全文获取类型
收费全文 | 357篇 |
免费 | 31篇 |
出版年
2021年 | 10篇 |
2018年 | 6篇 |
2017年 | 10篇 |
2016年 | 10篇 |
2015年 | 11篇 |
2014年 | 18篇 |
2013年 | 18篇 |
2012年 | 27篇 |
2011年 | 13篇 |
2010年 | 23篇 |
2009年 | 10篇 |
2008年 | 16篇 |
2007年 | 12篇 |
2006年 | 9篇 |
2005年 | 9篇 |
2004年 | 10篇 |
2003年 | 10篇 |
2002年 | 7篇 |
2000年 | 3篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1992年 | 7篇 |
1991年 | 2篇 |
1990年 | 5篇 |
1989年 | 7篇 |
1988年 | 10篇 |
1987年 | 4篇 |
1986年 | 9篇 |
1984年 | 2篇 |
1981年 | 3篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1976年 | 4篇 |
1974年 | 3篇 |
1973年 | 6篇 |
1972年 | 4篇 |
1970年 | 2篇 |
1968年 | 2篇 |
1967年 | 2篇 |
1959年 | 2篇 |
1957年 | 3篇 |
1948年 | 2篇 |
1947年 | 2篇 |
1935年 | 3篇 |
1933年 | 2篇 |
1909年 | 2篇 |
排序方式: 共有388条查询结果,搜索用时 15 毫秒
41.
Blaney Davidson EN Scharstuhl A Vitters EL van der Kraan PM van den Berg WB 《Arthritis research & therapy》2005,7(6):R1338-R1347
Osteoarthritis (OA) is a common joint disease, mainly effecting the elderly population. The cause of OA seems to be an imbalance
in catabolic and anabolic factors that develops with age. IL-1 is a catabolic factor known to induce cartilage damage, and
transforming growth factor (TGF)-beta is an anabolic factor that can counteract many IL-1-induced effects. In old mice, we
observed reduced responsiveness to TGF-beta-induced IL-1 counteraction. We investigated whether expression of TGF-beta and
its signaling molecules altered with age. To mimic the TGF-beta deprived conditions in aged mice, we assessed the functional
consequence of TGF-beta blocking. We isolated knee joints of mice aged 5 months or 2 years, half of which were exposed to
IL-1 by intra-articular injection 24 h prior to knee joint isolation. Immunohistochemistry was performed, staining for TGF-beta1,
-2 or -3, TGF-betaRI or -RII, Smad2, -3, -4, -6 and -7 and Smad-2P. The percentage of cells staining positive was determined
in tibial cartilage. To mimic the lack of TGF-beta signaling in old mice, young mice were injected with IL-1 and after 2 days
Ad-LAP (TGF-beta inhibitor) or a control virus were injected. Proteoglycan (PG) synthesis (35S-sulfate incorporation) and PG content of the cartilage were determined. Our experiments revealed that TGF-beta2 and -3 expression
decreased with age, as did the TGF-beta receptors. Although the number of cells positive for the Smad proteins was not altered,
the number of cells expressing Smad2P strongly dropped in old mice. IL-1 did not alter the expression patterns. We mimicked
the lack of TGF-beta signaling in old mice by TGF-beta inhibition with LAP. This resulted in a reduced level of PG synthesis
and aggravation of PG depletion. The limited response of old mice to TGF-beta induced-IL-1 counteraction is not due to a diminished
level of intracellular signaling molecules or an upregulation of intracellular inhibitors, but is likely due to an intrinsic
absence of sufficient TGF-beta receptor expression. Blocking TGF-beta distorted the natural repair response after IL-1 injection.
In conclusion, TGF-beta appears to play an important role in repair of cartilage and a lack of TGF-beta responsiveness in
old mice might be at the root of OA development. 相似文献
42.
