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991.
In order to maintain a stable genome, cells need to detect and repair DNA damage before they complete the division cycle. To this end, cell cycle checkpoints prevent entry into the next cell cycle phase until the damage is fully repaired. Proper reentry into the cell cycle, known as checkpoint recovery, requires that a cell retains its original cell cycle state during the arrest. Here, we have identified Tousled‐like kinase 2 (Tlk2) as an important regulator of recovery after DNA damage in G2. We show that Tlk2 regulates the Asf1A histone chaperone in response to DNA damage and that depletion of Asf1A also produces a recovery defect. Both Tlk2 and Asf1A are required to restore histone H3 incorporation into damaged chromatin. Failure to do so affects expression of pro‐mitotic genes and compromises the cellular competence to recover from damage‐induced cell cycle arrests. Our results demonstrate that Tlk2 promotes Asf1A function during the DNA damage response in G2 to allow for proper restoration of chromatin structure at the break site and subsequent recovery from the arrest. 相似文献
992.
Johanna Szabó Ildikó Bacsa János Wölfling Gyula Schneider István Zupkó Mónika Varga 《Journal of enzyme inhibition and medicinal chemistry》2016,31(4):574-579
An efficient synthesis of several N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]carboxamides in the 13β- and 13α-d-secoestrone series is reported. Novel triazoles were synthesized via the Cu(I)-catalyzed azide–alkyne cycloaddition of steroidal alkynyl carboxamides and p-substituted benzyl azides. Each of the products was evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431 and A2780). Some of them exhibited activities similar to those of the reference agent cisplatin. On change of the substitution pattern of the benzyl group of the azide, great differences in the cell growth-inhibitory properties were observed. The p-alkylbenzyl-substituted triazoles selectively exerted high cytostatic action against A2780 cells, with IC50 values of 1?µM. We investigated the potential inhibitory action exerted on the human 17β-HSD1 activity of the new secosteroids. Three triazoles effectively suppressed the estrone to 17β-estradiol conversion with IC50 values in low micromolar range. 相似文献
993.
目的:探讨乌司他丁对慢性阻塞性肺疾病(COPD)患者血清环氧合酶-2(COX-2)、磷脂酶A2(PLA-2)及肺功能的影响。方法:选取2015年1月至2016年1月我院收治的82例COPD患者,随机分为观察组和对照组。对照组患者采取COPD常规处理,观察组在对照组的基础上给予乌司他丁,检测两组患者治疗前后的COX-2、PLA-2以及肺功能指标FEV1、FVC及FEV1/FVC。结果:治疗前,观察组和对照组的COX-2、PLA-2水平均无统计学差异(P0.05);治疗后,观察组和对照组的COX-2、PLA-2均比治疗前显著降低,且观察组低于同期对照组,差异均有统计学意义(P0.05)。治疗前,两组患者各项肺功能指标均无统计学差异(P0.05);治疗后,观察组的FEV1、FVC及FEV1/FVC均优于对照组(P0.05)。结论:乌司他丁能够有效降低COPD患者血清COX-2、PLA-2浓度,改善肺功能。 相似文献
994.
目的:探讨血清妊娠相关血浆蛋白A(PAPP-A)在诊断异常妊娠中的临床意义,分析其与异常妊振的关系。方法:选取299例5~13周的正常早孕妇为正常早孕组,同期选取稽留流产86例,先兆流产54例,异位妊娠76例为异常妊娠组,用酶联免疫吸附试验(ELASA)测定两组受试者的血清PAPP-A水平,分析两组受试者各个孕周内的血清PAPP-A水平的差异。结果:稽留流产孕妇在各个孕周内(9~13周)的血清PAPP-A水平显著低于同孕周内正常早孕孕妇(t值分别为9.500,8.113,3.511,9.538,8.504,P值均0.05);稽留流产孕妇总的平均血清PAPP-A水平亦低于常早孕孕妇(t=3.651,P值均0.05);异位妊娠孕妇在各个孕周内(9~13周)的血清PAPP-A水平显著低于同孕周内正常早孕孕妇(t值分别为7.976,9.030,9.941,11.625,14.079,12.569,P值均0.05),异位妊娠孕妇总的平均血清PAPP-A水平亦低于常早孕孕妇(t=28.168,P值均0.05);先兆流产孕妇(除孕8周)与正常早孕妊娠血清PAPP-A水平比较无显著统计学意义。结论:血清PAPP-A水平在异常妊娠如异位妊娠、稽留流产中显著降低,可作为诊断异位妊娠、稽留流产及先兆流产辅助诊断的生物学指标。 相似文献
995.
目的:研究丹参酮ⅡA磺酸钠注射液对原发性高血压患者血脂水平及内皮功能的影响。方法:选择2013年5月-2015年10月在我院首次诊断为原发性高血压的80例患者作为研究对象,根据治疗方法不同将入组患者随机分为实验组和对照组。实验组患者接受丹参酮ⅡA磺酸钠注射液联合口服降压药物治疗,对照组患者仅接受口服降压药物治疗,比较两者患者治疗前后的血压、肝肾功能、血脂水平以及内皮功能指标的变化。结果:治疗后,两组患者的收缩压、舒张压水平均低于治疗前,且实验组患者的收缩压、舒张压水平与对照组比较均无统计学差异。治疗后,两组患者的ALT、AST、Scr水平均与治疗前比较均无显著差异,且实验组患者的ALT、AST、Scr水平与对照组比较无统计学差异。治疗后,实验组患者的TC、TG、LDL水平明显低于治疗前(P0.05),对照组患者的TC、TG、LDL与治疗前比较无统计学差异(P0.05),实验组患者的TC、TG、LDL水平显著低于对照组(P0.05)。结论:丹参酮ⅡA磺酸钠注射液有助于改善原发性高血压患者的血脂代谢以及内皮功能,且对患者的肝肾功能无明显影响。 相似文献
996.
