全文获取类型
收费全文 | 27642篇 |
免费 | 2881篇 |
国内免费 | 1443篇 |
出版年
2024年 | 20篇 |
2023年 | 591篇 |
2022年 | 405篇 |
2021年 | 954篇 |
2020年 | 1120篇 |
2019年 | 1253篇 |
2018年 | 1223篇 |
2017年 | 1065篇 |
2016年 | 1167篇 |
2015年 | 1216篇 |
2014年 | 1427篇 |
2013年 | 2332篇 |
2012年 | 1203篇 |
2011年 | 1157篇 |
2010年 | 1061篇 |
2009年 | 1282篇 |
2008年 | 1415篇 |
2007年 | 1391篇 |
2006年 | 1234篇 |
2005年 | 1144篇 |
2004年 | 1063篇 |
2003年 | 1037篇 |
2002年 | 930篇 |
2001年 | 703篇 |
2000年 | 651篇 |
1999年 | 525篇 |
1998年 | 438篇 |
1997年 | 369篇 |
1996年 | 364篇 |
1995年 | 351篇 |
1994年 | 330篇 |
1993年 | 316篇 |
1992年 | 275篇 |
1991年 | 216篇 |
1990年 | 200篇 |
1989年 | 187篇 |
1988年 | 153篇 |
1987年 | 142篇 |
1986年 | 102篇 |
1985年 | 131篇 |
1984年 | 174篇 |
1983年 | 103篇 |
1982年 | 121篇 |
1981年 | 120篇 |
1980年 | 85篇 |
1979年 | 60篇 |
1978年 | 50篇 |
1977年 | 51篇 |
1976年 | 29篇 |
1974年 | 12篇 |
排序方式: 共有10000条查询结果,搜索用时 24 毫秒
1.
2.
《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
3.
Kurt B. Petersen Martin Burd 《Biological reviews of the Cambridge Philosophical Society》2017,92(3):1739-1754
The primitive land plant life cycle featured the production of spores of unimodal size, a condition called homospory. The evolution of bimodal size distributions with small male spores and large female spores, known as heterospory, was an innovation that occurred repeatedly in the history of land plants. The importance of desiccation‐resistant spores for colonization of the land is well known, but the adaptive value of heterospory has never been well established. It was an addition to a sexual life cycle that already involved male and female gametes. Its role as a precursor to the evolution of seeds has received much attention, but this is an evolutionary consequence of heterospory that cannot explain the transition from homospory to heterospory (and the lack of evolutionary reversal from heterospory to homospory). Enforced outcrossing of gametophytes has often been mentioned in connection to heterospory, but we review the shortcomings of this argument as an explanation of the selective advantage of heterospory. Few alternative arguments concerning the selective forces favouring heterospory have been proposed, a paucity of attention that is surprising given the importance of this innovation in land plant evolution. In this review we highlight two ideas that may lead us to a better understanding of why heterospory evolved. First, models of optimal resource allocation – an approach that has been used for decades in evolutionary ecology to help understand parental investment and other life‐history patterns – suggest that an evolutionary increase in spore size could reach a threshold at which small spores yielding small, sperm‐producing gametophytes would return greater fitness per unit of resource investment than would large spores and bisexual gametophytes. With the advent of such microspores, megaspores would evolve under frequency‐dependent selection. This argument can account for the appearance of heterospory in the Devonian, when increasingly tall and complex vegetative communities presented competitive conditions that made large spore size advantageous. Second, heterospory is analogous in many ways to anisogamy. Indeed, heterospory is a kind of re‐invention of anisogamy within the context of a sporophyte‐dominant land plant life cycle. The evolution of anisogamy has been the subject of important theoretical and empirical investigation. Recent work in this area suggests that mate‐encounter dynamics set up selective forces that can drive the evolution of anisogamy. We suggest that similar dispersal and mating dynamics could have underlain spore size differentiation. The two approaches offer predictions that are consistent with currently available data but could be tested far more thoroughly. We hope to re‐establish attention on this neglected aspect of plant evolutionary biology and suggest some paths for empirical investigation. 相似文献
4.
