela N Miranda A Aguilar E Agell N Bachs O Rubio-Martinez J Pujol MD Lee WN Marin S Cascante M 《Metabolomics : Official journal of the Metabolomic Society》2012,8(3):454-464
Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G(1) phase. Aberrant expression of CDK4 and CDK6 is a hallmark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM (the calcein acetoxymethyl-ester) is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G(1) phase. The metabolic effects of calcein AM on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phosphate pathway was significantly altered. To elucidate whether these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors. 相似文献
52.
Roca-Cusachs P Alcaraz J Sunyer R Samitier J Farré R Navajas D 《Biophysical journal》2008,94(12):4984-4995
Shape-dependent local differentials in cell proliferation are considered to be a major driving mechanism of structuring processes in vivo, such as embryogenesis, wound healing, and angiogenesis. However, the specific biophysical signaling by which changes in cell shape contribute to cell cycle regulation remains poorly understood. Here, we describe our study of the roles of nuclear volume and cytoskeletal mechanics in mediating shape control of proliferation in single endothelial cells. Micropatterned adhesive islands were used to independently control cell spreading and elongation. We show that, irrespective of elongation, nuclear volume and apparent chromatin decondensation of cells in G1 systematically increased with cell spreading and highly correlated with DNA synthesis (percent of cells in the S phase). In contrast, cell elongation dramatically affected the organization of the actin cytoskeleton, markedly reduced both cytoskeletal stiffness (measured dorsally with atomic force microscopy) and contractility (measured ventrally with traction microscopy), and increased mechanical anisotropy, without affecting either DNA synthesis or nuclear volume. Our results reveal that the nuclear volume in G1 is predictive of the proliferative status of single endothelial cells within a population, whereas cell stiffness and contractility are not. These findings show that the effects of cell mechanics in shape control of proliferation are far more complex than a linear or straightforward relationship. Our data are consistent with a mechanism by which spreading of cells in G1 partially enhances proliferation by inducing nuclear swelling and decreasing chromatin condensation, thereby rendering DNA more accessible to the replication machinery. 相似文献
53.
In a previous study we have shown that SGS742, a cognitive enhancer acting by GABA(B) receptor antagonism improved spatial learning in OF1 mice. The aim of the study was therefore to screen representatives of several signaling cascades known to be involved in memory formation at the protein level. NaCl-, SGS742- treatment and yoked controls for NaCl and SGS742 were studied. Six hours following testing OF1 mice in the Morris water maze, hippocampal signaling proteins calmodulin kinase II (CaMKII) (phosphorylated (P) and non-phosphorylated (NP) form), CREB (P, NP), ERK (P, NP), BDNF, Egr-1, Trk-B and neuro-cytoskeleton elements drebrin and PSD-95 were determined by immunoblotting. Protein patterns were comparable between the control and SGS742 treated group revealing that these proteins may not be involved in the mechanisms underlying cognitive enhancement by SGS742 and this should be taken into account for interpretation and design of previous and future related neurochemical studies. 相似文献
54.
Evan S. Berk Albert J. Kovera Carol N. Boozer F.X. Pi‐Sunyer Julia A. Johnson Jeanine B. Albu 《Obesity (Silver Spring, Md.)》2005,13(9):1566-1571
Objective: Adiponectin influences insulin sensitivity (SI) and fat oxidation. Little is known about changes in adiponectin with changes in the fat content of eucaloric diets. We hypothesized that dietary fat content may influence adiponectin according to an individual's SI. Research Methods and Procedures: We measured changes in adiponectin, insulin, glucose, and leptin in response to high‐fat (HF) and low‐fat (LF) eucaloric diets in lean (n = 10) and obese (n = 11) subjects. Obese subjects were further subdivided in relation to a priori SI. Results: We found significantly higher insulin, glucose, and leptin and lower adiponectin in obese vs. lean subjects during both HF and LF. The mean group values of these measurements, including adiponectin (lean, HF 21.9 ± 9.8; LF, 20.8 ± 6.6; obese, HF 10.0 ± 3.3; LF, 9.5 ± 2.3 ng/mL; mean ± SD), did not significantly change between HF and LF diets. However, within the obese group, the insulin‐sensitive subjects had significantly higher adiponectin during HF than did the insulin‐resistant subjects. Additionally, the change in adiponectin from LF to HF diet correlated positively with the obese subjects’ baseline SI. Discussion: Although in lean and obese women, group mean values for adiponectin did not change significantly with a change in fat content of a eucaloric diet, a priori measured SI in obese subjects predicted an increase in adiponectin during the HF diet; this may be a mechanism that preserves SI in an already obese group. 相似文献
55.