Franziska Foertsch Anna Szambowska Anja Weise Alexandra Zielinski Bernhard Schlott Florian Kraft 《Cell cycle (Georgetown, Tex.)》2016,15(20):2766-2779
The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is an essential process in maintenance of chromosomal stability. A key player of HR is the strand exchange factor RAD51 whose assembly at sites of DNA damage is tightly regulated. We detected an endogenous complex of RAD51 with the calcium-binding protein S100A11, which is localized at sites of DNA repair in HaCaT cells as well as in normal human epidermal keratinocytes (NHEK) synchronized in S phase. In biochemical assays, we revealed that S100A11 enhanced the RAD51 strand exchange activity. When cells expressing a S100A11 mutant lacking the ability to bind Ca2+, a prolonged persistence of RAD51 in repair sites and nuclear γH2AX foci was observed suggesting an incomplete DNA repair. The same phenotype became apparent when S100A11 was depleted by RNA interference. Furthermore, down-regulation of S100A11 resulted in both reduced sister chromatid exchange confirming the restriction of the recombination capacity of the cells, and in an increase of chromosomal aberrations reflecting the functional requirement of S100A11 for the maintenance of genomic stability. Our data indicate that S100A11 is involved in homologous recombination by regulating the appearance of RAD51 in DSB repair sites. This function requires the calcium-binding activity of S100A11. 相似文献
997.
Zhiying You Koji L. Ode Mayumi Shindo Haruhiko Takisawa Hisao Masai 《Cell cycle (Georgetown, Tex.)》2016,15(9):1213-1226
All organisms ensure once and only once replication during S phase through a process called replication licensing. Cdt1 is a key component and crucial loading factor of Mcm complex, which is a central component for the eukaryotic replicative helicase. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent rereplication. Here, we address the mechanism of DNA licensing using purified Cdt1, Mcm and Geminin proteins in combination with replication in Xenopus egg extracts. We mutagenized the 223th arginine of mouse Cdt1 (mCdt1) to cysteine or serine (R-S or R-C, respectively) and 342nd and 346th arginines constituting an arginine finger-like structure to alanine (RR-AA). The RR-AA mutant of Cdt1 could not only rescue the DNA replication activity in Cdt1-depleted extracts but also its specific activity for DNA replication and licensing was significantly increased compared to the wild-type protein. In contrast, the R223 mutants were partially defective in rescue of DNA replication and licensing. Biochemical analyses of these mutant Cdt1 proteins indicated that the RR-AA mutation disabled its functional interaction with Geminin, while R223 mutations resulted in ablation in interaction with the Mcm2~7 complex. Intriguingly, the R223 mutants are more susceptible to the phosphorylation-induced inactivation or chromatin dissociation. Our results show that conserved arginine residues play critical roles in interaction with Geminin and Mcm that are crucial for proper conformation of the complexes and its licensing activity. 相似文献
998.
Hélène Malka-Mahieu Isabelle Girault Margot Rubington Melissa Leriche Caroline Welsch Nyam Kamsu-Kom 《Cell cycle (Georgetown, Tex.)》2016,15(18):2405-2409
Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5′ end of messenger RNAs. Small molecules targeting MEK (MEKi: MEK inhibitors) have demonstrated activity in NRAS-mutant cell lines and tumors, but resistance sets in most cases within months of treatment. Using proximity ligation assays, that allows visualization of the binding of eIF4E to the scaffold protein eIF4G, generating the active eIF4F complex, we have found that resistance to MEKi is associated with the persistent formation of the eIF4F complex in MEKi-treated NRAS-mutant cell lines. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a small molecule of the flavagline/rocaglate family, synergizes with inhibiting MEK to kill NRAS-mutant cancer cell lines. 相似文献
999.
1000.
The influence of AVPR1A genotype on individual differences in behaviors during a mirror self‐recognition task in chimpanzees (Pan troglodytes) 下载免费PDF全文
The mark/rouge test has been used to assess mirror self‐recognition (MSR) in many species. Despite consistent evidence of MSR in great apes, genetic or non‐genetic factors may account for the individual differences in behavioral responses that have been reported. We examined whether vasopressin receptor gene (AVPR1A) polymorphisms are associated with MSR‐related behaviors in chimpanzees since vasopressin has been implicated in the development and evolution of complex social relations and cognition and chimpanzees are polymorphic for the presence of the RS3‐containing DupB region. We compared a sample of DupB+/? and DupB?/? chimpanzees on a mark test to assess its role on social behavior toward a mirror. Chimpanzees were administered two, 10‐min sessions where frequencies of mirror‐guided self‐directed behaviors, contingent actions and other social behaviors were recorded. Approximately one‐third showed evidence of MSR and these individuals exhibited more mirror‐guided self‐exploratory behaviors and mouth contingent actions than chimpanzees not classified as passers. Moreover, DupB+/? males exhibited more scratching and agonistic behaviors than other male and female cohorts. Our findings support previous studies demonstrating individual differences in MSR abilities in chimpanzees and suggest that AVPR1A partly explains individual differences in MSR by influencing the behavioral reactions of chimpanzees in front of a mirror. 相似文献