Rowlands MG Newbatt YM Prodromou C Pearl LH Workman P Aherne W 《Analytical biochemistry》2004,327(2):176-183
The molecular chaperone heat-shock protein 90 (HSP90) plays a key role in the cell by stabilizing a number of client proteins, many of which are oncogenic. The intrinsic ATPase activity of HSP90 is essential to this activity. HSP90 is a new cancer drug target as inhibition results in simultaneous disruption of several key signaling pathways, leading to a combinatorial approach to the treatment of malignancy. Inhibitors of HSP90 ATPase activity including the benzoquinone ansamycins, geldanamycin and 17-allylamino-17-demethoxygeldanamycin, and radicicol have been described. A high-throughput screen has been developed to identify small-molecule inhibitors that could be developed as therapeutic agents with improved pharmacological properties. A colorimetric assay for inorganic phosphate, based on the formation of a phosphomolybdate complex and subsequent reaction with malachite green, was used to measure the ATPase activity of yeast HSP90. The Km for ATP determined in the assay was 510+/-70 microM. The known HSP90 inhibitors geldanamycin and radicicol gave IC(50) values of 4.8 and 0.9 microM respectively, which compare with values found using the conventional coupled-enzyme assay. The assay was robust and reproducible (2-8% CV) and used to screen a compound collection of approximately 56,000 compounds in 384-well format with Z' factors between 0.6 and 0.8. 相似文献
43.
Collins CW Songsasen NS Vick MM Wolfe BA Weiss RB Keefer CL Monfort SL 《Biology of reproduction》2012,86(2):28
The ex situ population of the Przewalski's horse (Equus ferus przewalskii) is not self-sustaining (20% foaling rate), and the demography is skewed toward aging individuals with low gene diversity. We designed the present study to gain a better understanding of the reproductive biology of the Przewalski's mare and to determine whether age and gene diversity influenced reproductive function. Urine samples were collected 3-7 days/wk from 19 mares from May to September, and ultrasound examinations of follicular structures were performed 3 days/wk for 5 wk from May through July in nine individuals. A high proportion of mares exhibited abnormal (endocrine, 5 [26.3%] of 19; follicular, 2 [22.2%] of 9) or acyclic (endocrine, 4 [21.1%] of 19; follicular, 3 [33.3%] of 9) reproductive patterns. In four cyclic mares, estrous cycle length was 25.1 ± 1.2 days, with 12.2 ± 0.9 days of diestrus. Follicles in cyclic mares grew 1.2 ± 0.6 mm per day and ovulated after reaching 40.4 ± 8.9 mm. Mares with a high coefficient of inbreeding excreted reduced levels of mean urinary estrogens (r(2) = 0.476, P < 0.05), but age had no significant impact on reproductive patterns in this population. Overall, these data suggest that long-term genetic management of this population is necessary to maintain reproductive fitness. 相似文献
44.
DNA damage activates checkpoint controls which block progression of cells through the division cycle. Several different checkpoints exist that control transit at different positions in the cell cycle. A role for checkpoint activation in providing resistance of cells to genotoxic anticancer therapy, including chemotherapy and ionizing radiation, is widely recognized. Although the core molecular functions that execute different damage activated checkpoints are known, the signals that control checkpoint activation are far from understood. We used a kinome-spanning RNA interference screen to delineate signalling required for radiation-mediated retinoblastoma protein activation, the recognized executor of G(1) checkpoint control. Our results corroborate the involvement of the p53 tumour suppressor (TP53) and its downstream targets p21(CIP1/WAF1) but infer lack of involvement of canonical double strand break (DSB) recognition known for its role in activating TP53 in damaged cells. Instead our results predict signalling involving the known TP53 phosphorylating kinase PRPK/TP53RK and the JNK/p38MAPK activating kinase STK4/MST1, both hitherto unrecognised for their contribution to DNA damage G1 checkpoint signalling. Our results further predict a network topology whereby induction of p21(CIP1/WAF1) is required but not sufficient to elicit checkpoint activation. Our experiments document a role of the kinases identified in radiation protection proposing their pharmacological inhibition as a potential strategy to increase radiation sensitivity in proliferating cancer cells. 相似文献
45.
46.
Interannual variability of cyanobacterial blooms in lake erie 总被引:3,自引:0,他引:3
After a 20-year absence, severe cyanobacterial blooms have returned to Lake Erie in the last decade, in spite of negligible change in the annual load of total phosphorus (TP). Medium-spectral Resolution Imaging Spectrometer (MERIS) imagery was used to quantify intensity of the cyanobacterial bloom for each year from 2002 to 2011. The blooms peaked in August or later, yet correlate to discharge (Q) and TP loads only for March through June. The influence of the spring TP load appears to have started in the late 1990 s, after Dreissenid mussels colonized the lake, as hindcasts prior to 1998 are inconsistent with the observed blooms. The total spring Q or TP load appears sufficient to predict bloom magnitude, permitting a seasonal forecast prior to the start of the bloom. 相似文献
47.