The late Neogene rodent succession of the Guadix–Baza Basin (south‐eastern Spain) and its magnetostratigraphic correlation
下载免费PDF全文
![点击此处可从《Palaeontology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
In this paper a magnetostratigraphically calibrated biozonation of the Miocene–Pliocene continental record of the Guadix–Baza Basin (south‐eastern Spain) is presented. This biozonation is based on a rodent succession which ranges from the latest Miocene (c. 6 Ma) to the latest Pliocene (c. 2.6 Ma). A total of nine biozones have been defined for the late Miocene and Pliocene, all of them based on the range or concurrent‐range of rodent species: Apodemus gudrunae – Apocricetus alberti Zone, Apocricetus barrierei Zone, Paraethomys aff. abaigari Zone, Trilophomys Zone, Mimomys davakosi Zone, Dolomys adroveri Zone, Mimomys hassiacus Zone, Mimomys polonicus Zone and Kislangia ischus Zone. A magnetobiostratigraphical correlation has been established between these biozones and the standard ATNTS scale, on the basis of the palaeomagnetic analysis carried out on the sections of Negratín, Botardo‐1 and Gorafe. The correlation has been completed with previous palaeomagnetic analysis in the sections of Galera and Zújar. The magnetobiostratigraphical correlation here established indicates a late Messinian age for the Apodemus gudrunae – Apocricetus alberti Zone, a Zanclean age for the Apocricetus barrierei, Paraethomys aff. abaigari, Trilophomys and Mimomys davakosi zones and a Piazencian age for the Mimomys hassiacus, Mimomys polonicus and Kislangia ischus zones. The Dolomys adroveri Zone is mostly Zanclean in age, but its uppermost part belongs to the Piazencian. Therefore, unit MN13 is correlated with the late Messinian, MN14 is correlated with the early Zanclean, most of MN15 is correlated with the late Zanclean, while the uppermost part of MN15 and MN16 are correlated with the Piazencian. 相似文献
56.
Anna Boladeras Ferran Ferrer Valentin Navarro Rodolfo De Blas Oriol Cunillera David Mateo Cristina Gutierrez Evelyn Martinez Salvador Villà Joan Pera Montse Ferrer Ferran Guedea 《Reports of Practical Oncology and Radiotherapy》2018,23(5):360-368
Aim
To evaluate the association between dose–volume histogram (DVH) values in organs at risk (OAR) and patient-reported HRQoL outcomes.Background
Data on the association between DVHs and health-related quality of life (HRQoL) in prostate cancer (PCa) patients are limited.Materials and methods
Five-year follow-up study of 154 patients with organ-confined (stage T1/T2) PCa treated with EBRT between January 2003 and November 2005. HRQoL was evaluated with the Expanded Prostate Cancer Index (EPIC). DVH for OARs (penile bulb, rectum and bladder) were created for all patients for whom data were available (119/154; 77%). The functional data analysis (FDA) statistical method was used. HRQoL data was collected prospectively and data analysis was performed retrospectively.Results
Worsening of urinary incontinence and obstructive symptoms correlated with higher DVH dose distributions at 24 months. Increased rectal bleeding at months 24 and 60 correlated with higher DVH dose distributions in the 40–70?Gy range. Patients with deterioration in rectal incontinence presented a higher DVH distribution range than patients without rectal incontinence. Penile bulb DVH values and erectile dysfunction were not significantly associated.Conclusions
DVH parameters and post-radiotherapy HRQoL appear to be closely correlated, underscoring the importance of assessing DVH values prior to initiating EBRT to determine the risk of developing HRQoL related adverse effects. Advanced treatment modalities may be appropriate in high risk cases to minimize treatment-related toxicity and to improve treatment outcomes and HRQoL. Future studies are needed to better elucidate the association between pre-treatment DVH parameters in organs at risk and subsequent HRQoL. 相似文献57.