A testis‐specific gene within a widely expressed gene: Contrasting evolutionary patterns of two differentially expressed mammalian proteins encoded by a single gene,CAMK4 下载免费PDF全文
Understanding the patterns of genetic variations within fertility‐related genes and the evolutionary forces that shape such variations is crucial in predicting the fitness landscapes of subsequent generations. This study reports distinct evolutionary features of two differentially expressed mammalian proteins [CaMKIV (Ca2+/calmodulin‐dependent protein kinase IV) and CaS (calspermin)] that are encoded by a single gene, CAMK4. The multifunctional CaMKIV, which is expressed in multiple tissues including testis and ovary, is evolving at a relatively low rate (0.46–0.64 × 10?9 nucleotide substitutions/site/year), whereas the testis‐specific CaS gene, which is predominantly expressed in post‐meiotic cells, evolves at least three to four times faster (1.48–1.98 × 10?9 substitutions/site/year). Concomitantly, maximum‐likelihood‐based selection analyses revealed that the ubiquitously expressed CaMKIV is constrained by intense purifying selection and, therefore, remained functionally highly conserved throughout the mammalian evolution, whereas the testis‐specific CaS gene is under strong positive selection. The substitution rates of different mammalian lineages within both genes are positively correlated with GC content, indicating the possible influence of GC‐biased gene conversion on the estimated substitution rates. The observation of such unusually high GC content of the CaS gene (≈74%), particularly in the lineage that comprises the bovine species, suggests the possible role of GC‐biased gene conversion in the evolution of CaS that mimics positive selection. 相似文献
5.
6.
The probable misfit between feet, particularly toes II–V, of 3.0-million-year-oldAustralopithecus afarensis from Hadar, Ethiopia, and the 3.5-million-year-old hominid footprints at Site G, Laetoli, Tanzania, casts doubt thatA. Afarensis made the Laetoli trails. We suggest that another species ofAustralopithecus or an anonymous genus of the Hominidae, with remarkably humanoid feet, walked at Laetoli. It would be imprudent to declare
thatHomo was present at Laetoli 3.5 million years ago (my) because there is no evidence of brain expansion, advanced tool manufacture, or other non-locomotor hallmarks of the human
condition at Site G. 相似文献
7.
Robert L. Post Jr. 《Journal of molecular evolution》1990,31(4):257-264
Summary An equation is developed that describes the condition of homeostasis in a general molecular system containing catalysts. In a prebiotic environment, this condition first results from a critical level of catalytic feedback in feedback loops containing differing organic molecular species. This critical level results in temporary exponential growth in concentrations of those catalyst species participating in the feedback loops, leading to homeostasis as the steady-state endpoint. None of the molecules in any feedback loop need be self-replicating for this autocatalysis to occur. Homeostasis is regarded as a definition of life at the lowest possible hierarchical level. A general mathematical boundary condition is derived for the critical level of catalytic feedback mentioned above-in effect, an origin of life condition. The paper argues that any natural prebiotic system of organic molecules in an H2O medium will automatically form many catalytic feedback loops, even if of very low catalytic efficiency. The analysis in this paper indicates that high temperatures strongly increase the efficiency of such catalytic feedback. If the temperature and total concentration of carbon in the system (e.g., in CO2, CH4, etc.) are sufficiently high, the critical condition for initial exponential growth will be attained. High initial temperatures for the earth are predicted by the planetesimal accretion model. 相似文献
8.
9.
Tetrahydroindolocarbazoles (THICZs) with versatile substituents, have been designed, synthesized, structure characterized, then investigated for their in-vitro anticancer screening, urokinase inhibition (uPA) evaluated, DNA-damage determination was further explored. Compounds 5, 8, 10 and 17 displayed the most promising antitumor activities against the breast cancer cell line as compared to the standard drug, doxorubicin with IC50 = 5.24 ± 0.37, 4.00 ± 0.52, 7.20 ± 0.90 and 9.60 ± 1.10 µg/ml (versus 3.30 ± 0.48 µg/ml for doxorubicin). Compounds 5, 8, 10 and 17 represents the most significant uPA inhibitors of our study with IC50 of 3.80, 2.70. 4.75, 10.80 (ng/ml) respectively. The expression levels of CDKN2A gene were decreased in 8, 10 and 17 cell lines as compared to those in positive control samples. Cell lines treated with 5, 8, 10 and 17 clearly observed a high score of damaged DNA cells. A deeper examination revealed that our hetroaromatics showed an extensive hydrogen bonding interactions that is required in the S pocket which is important for activity Arg 217, Gly 219, Gly 216, Lys 143 and Ser 190. So we present THICZs as promising uPA inhibitors expected as significant promise for further development as anti-invasiveness drugs. 相似文献
10.