全文获取类型
收费全文 | 706篇 |
免费 | 30篇 |
国内免费 | 21篇 |
出版年
2024年 | 2篇 |
2023年 | 5篇 |
2022年 | 10篇 |
2021年 | 8篇 |
2020年 | 4篇 |
2019年 | 19篇 |
2018年 | 15篇 |
2017年 | 10篇 |
2016年 | 11篇 |
2015年 | 21篇 |
2014年 | 49篇 |
2013年 | 56篇 |
2012年 | 57篇 |
2011年 | 43篇 |
2010年 | 26篇 |
2009年 | 24篇 |
2008年 | 26篇 |
2007年 | 35篇 |
2006年 | 24篇 |
2005年 | 38篇 |
2004年 | 29篇 |
2003年 | 21篇 |
2002年 | 18篇 |
2001年 | 7篇 |
2000年 | 11篇 |
1999年 | 5篇 |
1998年 | 8篇 |
1997年 | 11篇 |
1996年 | 9篇 |
1995年 | 21篇 |
1994年 | 9篇 |
1993年 | 25篇 |
1992年 | 9篇 |
1991年 | 10篇 |
1990年 | 5篇 |
1989年 | 11篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 7篇 |
1985年 | 5篇 |
1984年 | 11篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1972年 | 2篇 |
排序方式: 共有757条查询结果,搜索用时 203 毫秒
31.
Identification of a calmodulin-dependent glycogen synthase kinase in rabbit skeletal muscle, distinct from phosphorylase kinase 总被引:3,自引:0,他引:3
A glycogen synthase kinase that is completely dependent on Ca2+ and calmodulin has been identified in mammalian skeletal muscle, and purified approximately 3000-fold by chromatography on phosphocellulose and calmodulin--Sepharose. The presence of 50 mM NaCl in the homogenisation buffer was critical for extraction of the enzyme. The calmodulin-dependent glycogen synthase kinase (app. Mr 850 000) is distinct from myosin light-chain kinase and phosphorylase kinase, but phosphorylates the same serine residue on glycogen synthase as phosphorylase kinase. The physiological role of the enzyme is discussed. 相似文献
32.
Summary (1) The fine structure of the cercal campaniform sensilla and epidermal cells of Gryllus bimaculatus Deg. (Saltatoria, Gryllidae) was examined, and the ecdysteroid level was monitored throughout the last larval instar. (2) The epidermal cells show changes in shape, cytoplasmic inclusions and differentiation of the apical cell membrane, coupled to the phases of buildup and breakdown of the (cercus) cuticle. (3) The imaginal epicuticle of the epidermal cells begins to form later (by about approximately 6 h) than that of the campaniform sensilla. (4) The campaniform sensilla were studied with respect to (a) the morphogenesis of the cuticular apparatus, (b) the inclusion of phenol oxidases in the cuticular apparatus, and (c) changes in the sensory apparatus preparatory to molting. (5) After apolysis the folding of the tormogen-cell wall into microvilli transiently disappears. Microvilli re-form shortly before imaginai ecdysis, and at the same time an outer receptor-lymph space develops. The role of the tormogen-cell plaques is discussed. (6) The levels of - and -ecdysone were determined separately by radioimmunoassay. (7) At the beginning of the instar the hormone level, especially that of -ecdysone, falls. Prior to apolysis, the concentration of -ecdysone rises, reaching an intermediate peak after apolysis is complete. The maximum hormone concentration (approximately 2,000 ng/g) is reached after the cuticulin layer is deposited, primarily due to the increase in -ecdysone. While the proecdysial cuticle is forming, the hormone titer is reduced; at this time -ecdysone is its chief component. (8) The identification of the ecdysteroids monitored by radioimmunoassay was confirmed by gas chromatography.This paper is dedicated to Professor H. Risler on the occasion of his 65th birthdaySupported by the Deutsche Forschungsgemeinschaft 相似文献
33.