Maternal Metabolic Health Parameters During Pregnancy in Relation to Early Childhood BMI Trajectories
下载免费PDF全文
![点击此处可从《Obesity (Silver Spring, Md.)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
58.
Sílvia Martras Rosana Alvarez Susana E Martínez Dámaso Torres Oriol Gallego Gregg Duester Jaume Farrés Angel R de Lera Xavier Parés 《European journal of biochemistry》2004,271(9):1660-1670
Studies in knockout mice support the involvement of alcohol dehydrogenases ADH1 and ADH4 in retinoid metabolism, although kinetics with retinoids are not known for the mouse enzymes. Moreover, a role of alcohol dehydrogenase (ADH) in the eye retinoid interconversions cannot be ascertained due to the lack of information on the kinetics with 11-cis-retinoids. We report here the kinetics of human ADH1B1, ADH1B2, ADH4, and mouse ADH1 and ADH4 with all-trans-, 7-cis-, 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinal. These retinoids are substrates for all enzymes tested, except the 13-cis isomers which are not used by ADH1. In general, human and mouse ADH4 exhibit similar activity, higher than that of ADH1, while mouse ADH1 is more efficient than the homologous human enzymes. All tested ADHs use 11-cis-retinoids efficiently. ADH4 shows much higher k(cat)/K(m) values for 11-cis-retinol oxidation than for 11-cis-retinal reduction, a unique property among mammalian ADHs for any alcohol/aldehyde substrate pair. Docking simulations and the kinetic properties of the human ADH4 M141L mutant demonstrated that residue 141, in the middle region of the active site, is essential for such ADH4 specificity. The distinct kinetics of ADH4 with 11-cis-retinol, its wide specificity with retinol isomers and its immunolocalization in several retinal cell layers, including pigment epithelium, support a role of this enzyme in the various retinol oxidations that occur in the retina. Cytosolic ADH4 activity may complement the isomer-specific microsomal enzymes involved in photopigment regeneration and retinoic acid synthesis. 相似文献
59.
Núria Gavara Raimon Sunyer Pere Roca-Cusachs Ramon Farré Mar Rotger Daniel Navajas 《Journal of applied physiology》2006,101(2):512-520
Contractile tension of alveolar epithelial cells plays a major role in the force balance that regulates the structural integrity of the alveolar barrier. The aim of this work was to study thrombin-induced contractile forces of alveolar epithelial cells. A549 alveolar epithelial cells were challenged with thrombin, and time course of contractile forces was measured by traction microscopy. The cells exhibited basal contraction with total force magnitude 55.0 +/- 12.0 nN (mean +/- SE, n = 12). Traction forces were exerted predominantly at the cell periphery and pointed to the cell center. Thrombin (1 U/ml) induced a fast and sustained 2.5-fold increase in traction forces, which maintained peripheral and centripetal distribution. Actin fluorescent staining revealed F-actin polymerization and enhancement of peripheral actin rim. Disruption of actin cytoskeleton with cytochalasin D (5 microM, 30 min) and inhibition of myosin light chain kinase with ML-7 (10 microM, 30 min) and Rho kinase with Y-27632 (10 microM, 30 min) markedly depressed basal contractile tone and abolished thrombin-induced cell contraction. Therefore, the contractile response of alveolar epithelial cells to the inflammatory agonist thrombin was mediated by actin cytoskeleton remodeling and actomyosin activation through myosin light chain kinase and Rho kinase signaling pathways. Thrombin-induced contractile tension might further impair alveolar epithelial barrier integrity in the injured lung. 相似文献
60.