Zaghloul N Nasim M Patel H Codipilly C Marambaud P Dewey S Schiffer WK Ahmed M 《The FEBS journal》2012,279(5):871-881
There is increasing evidence that hyperoxia, particularly at the time of birth, may result in neurological injury, in particular to the susceptible vasculature of these tissues. This study was aimed at determining whether overexpression of extracellular superoxide dismutase (EC-SOD) is protective against brain injury induced by hyperoxia. Transgenic (TG) mice (with an extra copy of the human extracellular superoxide dismutase gene) and wild-type (WT) neonate mice were exposed to hyperoxia (95% of F(i) o(2) ) for 7 days after birth versus the control group in room air. Brain positron emission tomography (PET) scanning with fludeoxyglucose (FDG) isotope uptake was performed after exposure. To assess apoptosis induced by hyperoxia exposure, caspase 3 ELISA and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed. Quantitative western blot for the following inflammatory markers was performed: glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, macrophage-inhibiting factor, and phospho-AMP-activated protein kinase. PET scanning with FDG isotope uptake showed significantly higher uptake in the WT hyperoxia neonate brain group (0.14 ± 0.03) than in both the TG group (0.09 ± 0.01) and the control group (0.08 ± 0.02) (P< 0.05). Histopathological investigation showed more apoptosis and dead neurons in hippocampus and cerebellum brain sections of WT neonate mice after exposure to hyperoxia than in TG mice; this finding was also confirmed by TUNEL staining. The caspase 3 assay confirmed the finding of more apoptosis in WT hyperoxia neonates (0.814 ± 0.112) than in the TG hyperoxic group (0.579 ± 0.144) (P < 0.05); this finding was also confirmed by TUNEL staining. Quantitative western blotting for the inflammatory and metabolic markers showed significantly higher expression in the WT group than in the TG and control groups. Thus, overexpression of EC-SOD in the neonate brain offers significant protection against hyperoxia-induced brain damage. 相似文献
48.
Timothy T. Wynne Richard P. Stumpf Michelle C. Tomlinson Varis Ransibrahmanakul Tracy A. Villareal 《Harmful algae》2005,4(6):224
Blooms of the toxic dinoflagellate, Karenia brevis, have had detrimental impacts on the coastal Gulf of Mexico for decades. Detection of Karenia brevis blooms uses an ecological approach based on anomalies derived from ocean color imagery. The same anomaly product used in Florida produces frequent false positives on the Texas coast. These failures occurred during wind-driven resuspension events. During these events resuspension of benthic algae significantly increases chlorophyll concentrations in the water, resulting in confusion with normal water column phytoplankton, such as Karenia. A method was developed to separate the resuspended chlorophyll from the water column chlorophyll, decreasing the false positives used with the detection method. 相似文献
49.
Alternaria alternata is a common fungal parasite on fruits and other plants and produces a number of mycotoxins, including alternariol (3,7,9-trihydroxy-1-methyl-6H-dibenzo [b,d]pyran-6-one), alternariol monomethyl ether (3,7-dihydroxy-9-methoxy-1-methyl-6H-dibenzo[b,d]pyran-6-one), and the mutagen altertoxin I {[1S-(1α,12aβ,12bα)] 1,2,11,12,12a, 12b-hexahydro-1,4,9,12a-tetrahydroxy-3,10-perylenedione}.
Alternariol and alternariol monomethyl ether have previously been detected in some samples of fruit beverages. Stability studies
of these toxins as well as altertoxin I added to fruit juices and wine (10–100 ng/mL) were carried out. To include altertoxin
I in the analysis, cleanup with a polymer-based Varian Abselut solid phase extraction column was used, as recoveries from
C-18 columns were low. The stabilities of alternariol and alternariol monomethyl ether in a low acid apple juice containing
no declared vitamin C were compared with those in the same juice containing added vitamin C (60 mg/175 ml); there were no
apparent losses at room temperature over 20 days or at 80°C after 20 min. in either juice. Altertoxin I was moderately stable
in pH 3 buffer (75% remaining after a two week period). Furthermore, altertoxin I was stable or moderately stable in three
brands of apple juice tested over 1–27 day periods and in a sample of red grape juice over 7 days. It is concluded that altertoxin
I is sufficiently stable to be found in fruit juices and should be included in methods for alternariol and alternariol monomethyl
ether. 相似文献
50.
A. J. Cowley R. D. Wynne K. Stainer L. Fullwood J. M. Rowley J. R. Hampton 《BMJ (Clinical research ed.)》1988,297(6642):169-173
There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure. 相似文献