目的:探讨脐带间充质干细胞移植联合表皮生长因子治疗III、Ⅳ期压疮的临床效果。方法:选取我院2011-2012年收治的III、Ⅳ期压疮患者143例为研究对象,随机分为对照组、实验一组和实验二组。对照组30例压疮患者行常规换药,实验一组58例压疮患者应用脐带间充质干细胞移植联合表皮生长因子治疗,实验二组55例压疮患者仅应用表皮生长因子治疗。治疗后,比较三组患者愈合时间及愈合效果。结果:实验一组和实验二组的显效时间和愈合时间均较对照组显著缩短,且实验一组的显效时间和愈合时间较实验二组更短,差异均有统计学意义(均P〈0.05)。实验一组的治愈率显著高于对照组(P〈0.05),而与实验二组比较无统计学差异(P〉0.05),实验二组的治愈率与对照组比较无统计学差异(P〈0.05)。实验一组的总有效率显著高于对照组和实验二组(P〈0.05),而实验二组的总有效率与对照组比较无统计学差异(P〉0.05)。结论:脐带间充质干细胞移植联合表皮生长因子较单用表皮生长因子及常规治疗方法更好的改善III、Ⅳ期压疮创面的愈合,避免患者组织感染,提高压疮患者的生活质量。 相似文献
34.
As a major class of pattern-recognition receptors, Toll-like receptors (TLRs) play a critical role in defense against invading pathogens. Increasing evidence demonstrates that, in addition to infection, TLRs are involved in other important pathological processes, such as tumorigenesis. Activation of TLRs results in opposing outcomes, pro-tumorigenic effects and anti-tumor functions. TLR signaling can inhibit apoptosis and promote chronic inflammation-induced tumorigenesis. TLR activation in tumor cells and immune cells can induce production of cytokines, increase tumor cell proliferation and apoptosis resistance, promote invasion and metastasis, and inhibit immune cell activity resulting in tumor immune escape. In contrast, the engagement of other TLRs directly induces growth inhibition and apoptosis of tumor cells and triggers activation of immune cells enhancing anti-tumor immune responses. Thus, the interpretation of the precise function of each TLR in tumors is very important for targeting TLRs and using TLR agonists in tumor therapy. We review the role of TLR signaling in tumors and discuss the factors that affect outcomes of TLR activation. 相似文献
35.
Purpose
Overexpression of proto-oncogene HER-2 is one of the main molecular markers of breast cancer involved in prognosis and diagnosis and also in trastuzumab therapy. Thus, a request for the evaluation of HER-2 status in breast cancer has been increasing. The aim of our study was assessment of HER-2 overexpression in malignant and benign breast cancer specimens by Real Time RT-PCR technique and comparison of its results with IHC outcomes.Methods
Twenty benign and sixty malignant breast cancers in addition to fifteen normal breast tissue specimens were analyzed by Real Time RT-PCR method. Fresh tissue samples were disrupted by mortar and pestle. A syringe and a needle were used for complete homogenization of the tissues. The RNA was then isolated from the samples and converted to cDNA. A standard curve was initially plotted using BioEasy SYBR Green I and then all 95 specimens were studied by Real Time RT-PCR using 2− ΔΔCt method.Results
23.3% of 60 malignant specimens showed HER-2 overexpression, while all of the benign samples represented the normal expression level of HER-2 gene. The concordance rate between the results of Real Time RT-PCR and IHC was 86.6%.Conclusion
Real Time RT-PCR method is an almost reliable technique and at least can be used as a complementary method for confirming IHC results. This is emanated from relatively high rate of concordance between outcomes of IHC test, as a routine method of detecting the HER-2 gene expression status, and Real Time RT-PCR technique. 相似文献36.
G. Daniel Grass Lauren B. Tolliver Momka Bratoeva Bryan P. Toole 《The Journal of biological chemistry》2013,288(36):26089-26104
The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777–788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer. 相似文献
37.
The formation of tissues is essential for metazoan development. During Caenorhabditis elegans embryogenesis, ventral epidermal cells migrate to encase the ventral surface of the embryo in a layer of epidermis by a process known as ventral enclosure. This process is regulated by guidance cues secreted by the underlying neuroblasts. However, since the cues and their receptors are differentially expressed in multiple cell types, the role of the neuroblasts in ventral enclosure is not fully understood. Furthermore, although F-actin is required for epidermal cell migration, it is not known if nonmuscle myosin is also required. Anillin (ANI-1) is an actin and myosin-binding protein that coordinates actin–myosin contractility in the early embryo. Here, we show that ANI-1 localizes to the cleavage furrows of dividing neuroblasts during mid-embryogenesis and is required for their division. Embryos depleted of ani-1 display a range of ventral enclosure phenotypes, where ventral epidermal cells migrate with similar speeds to control embryos, but contralateral neighbors often fail to meet and are misaligned. The ventral enclosure phenotypes in ani-1 RNAi embryos suggest that the position or shape of neuroblasts is important for directing ventral epidermal cell migration, although does not rule out an autonomous requirement for ani-1 in the epidermal cells. Furthermore, we show that rho-1 and other regulators of nonmuscle myosin activity are required for ventral epidermal cell migration. Interestingly, altering nonmuscle myosin contractility alleviates or strengthens ani-1's ventral enclosure phenotypes. Our findings suggest that ventral enclosure is a complex process that likely relies on inputs from multiple tissues. 相似文献
38.
