全文获取类型
收费全文 | 44025篇 |
免费 | 3848篇 |
国内免费 | 124篇 |
出版年
2022年 | 376篇 |
2021年 | 822篇 |
2020年 | 526篇 |
2019年 | 681篇 |
2018年 | 812篇 |
2017年 | 670篇 |
2016年 | 1069篇 |
2015年 | 1767篇 |
2014年 | 1908篇 |
2013年 | 2436篇 |
2012年 | 2911篇 |
2011年 | 2873篇 |
2010年 | 1952篇 |
2009年 | 1582篇 |
2008年 | 2226篇 |
2007年 | 2143篇 |
2006年 | 2056篇 |
2005年 | 1750篇 |
2004年 | 1853篇 |
2003年 | 1690篇 |
2002年 | 1752篇 |
2001年 | 1099篇 |
2000年 | 951篇 |
1999年 | 896篇 |
1998年 | 519篇 |
1997年 | 464篇 |
1996年 | 368篇 |
1995年 | 374篇 |
1994年 | 302篇 |
1993年 | 369篇 |
1992年 | 590篇 |
1991年 | 560篇 |
1990年 | 514篇 |
1989年 | 461篇 |
1988年 | 381篇 |
1987年 | 376篇 |
1986年 | 352篇 |
1985年 | 403篇 |
1984年 | 388篇 |
1983年 | 333篇 |
1982年 | 264篇 |
1981年 | 264篇 |
1980年 | 239篇 |
1979年 | 295篇 |
1978年 | 273篇 |
1977年 | 279篇 |
1976年 | 270篇 |
1975年 | 263篇 |
1974年 | 257篇 |
1973年 | 243篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
91.
92.
93.
Jonathan T. Sims Sourik S. Ganguly Holly Bennett J. Woodrow Friend Jessica Tepe Rina Plattner 《PloS one》2013,8(1)
Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis. 相似文献
94.
Paolo d’Errico Marina Boido Antonio Piras Valeria Valsecchi Elena De Amicis Denise Locatelli Silvia Capra Francesco Vagni Alessandro Vercelli Giorgio Battaglia 《PloS one》2013,8(12)
Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients. 相似文献
95.
96.
L Missiaen J B Parys A F Weidema H Sipma S Vanlingen P De Smet G Callewaert H De Smedt 《The Journal of biological chemistry》1999,274(20):13748-13751
Calmodulin inhibits inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor in both a Ca2+-dependent and a Ca2+-independent way. Because there are no functional data on the modulation of the IP3-induced Ca2+ release by calmodulin at various Ca2+ concentrations, we have studied how cytosolic Ca2+ and Sr2+ interfere with the effects of calmodulin on the IP3-induced Ca2+ release in permeabilized A7r5 cells. We now report that calmodulin inhibited Ca2+ release through the IP3 receptor with an IC50 of 4.6 microM if the cytosolic Ca2+ concentration was 0.3 microM or higher. This inhibition was particularly pronounced at low IP3 concentrations. In contrast, calmodulin did not affect IP3-induced Ca2+ release if the cytosolic Ca2+ concentration was below 0.3 microM. Calmodulin also inhibited Ca2+ release through the IP3 receptor in the presence of at least 10 microM Sr2+. We conclude that cytosolic Ca2+ or Sr2+ are absolutely required for the calmodulin-induced inhibition of the IP3-induced Ca2+ release and that this dependence represents the formation of the Ca2+/calmodulin or Sr2+/calmodulin complex. 相似文献
97.
Most adult Barbus haasi , at a 1950 m-long site in Vallvidrera creek, were highly sedentary and resided within a home range <20 m (32 m2 ), while a small group were more mobile. On successive sampling occasions, between 52·3 and 64·9% of fish were recaptured in the same 10-m-long section in which they had previously been captured. Movements over long distances were infrequent, and only 5·6% of the fish moved >100 m. The movement pattern of the population was seasonally stable, although the mean distances were slightly greater in summer because of the medium-range movements of a few individuals. Overall, upstream and downstream movements were equally common but a significant downstream movement occurred in spring. The size of the fish did not influence the movement rate. Fish inhabiting those sections of the stream with greater depth, slower current and more cover had a lower movement rate than fish occupying shallower, exposed sections. The restricted movement of B. haasi could increase the survival of fish by increasing the probability of staying in the remaining pools during summer dry-out, and may therefore be of adaptive significance. 相似文献
98.
99.
A dipstick enzyme immunoassay for the rapid detection of Fusarium T-2 toxin in wheat was developed. An Immunodyne ABC membrane was precoated with rabbit anti-mouse immunoglobulins. After the strips were immersed in a solution of monoclonal anti-T-2 toxin antibodies, a direct competitive enzyme immunoassay was performed. This assay included the incubation of the antibody-coated dipsticks in a mixture of sample and T-2 toxin-horseradish peroxidase conjugate. Afterwards, the strips were placed in a chromogen-containing substrate solution (H202-3,3',5,5'-tetramethylbenzidine) for color reaction. The dot color intensity of toxin-positive dipsticks was visually distinguishable from that of the negative control. A portable colorimeter was used to confirm and quantify the visual observations. With coated strips, the tests could be performed in 45 min. The visual detection limit for T-2 toxin in buffer solution was 0.25 ng/ml. Artificially infected wheat samples were extracted with 80% methanol-water. A dilution of the raw extract of 1:8 was sufficient to avoid matrix effects. It was possible to make visually a clear distinction between the negative control and a wheat extract spiked with 12 ng/g. 相似文献
100.