Ben Mersey Rebecca S. Jabbour Kyle Brudvik Alban Defleur 《American journal of physical anthropology》2013,152(4):516-529
The hand and foot remains from Moula‐Guercy cave (Ardèche, France) comprise 24 specimens of Eemian age (ca. 120 ka). The specimens include primarily complete elements, which are rare among the Moula‐Guercy postcrania. The hand remains have several characteristic Neanderthal traits including a laterally facing (parasagittally oriented) second metacarpal‐capitate articulation, a short styloid process, a wide proximal articular surface on the third metacarpal, and absolutely expanded apical tuberosities on the distal hand phalanges relative to modern humans. The foot remains include several incomplete elements along with an antimeric pair of naviculars, a medial cuneiform and cuboid, and a single complete element from each of the distal segments (one each: metatarsal, proximal foot phalanx, intermediate foot phalanx, distal foot phalanx). Consistent among the specimens are relatively wide diaphyses for length in the metatarsals and phalanges and large and prominent muscle attachments, both consistent with previously published Neanderthal morphology. The hand and foot collection from Moula‐Guercy is an important dataset for future studies of Neanderthal functional morphology, dexterity, and behavior as it represents a previously undersampled time period for European Neanderthals. Am J Phys Anthropol 152:516–529, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
39.
Inhibition of animal cell phospholipid biosynthesis has been proposed for anticancer and antiviral therapies. Using CHOK1 derived cell lines, we have developed and used a cell-based high-throughput procedure to screen a 1280 compound, small molecule library for inhibitors of phospholipid biosynthesis. We identified tyrphostin AG 879 (AG879), which inhibited phospholipid biosynthesis by 85–90% at a concentration of 10 μM, displaying an IC50 of 1–3 μM. The synthesis of all phospholipid head group classes was heavily affected. Fatty acid biosynthesis was also dramatically inhibited (90%). AG879 inhibited phospholipid biosynthesis in all additional cell lines tested, including MDCK, HUH7, Vero, and HeLa cell lines. In CHO cells, AG879 was cytostatic; cells survived for at least four days during exposure and were able to divide following its removal. AG879 is an inhibitor of receptor tyrosine kinases (RTK) and inhibitors of signaling pathways known to be activated by RTK's also inhibited phospholipid biosynthesis. We speculate that inhibition of RTK by AG879 results in an inhibition of fatty acid biosynthesis with a resulting decrease in phospholipid biosynthesis and that AG879's effect on fatty acid synthesis and/or phospholipid biosynthesis may contribute to its known capacity as an effective antiviral/anticancer agent. 相似文献
40.
Epidermal hyperplasia and expansion of the interfollicular stem cell compartment in mutant mice with a C-terminal truncation of Patched1 总被引:1,自引:0,他引:1
Hedgehog (Hh) signaling is conserved from flies to humans and is indispensable in embryogenesis and adulthood. Patched (Ptc) encodes a receptor for Hh ligands and functions as a tumor suppressor. PTCH1 mutations in humans are found in basal cell carcinoma (BCC) and irradiated Ptc1(+/-) mice recapitulate this phenotype. However, due to embryonic lethality associated with the Ptc1 null mutation, its normal function in embryonic and adult skin remains unknown. Here we describe the epidermal phenotypes of a spontaneous and viable allele of Ptc1, Ptc1(mes), in which the C-terminal domain (CTD) is truncated. Ptc1(mes/mes) embryos display normal epidermal and hair follicle development. Postnatal Ptc1(mes/mes) skin displays severe basal cell layer hyperplasia and increased proliferation, while stratification of the suprabasal layers is mostly normal. Interestingly, truncation of the Ptc1 CTD did not result in skin tumors. However, long term labeling studies revealed a greater than three-fold increase in label-retaining cells in the interfollicular epidermis of Ptc1(mes/mes) adults, indicating possible expansion of the epidermal stem cell compartment. Increased expression of regulators of epidermal homeostasis, c-Myc and p63, was also observed in Ptc1(mes/mes) adult skin. These results suggest that the CTD of Ptc1 is involved in regulating epidermal homeostasis in mature skin. 相似文献